The kidney stroma in development and disease

Alexandria N Fusco; Leif Oxburgh; Thomas J Carroll

doi:10.1038/s41581-025-00985-8

. Author manuscript; available in PMC: 2026 Jul 28.

Published in final edited form as: Nat Rev Nephrol. 2025 Jul 29;21(11):756–777. doi: 10.1038/s41581-025-00985-8

The kidney stroma in development and disease

Alexandria N Fusco ^1,², Leif Oxburgh ³, Thomas J Carroll ^1,^2,^✉

PMCID: PMC13404121 NIHMSID: NIHMS2190872 PMID: 40730917

Abstract

The kidney is one of the most complex organs in the body. It is made up of thousands of patterned epithelial and endothelial tubules that work together to maintain body chemistry. Precise spatial integration of these different cell types is essential for the organ to function optimally. A complex and heterogeneous network of cells collectively referred to as ‘stroma’ lies between the epithelial and endothelial tubules. A growing body of evidence suggests that the stroma mediates communication between the epithelia and endothelia, and functions to support a variety of processes during kidney development and in the adult kidney, with implications for disease. However, stromal cells remain far less well defined than the epithelia and endothelia, and we understand only a fraction of their functions, leading some to refer to the stroma as the ‘dark matter’ of the kidney. In this Review, we discuss the developmental origins of the stroma and describe current understanding of its roles in the growth and patterning of the renal epithelia and endothelia, and in the maintenance and repair of the adult organ. Finally, we highlight critical questions that remain unanswered and the resources that will be required to answer them so that we can fully understand the function of these enigmatic cells.

Introduction

The human kidney contains a tightly packed array of nephrons that are patterned along a proximal–distal axis into functionally distinct domains that enable the sequential processing of blood filtrate. The distinct segments of the nephron tubule have specialized uptake and secretory functions, which ensure that essential components of the filtrate are reclaimed into the circulation via fenestrated capillaries that surround the nephron, and that waste products are concentrated in the urine for disposal. Nephrons, blood vessels and the collecting ducts are enclosed in a type of extracellular matrix (ECM), which is essential for the structural integrity of these tubes. A distinct type of ECM, referred to as the interstitial matrix, is located in the interstitial space between the epithelial tubules and blood vessels. The interstitial matrix is largely produced by the stroma, and is essential for the higher-order structure of the organ. However, despite intense research into the development, physiology and associated pathologies of the epithelial and endothelial cells that comprise the nephrons, blood vessels and collecting ducts, relatively little attention has been paid to the renal stroma. Stromal cells — which we define here as the non-epithelial and non-endothelial components of the kidney, including fibroblasts, vascular mural cells, smooth muscle cells (SMCs), resident macrophages and cells of the renal capsule — can be found in every zone of the embryonic and adult kidney from the cortex to the inner medulla (Fig. 1). Growing evidence suggests that they have essential roles in the development, maintenance and physiology of the organ.

Fig. 1 | — a, The kidney is encased by the renal capsule which is just exterior to the cortex. The cortex of the adult kidney primarily contains glomeruli, proximal and distal tubules, and some collecting duct structures. The medullary zone contains the loop of Henle and collecting ducts, which empty through the papilla into the connected ureter. b, Within the cortical zone, the cortical stroma consists of erythropoietin (EPO)-producing ‘Norn’ fibroblasts localized around the proximal tubules, non-EPO producing fibroblasts dispersed between the proximal tubules, distal tubules, and collecting ducts and pericytes surrounding the capillaries. c, The glomerulus and juxtaglomerular apparatus (JGA) contain three populations of stromal mural cells: the intraglomerular mesangial cells, the extraglomerular mesangial cells and the renin-producing juxtaglomerular cells. The JGA is important for detecting mechanical and chemical stimuli and regulates glomerular filtration rate and blood pressure via renin secretion. d, The medullary stroma consists of fibroblasts that have been likened to rungs on a ladder that surround the loop of Henle and collecting ducts and connect the epithelia to the adjacent blood vessels. e, The ureteric epithelium is surrounded by a diverse population of stromal cells, including the lamina propria, ureteric smooth muscle and adventitial cells.

Far from simply providing a structural framework to bind the nephrons and vasculature, available evidence suggests that the stroma is a multifunctional and essential component of the organ. It comprises heterogeneous cell types, with functions as diverse as interstitial matrix synthesis, the production of growth factors, small molecules and hormones, and antigen presentation. Loss of specific stromal cell functions, such as hormone production, are commonly seen in patients with chronic kidney disease (CKD)¹. Tubulointerstitial fibrosis, or scarring of the kidney, involves excessive ECM deposition and the dilution and replacement of healthy stromal cell types, such as erythropoietin (EPO)-producing interstitial cells, with contractile and highly secretory fibroblasts². A number of human genetic diseases, collectively referred to as tubulointerstitial diseases, show defects in epithelia–stromal crosstalk³ and given the extensive crosstalk that has been documented between epithelia and stroma in both the embryonic and the adult kidney, it seems likely that at least in some cases, defects in stromal cells may have a causal role in human pathologies with secondary effects on the epithelium and vasculature. As our appreciation of stromal function grows, it seems likely that primary defects in the renal stroma will be attributable to additional human diseases.

In this Review, we discuss the current understanding of the development of the stroma and its roles in the formation of the renal epithelia and endothelia. We also cover new concepts in kidney stromal heterogeneity and explore how this may influence organ homeostasis and repair.

Stromal cells of the kidney

Stromal cells comprise only a small fraction of the total cells of the healthy adult kidney. Their characterization has historically been hindered by a lack of specific cell markers. However, the advent of single-cell transcriptomics has revealed a previously unappreciated level of cell heterogeneity within the stromal compartment. The term ‘stroma’ is used broadly and with varied definitions. In this Review, and as outlined below, we use it to refer to all non-epithelial and non-endothelial cells in the organ. However, it is important to note that despite advances, stromal cells remain histologically and molecularly far less well defined than the epithelia and endothelia of the kidney, and thus in many cases cell type classifications remain a work in progress.

Fibroblasts

Fibroblasts are mesenchymal cells — generally defined by their flat, spindle-like morphology — that provide the structural framework to support a variety of tissues. In addition to producing structural ECM components that provide mechanical force, they also produce growth factors and cytokines that can act in a paracrine fashion as reviewed elsewhere⁴. Single-cell analyses of mouse fibroblasts have revealed unique fibroblast repertoires within distinct organs, but also fibroblast identities that are present across multiple organ systems, such as the dermatopontin-expressing (DPT⁺) fibroblast subset⁵. Fibroblasts are a key component of the kidney interstitium and together with pericytes they form a continuous network through the interstitial space of the cortex and medulla where they provide structural support for nephrons and blood vessels through the synthesis of ECM components, such as collagens and fibronectin, as well as through direct cell-to-cell interactions^4,6–9 (Fig. 1b,d).

Adult renal fibroblasts have historically been classified into cortical and medullary types. Cortical fibroblasts are widely spaced and relatively rare. A subset closely associated with the proximal tubules at the corticomedullary border express the gene that encodes EPO in a hypoxia-dependent manner (Fig. 1b), which is necessary for red blood cell production in the bone marrow^10–13. The precise identity and physiology of EPO-producing fibroblasts is of particular interest, given that loss of EPO production with resulting anaemia is a common consequence of CKD and given the potential to exploit these cells to boost or maintain endogenous EPO levels in these patients. Although multiple independent experimental approaches, including in situ hybridization and the generation of genetic reporter mice have verified the location of Epo-expressing fibroblasts at the corticomedullary junction, it is unclear whether these represent a population dedicated to producing EPO, or if EPO production may be a property that any cortical fibroblast can acquire in response to hypoxia. In support of the latter proposal, mice that are chronically anaemic from 2 weeks of age due to an incapacity to produce EPO in the kidney develop strong expression of Epo in fibroblasts throughout the cortex and medulla, rather than in the restricted corticomedullary region that has been described in studies of transient hypoxia. Genetic lineage tracing has revealed that only a fraction of cells with historical evidence of Epo expression actively express the gene, indicating that a broad population of fibroblasts has the capacity for punctuated Epo expression¹⁴. By contrast, support for the presence of a dedicated Epo-expressing interstitial cell is derived from genetic lineage tracing studies in adult mice using tamoxifen-inducible Cre expressed from the Epo locus following transient anaemia, which indicated that a large proportion of Epo-expressing fibroblasts located at the corticomedullary boundary retain their capacity for Epo expression up to 16 weeks following a hypoxic event¹⁵. Further genetic labelling studies to determine whether a discrete sublineage of kidney fibroblasts is dedicated to the production of EPO may be facilitated by the 2023 description of a molecular signature of Epo-expressing cells in the mouse kidney. Single-cell RNA sequencing (scRNA-seq) together with fluorescence in situ hybridization has revealed that these cells, named ‘Norn’ cells, can be distinguished from other fibroblasts by the transcriptional profile Cxcl14⁺;Col1a1⁺;Dcn⁺;Lpar1⁺ (ref. 16).

Fibroblasts in the inner medulla form structures that have been likened to rungs on a ladder, and seem to physically link groups of adjacent epithelial tubules with blood vessels⁹ (Fig. 1d). The function of these cells is unknown, although they may act as mechanosensors or potentially contribute to compartmentalization of the interstitial space to facilitate fluid transport between nephron tubules and vessels. Single-cell transcriptomic analyses of adult human and mouse kidneys suggests that further fibroblast heterogeneity exists beyond the presence of Epo-expressing (Norn) cells, non-Epo-expressing fibroblasts of the cortex and outer medulla, and the ladder rung-like inner medullary fibroblasts^17–20. However, these analyses were based on relatively small numbers of sequenced cells and little validation has been performed. More comprehensive analyses are therefore essential.

In addition to their hormone-producing and structural roles, fibroblasts can be activated by inflammatory cytokines and other stimuli in response to kidney injury, resulting in their transdifferentiation into myofibroblasts that have the contractile properties of smooth muscle as well as the ability to produce ECM. The origins of myofibroblasts have been explored using single-cell transcriptome analyses²¹, resulting in the identification of MEG3⁺;PDGFRA⁺ and COLEC11⁺;CXCL12⁺ cells as myofibroblast progenitor cells.

Vascular mural cells

The term ‘mural cell’ collectively refers to non-endothelial cells associated with blood vessels. Based on traditional anatomical definitions, mural cells that line the renal arteries and arterioles are referred to as vascular SMCs (VSMCs) and those associated with capillaries are referred to as pericytes. VSMCs form concentric rings around larger blood vessels and regulate blood flow and vascular tone by dynamically adjusting the diameter of blood vessels in response to physiological stimuli such as angiotensin II (ANGII) and nitric oxide, and therefore have a key role in regulating blood pressure. Pericytes are highly branched interstitial cells embedded in the microvascular basement membrane in close contact with the capillary endothelial cells (Fig. 1b), and contribute to the maintenance of microvascular stability and function. Fibroblasts and pericytes share expression of many molecular markers, and distinguishing them can be difficult. However, they can be identified based on ultrastructural characteristics. By definition, the pericyte is embedded within the basement membrane of the vascular endothelium²², whereas the perivascular fibroblast is not.

Mesangial cells are specialized pericytes found within the glomerulus where they produce a glomerular matrix composed of type IV collagen, fibronectin, laminins, proteoglycans and other ECM components to support the glomerular capillaries. Mesangial cells are essential for glomerular function. Dysregulation of mesangial cell interactions with glomerular podocytes contributes to glomerulosclerosis, a common feature of CKD characterized by the excessive deposition of ECM²³. In contrast to glomerular mesangial cells, extraglomerular mesangial cells are a type of VSMC within the juxtaglomerular apparatus (Fig. 1c) — a region that contains the macula densa (tubular component), the afferent and efferent arterioles (vascular component), the renin-producing juxtaglomerular cells (JG cells), and the extraglomerular mesangium. This complex is essential for regulating blood pressure and fluid volume through the actions of JG cells, which synthesize and release renin in response to mechanical and biochemical signals from adjacent cells. Once released into the circulation, renin triggers an enzymatic cascade to produce ANGII^24,25, which acts as a vasoconstrictor to increase blood pressure and induces aldosterone release from the adrenal gland to promote sodium chloride reabsorption by the renal tubules. ANGII also inhibits renin synthesis via a negative feedback loop once blood pressure and extracellular fluid homeostasis is restored.

Smooth muscle

In addition to the VSMCs of the renal stroma, a second, distinct population of SMCs exists surrounding the ureter and pelvis (Fig. 1e). The ureteric SMCs exist as two distinct layers of stromal cells: an outer adventitial layer and an inner smooth muscle layer. It has been proposed that a pacemaker cell — which controls the timing and duration of ureteric SMC contractions that regulate the rhythmic peristaltic movements observed in the ureter, and promote the passage of urine into the bladder without apparent neural input²⁶ — exists within the ureteric stroma, although its precise cellular identity remains unclear²⁷.

Tissue-resident macrophages

Infiltrating immune cells that originate from the adult immune system can be found patrolling the healthy kidney (reviewed elsewhere^28,29). Tissue-resident macrophages are intrinsic to the kidney and have the capacity to proliferate within the organ. Although all macrophages found in the kidney express the markers CD74 and CD81 (refs. 30,31), resident macrophages exclusively express CX₃CR1 (refs. 32,33). The roles of tissue-resident macrophages under homeostatic conditions are not well understood, but studies of experimental kidney injury suggest both a regenerative role through the promotion of angiogenesis following kidney ischaemia³⁴, and a degenerative role through the promotion of cystogenesis in models of polycystic kidney disease³⁵. The mechanistic bases for these seemingly contradictory functions remain poorly understood, but regenerative and degenerative effects may be context-dependent outcomes resulting from the production of proliferative factors such as IL-6 and WNTs by tissue-resident macrophages³⁶.

Cells of the renal capsule

The adult kidney capsule is composed of multiple cell types, including fibroblasts, mesothelial cells, endothelial cells, macrophages and lymphocytes that are important for preserving renal interstitial hydrostatic pressure, and may have a protective role in kidney injury^37,38. The outer layer of the capsule faces the peritoneal cavity and consists of a single continuous layer of mesothelial cells, but single-cell transcriptome analyses of adult mouse kidney suggest that the majority of capsule cells that lie between this mesothelial layer and the kidney cortex are fibroblasts and macrophages³⁹. Mesothelial cells are epithelial-like cells that surround various organs and line the different body cavities. Although the mesothelium of the capsule is epithelial, it is not part of the nephron and it is derived from the same cells that give rise to the remainder of the stroma. Thus, for the purpose of this Review, we consider it to be stromal. Properties of mesothelial cells vary between abdominal organs⁴⁰, and investigations of kidney-specific mesothelial features have not been reported. Macrophages of the capsule express the TIMD4⁺;LYVE1⁺;FOLR2⁺ (TLF⁺) marker profile that distinguishes them as tissue-resident rather than monocyte-derived⁴¹. No specific function has been ascribed to this macrophage population but interestingly, they are distinct from macrophages found in other kidney compartments, and they may therefore represent a unique subset of tissue-resident macrophages in the organ. An intriguing characteristic of TLF⁺ macrophage populations isolated across organ systems is that they display transcriptional profiles suggestive of endocytic and/or phagocytic function⁴¹. Why a population of presumptive phagocytes would be located in the capsule is not obvious, but one possible explanation is that they are strategically located to scavenge the contents of peritoneal fluid transported across the mesothelium. A subcapsular lymphatic network has been reported in multiple species^42,43, suggesting that together with the mesothelium, subcapsular macrophages and lymphatic vessels may represent a system for sampling foreign antigens from the peritoneal space and relaying them to local lymph nodes for immune surveillance. Capsule fibroblasts characterized by single-cell analysis display some heterogeneity but the vast majority are DPT⁺, which as described above are a universal type of fibroblast found across multiple organ systems, including the heart, lungs and liver⁵, and may differentiate into phenotypes with specialized functions in healthy tissue or to myofibroblasts following injury. In the adult steady state, these fibroblasts probably provide structural support for the capsule, but following injury they may differentiate into cells with immune-regulatory and regenerative properties⁶ or into myofibroblasts with fibrotic properties.

Although a clearly delineated capsule can be identified and characterized in the adult kidney, characterization of the developing capsule is difficult as the temporal and spatial origins of the capsule have not yet been reported. A layer of Foxd1-expressing stromal cells covers the surface of the developing kidney from the onset of permanent kidney development at around embryonic day 11 (E11) in mice, but whether this layer can be considered an early ‘capsule’ is questionable, since these cells disappear shortly after birth. However, it has been reported that the Foxd1-expressing cells give rise to at least a subset of cells in the capsule⁴⁴. These cortical stromal cells provide important signals that prevent premature differentiation of the mesenchyme and orient growth of the ampullae towards the kidney surface^45–47. Additionally, the capsule contributes to proper separation of the kidneys from the dorsal body wall and its ascension from the pelvic region to the lumbar region^46,47. Given the potential importance of the capsule for kidney function and injury response, understanding its developmental origins should be a priority.

Origin of the stroma

The heterogeneity of the stroma might suggest that its developmental origins would be equally complex. However, findings from studies in mice suggest this is not the case. The metanephric kidney is derived from the intermediate mesoderm. The Wolffian ducts (WDs), which form by mesenchymal-to-epithelial transition (MET) of the dorsal part of the anterior intermediate mesoderm at around E8.5 in mice, then extend caudally into a specialized region of the intermediate mesoderm called the metanephric mesenchyme (MM). Inductive signals produced by the MM from around E10.5 cause the WD to evaginate into a single bilateral outgrowth called the ureteric bud (UB). The MM then condenses around the growing UB tip and by E11.5 the UB undergoes the first branching event to generate a T-like structure. Over the next several days, the UB continues to undergo branching morphogenesis within the MM, eventually forming the collecting duct network and ureter. Simultaneously with the UB undergoing branching morphogenesis, a subset of cells within the MM located on the underside of the UB tips undergoes MET to form an epithelial structure known as the renal vesicle. The renal vesicle undergoes extensive morphogenesis to form the nephron epithelia from the podocytes to the connecting segment.

Early histological studies of the developing kidney indicated that the MM consists of two types of cells: condensed mesenchyme and uncondensed mesenchyme. The condensed mesenchyme was sometimes referred to as the ‘induced’ mesenchyme because it was believed, based on its location closest to the UB epithelium and its ‘condensed’ phenotype, that it had received signals from the UB that had initiated the MET process. It was believed that the uncondensed mesenchyme could be induced at a later time point but mesenchyme that did not receive the inductive signal went on to form the stroma. We now know these assumptions are not true. Rather, the condensed and uncondensed mesenchyme are actually different cell populations with unique origins and completely distinct lineages. In mice, the condensed MM expresses a number of genes including the transcription factor Six2, whereas the uncondensed MM has a distinct transcriptome including expression of the transcription factor Foxd1. Lineage tracing experiments have demonstrated that the Six2-expressing cells undergo MET and give rise to the nephron⁴⁸. By contrast, the Foxd1-expressing, uncondensed cells give rise to the majority of the renal stroma (excluding macrophages, trafficking immune cells and the ureteral stroma)⁴⁴ (Fig. 2a,b). The stromal lineage is not capable of undergoing MET.

Fig. 2 | — a, By the first ureteric bud (UB) branching event at embryonic day 11.5 (E11.5) there are two distinct populations of stromal progenitors: the FOXD1⁺ stroma surrounding SIX2⁺ nephron progenitor cells in the cap mesenchyme (CM) and the TBX18⁺ stroma surrounding the Wolffian duct and lower UB. As nephrogenesis progresses, the FOXD1⁺ stroma gives rise to the vast majority of the intrarenal stroma cells, whereas the TBX18⁺ stroma mainly gives rise to the ureteric stroma and a small proportion of the deep medullary stroma within the kidney. b, Lineage tracing of E18.5 embryos shows that almost all of the stroma is labelled in the Foxd1cre;RosaTomato mice. c, By contrast, in Tbx18cre^ERT2; RosaTomato mice, the stroma surrounding the ureteric–kidney junction is clearly labelled whereas the intrarenal stroma has only sparse labelling in the medullary region. Part c image courtesy of O. Cleaver.

The origin of the FOXD1-expressing cells is unclear. One possibility is that they arise from the intermediate mesoderm along with the nephron progenitors and WD or UB progenitors but segregate into their own lineage early in development. In support of this model, fate mapping studies demonstrated that cells that express the transcription factor Osr1, a gene expressed throughout the intermediate mesoderm, give rise to all cell types in the kidney (that is, the UB, ureter, collecting ducts, nephron, stroma, endothelia and smooth muscle) if the labelling is performed prior to E9.5. If labelling is performed between E9.5 and E11, the UB and endothelial cells are no longer labelled, and Osr1-expressing cells become restricted to the MM derivatives (nephrons and stroma). However individual Osr1-expressing cells give rise to either epithelial or stromal progenitors but never both, suggesting that these lineages are distinct⁴⁹. This analysis is complicated by the fact that the Osr1CreERT2 transgene used to perform these experiments is expressed in both Foxd1-expressing and Six2-expressing cells until E11.5. After this time-point, expression is restricted to the Six2-expressing nephron progenitors. Further confounding interpretation of these findings are separate lineage tracing experiments that have shown that Osr1 expression is not confined to the nascent intermediate mesoderm or MM, but is also expressed in the early nascent mesoderm prior to the paraxial and intermediate split, and later on in the lateral plate mesoderm^50,51. Interestingly, Osr1 is required for the formation of SIX2⁺ nephron progenitors, but not for nephric duct formation or specification of FOXD1⁺ stromal progenitors, suggesting that although Osr1 has early broad expression in cells that generate multiple cellular lineages within the kidney, it is not a master regulator of the differentiation of these cell types.

An alternative theory that is supported by studies performed in chick embryos (and that is not ruled out by the above-described Osr1CreERT2 labelling studies) is that the stromal lineage originates from the paraxial mesoderm, which then migrates into the cortical region of the nascent kidney⁵². The use of a virus to transfer lacZ into the intermediate mesoderm of chick embryos enabled β-galactosidase-expressing cells to be traced in multiple epithelial components of the metanephros including the nephron and renal corpuscle, but not the interstitium or mesangial cells. By contrast, transfer of lacZ into the paraxial mesoderm labelled the most of the interstitium, including mesangial and capsule cells⁵². In separate studies, analysis of Foxd1-lacZ reporter mice identified β-galactosidase-labelled cells not only in the metanephric kidney but also in the paraxial mesoderm-derived dorsal body wall with ‘trailing β-galactosidase-positive cells’ appearing to move into the kidney^46,53. These two distinct studies suggest that the paraxial mesoderm may give rise to at least a portion of the stroma. Whatever their origin, by E11.5, Foxd1-expressing cells surround the nascent kidney sitting cortically to the SIX2-expressing nephron progenitors.

Although it is clear that the vast majority of renal stroma cells come from FOXD1⁺ progenitors (Fig. 2a,b), the ureteral stroma and a small subset of the medullary stroma arise from a Tbx18-expressing cell type that is not located within the MM, but instead seems to arise from a population of mesenchyme that surrounds the WD and ureteric stalk⁵⁴ (Fig. 2a,c). Tbx18-expressing cells have been identified as early as E9.5 within the coelomic epithelium and medial mesenchyme adjacent to the WD along with Osr1-expressing and Aldh1a2-expressing cells⁵⁴. At E10.5 when the MM begins to segregate into the nephrogenic mesenchyme and stromal mesenchyme, Tbx18 is expressed in a population of mesenchyme that lies dorsal and medial to the WD but ventral to the MM. Given that some Tbx18-expressing cells are found within the kidney, it is possible that the seemingly contradictory results described above could be explained by Foxd1 derivatives arising from the paraxial mesoderm and Tbx18 derivatives arising from the intermediate mesoderm (or vice versa).

The origins of the vast majority of renal stroma cells can be attributed to the Tbx18-expressing and Foxd1-expressing progenitor cells. However, the kidney macrophages have a distinct origin. Macrophages can be derived either from haematopoietic stem cells or from the yolk sac^55,56. Resident yolk sac-derived macrophages can differentiate to specialized cell types such as microglia in the central nervous system and Kupffer cells in the liver, and these functionally unique populations are maintained through the life of the organism. Yolk sac-derived macrophages constitute approximately 50% of macrophages in the kidney and persist throughout adult life. Specialized functions of yolk sac-derived macrophages have been reported in the kidney, including the scavenging of immune complexes derived from the circulation⁵⁷; interestingly, the proportion of yolk sac-derived macrophages increases with age in the mouse³³.

The roles of the stroma in development

Interactions between the UB and the MM have long been known to be essential for kidney development⁵⁸. However, and as described above, the discovery that the MM consists of two distinct cell types with distinct origins and lineages is relatively recent. As our ability to identify and manipulate the stromal lineage has developed, we have gained a greater appreciation of the roles of the stroma in organ development, as described below (Table 1).

Table 1 |.

Roles of the stroma in kidney development

Developmental process	Key signalling molecules or processes	Refs.
Ureteric bud branching	RET	59–70
	BMP4, SLIT2, ROBO2, GREM1	62,63,79–81
	Renin–angiotensin signalling	71–78
Mesenchyme-to-epithelial transition	FAT4–DCHS1/2	82–85
	YAP, TAZ	84,86,87
	BMP–SMAD	88–90
	ZEB2–SMAD	91,92
	HGF	93,94
NPC renewal–differentiation balance	FOXD1	46,70,82
NPC renewal–differentiation balance	BMP	46,82
Corticomedullary patterning	WNTs	90–98
	ZEB2, TGFB1, SMAD3	88–92
	HGF	93,94
Vascular patterning	NTN1	106–109
	PBX1	105,110,111
	PDGFRB	112–124
	YAP, TAZ	86,125–131
	ANGPT1/2, TIE2	132–141
	CXCL12	142–146
	EPHs, EPHRINs, NOTCH	147–153
Nephron growth and morphogenesis	FGFs	158–163
	WNTs	164–166, 168–171
	BMPs	167
	SHH, PTCH1, WNT5a	173–175
Matrix composition and biomechanics	Collagen I, laminin, Rho	166,189–195
Ureter differentiation and growth	Growth (TSHZ3)	182
	Survival (SIX1)	183–185
	Differentiation (TBX18, SOX9)	54,186–188

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ANGPT, angiopoietin; CXCL12, C-X-C motif chemokine 12; HGF, hepatocyte growth factor; NPC, nephron progenitor cell.

Ureteric bud branching

One of the first identified roles for the renal stroma in kidney development was in the regulation of UB branching (Fig. 3). Normal UB out-growth and branching is regulated in part by the GDNF–RET signalling pathway, where the MM secretes GDNF, which binds to and activates the receptor tyrosine kinase RET and its co-receptor GFRα1 complex in the UB, and triggers outgrowth of the UB towards the GDNF signal^59–61. UB outgrowth is restricted to a single induction site by inhibition of RET signalling by Sprouty1 (Spry1) in the WD or by inhibition of GDNF by BMP4 or Slit2–Robo2 (refs. 62,63) (Fig. 3a). Expression of Ret mRNA in the UB is mediated by retinoic acid signalling from the cortical stroma (Fig. 3b,c). Retinoic acid, the biologically active form of vitamin A, is synthesized from retinol through the conversion of retinol to retinaldehyde by retinol dehydrogenase, and from retinaldehyde to retinoic acid by retinaldehyde dehydrogenase. Gene targeting studies have shown that the retinaldehyde dehydrogenase encoded by Aldh1a2 (RALDH2) accounts for most of the retinoic acid synthesis in the mouse embryo. In the developing kidney, Aldh1a2 mRNA is expressed primarily in the cortical stroma^64–68. Available retinoic acid binds and activates retinoic acid receptors (RARs) that in turn control gene expression via retinoid response elements in regulatory sequences of target genes. In the kidney, the genes that encode the RAR subtypes RARα and RARβ (Rara and Rarb2, respectively) are expressed in the stroma and are crucial for regulating the expression of Ret, UB branching and stromal patterning^65,66,69. Mice that lack Aldh1a2 or both Rara and Rarb2 have impaired UB growth and downregulation of Ret. These phenotypes can be rescued by forced expression of Ret^64–66. The requirement for retinoic acid from the stroma may explain the observation that Ret mRNA is mis-expressed in Foxd1-null kidneys. In fact, one of the primary defects observed in Foxd1-null embryos is impaired UB branching, further supporting a role for the cortical stroma in UB branching⁷⁰. Vitamin A deficiency during embryogenesis is associated with UB developmental defects, demonstrating the importance of this pathway in human kidney health.

Insights into additional roles for the stroma in UB branching morphogenesis come from studies of the renin–angiotensin system. Angiotensinogen (AGT) is a precursor peptide produced by the liver. It is cleaved by the enzyme renin to create angiotensin I. Angiotensin I is further processed by the enzyme angiotensin-converting enzyme (ACE) to generate ANGII. ANGII can bind to either of two G protein coupled receptors (ANGII receptor type 1 (AT1R) and ANGII receptor type 2 (AT2R)), to activate a signal transduction cascade. Genetic or pharmacological perturbation of AGT, AT2R, AT1R or ACE in mice and humans causes UB branching defects, medullary hypoplasia and renal tubular dysgenesis^71–73. Activation of AT2R has been reported to enhance UB branching by downregulating BMP4. AT1R signalling has been reported to inhibit Spry1, which again would be predicted to enhance branching (Fig. 3c). Further, infants born to mothers who have been treated with ACE inhibitors during the second and third trimester frequently have birth defects including neonatal kidney failure and oligohydramnios, which may be caused by renal defects⁷⁴. Renin is produced by the renal stroma and, ablation of Ren1 using a Foxd1Cre driver results in early neonatal lethality. However, mutant pups can be kept alive by intraperitoneal injection of saline to maintain fluid volume, and although these animals develop hydronephrosis and fibrosis, there are no signs of UB branching defects^75,76.

The prorenin receptor (PRR) is a receptor for renin and prorenin and is a subunit of the vacuolar proton pump V-ATPase, which has an important role in protein trafficking and degradation via the acidification of intracellular organelles⁷⁷. Conditional deletion of Atp6ap2 (the gene that encodes PRR in mice) in Foxd1⁺ stromal progenitors results in neonatal lethality in the majority of pups; the kidneys of surviving mice have reduced expression of Foxd1 and Meis1 as well as impaired arterial and arteriolar development. This study also demonstrated a decrease in the number of glomeruli as well as expansion of Six2⁺ nephron progenitor cells (NPCs) and delayed nephron differentiation⁷⁷. Deletion of Atp6ap2 from the UB results in defects in UB branching and differentiation⁷⁸. As mentioned above, no UB branching or nephron induction defects have been described for mice in which renin has been deleted^75,76, suggesting that the roles for PRR and the angiotensin receptors may be renin-independent (see below).

In addition to promoting UB branching, the stroma may also repress branching of the medullary collecting ducts. BMP4 is expressed in the stroma adjacent to the WD and in the medullary stroma of the developing kidney and has been shown to prevent UB budding. GREM1, a secreted BMP4 antagonist, is produced by the MM, where it binds to and inhibits BMP4, thus permitting budding of the UB^79,80 (Fig. 3a,c). BMP4 is necessary and sufficient for SMC formation (see below). Whether BMP signalling blocks branching directly or whether SMCs indirectly repress branching is unclear⁸¹.

Mesenchymal-to-epithelial transition

In the earliest stages of nephron formation, a subset of NPCs form a tight cluster beneath each UB branch tip. This structure, referred to as a pretubular aggregate, undergoes MET to form the renal vesicle, which itself undergoes extensive morphogenesis to give rise to the nephron. The nephron is patterned along a proximal to distal axis, with Bowman’s capsule being the most proximal segment and the connecting segment the most distal.

Molecular crosstalk between the MM and UB is necessary to maintain the balance between renewing and differentiating NPCs (Fig. 4); multiple lines of evidence suggest that the stromal population within the MM affects this balance. Foxd1-null embryos show an expansion of NPCs and a deficit in nephron formation⁷⁰. Initially, it was believed that this defect was caused by a change in the molecular phenotype of the cortical-most stroma so that it ectopically produced BMP4 (refs. 46,70); in other words, that this was a gain-of-function phenotype, and that the stroma might not normally determine NPC fate. However, ‘stromaless’ kidneys induced by genetic ablation of stromal progenitors resemble Foxd1-mutant kidneys, with reduced nephron formation and an expansion of NPCs⁸², suggesting that the stroma has an active role in promoting NPC differentiation.

The mechanism by which the stroma promotes NPC differentiation is complex. UB-derived WNT9b signalling has an active role in both renewing and differentiating progenitors. In the absence of WNT9b, NPC populations form but do not expand and no renal vesicles or nephrons form⁸³. In stromaless mutants, the WNT9b progenitor renewal pathway is maintained whereas the differentiation pathway is lost⁸². Interestingly, the expression of WNT9b target genes in stromaless mutants requires β-catenin but no longer requires WNT9b, suggesting that ablation of stroma promotes β-catenin stability in a WNT-independent manner. Interestingly, ablation of the atypical cadherin Fat4 from the stroma partially phenocopies Foxd1-mutant and stromaless mutant phenotypes⁸². Similar to the stromaless mutants, the expression of WNT9b target genes in Fat4 mutants is β-catenin-dependent but WNT9b-independent⁸². FAT4 signals to NPCs at least in part through interactions with other atypical cadherins, namely DCHS1 and DCHS2 (also known as protocadherin 16 and protocadherin 23, and encoded by Dchs1 and Dchs2, respectively), which are expressed in NPCs^84,85. FAT-like and DCHS-like cadherins regulate the activity of the Hippo–Warts kinase cascade and the activity of the transcription factors YAP and TAZ, which themselves regulate β-catenin (Fig. 4a). One suggestion is that the extracellular domains of stroma-produced FAT4 and NPC-produced DCHS interact to regulate β-catenin activity in NPCs, potentially through regulation of YAP–TAZ activity; however, a caveat to this hypothesis is that manipulation of YAP–TAZ activity in NPCs does not seem to affect MET, whereas their manipulation in the stroma does^84,86,87.

NPC renewal and differentiation is also regulated by BMP signalling. BMP7 activates MAP kinase signalling to promote NPC renewal. To differentiate, NPCs must transition from a Cited1⁺Six2⁺ state to a Cited1⁻Six2⁺ primed state — a process that is promoted by BMP7–SMAD signalling. Transcriptome analysis of factors secreted from E14.5 Foxd1-null and wild-type kidneys demonstrated ectopic expression of the proteoglycan decorin, an inhibitor of BMP-SMAD activity, in the cortical-most stroma of Foxd1-null mutants^88,89. Inactivation of Dcn partially rescued the failed NPC differentiation phenotype observed in Foxd1-null mice⁹⁰, supporting a role for the stroma in regulating BMP pathway activation (Fig. 4b).

The SMAD-interacting transcription factor ZEB2 also represses TGFβ–BMP signalling, and has a critical role in kidney fibrosis^91,92. ZEB2 co-localizes with FOXD1 in stromal progenitors as early as E13.5 and in the FOXD1-derived medullary stroma at birth. Mice with stromal ablation of Zeb2 (Zeb2cKO) are viable at birth, but die prematurely around 4–5 weeks of age. Characterization of 3-week-old mutant kidneys revealed an increase in the expression of fibrosis-associated markers including αSMA, COL1a1 and vimentin. Examination of mutant embryonic kidneys suggested that FOXD1⁺ stromal progenitors directly differentiate into a myofibroblast-like cell, suggesting a role for ZEB2 in the normal differentiation of the stroma. Loss of Zeb2 in stromal progenitors also affected nephron differentiation, as demonstrated by a reduced number of SIX2⁺ NPCs, and reduced expression of WT1 (a MM and glomerulus marker), JAG1 (a marker of developing proximal tubules) and nephrin (a marker of podocytes) in newborn mice. These defects ultimately resulted in a substantial loss of the tubule markers LTL, megalin (LRP2) and UMOD, and the vascular marker PECAM1, indicative of not only a reduction in total nephron numbers, but also a failure of tubule and vascular maturation⁹¹. If ZEB2 negatively regulates SMAD signalling during development as proposed (Fig. 4b), stromal loss of Zeb2 would be expected to increase the activity of SMAD and WNT signalling pathways, resulting in the misdirected differentiation of stromal progenitors into myofibroblasts and impaired nephron differentiation⁹¹.

The process by which newly differentiated nephrons fuse with the collecting duct epithelium has been described morphologically, and emerging data suggest a role for the cortical stroma in promoting the cellular process that leads to the anastomosis of these two epithelia. Morphological analyses of the developing kidney suggest that loss of epithelial polarity and degradation of the ECM that surrounds both epithelial structures are prerequisites for their fusion⁹³. Hepatocyte growth factor (HGF) has been reported to promote fusion of distinct kidney epithelia in vitro through the concerted activation of MEK signalling and production of the metalloproteinase MMP9. This series of experiments also showed that HGF promotes fusion between established epithelia in developing kidneys cultured under organotypic conditions⁹⁴. The concordance between tissue morphology and cell biology strongly suggests that HGF-activated pathways are responsible for anastomosis between the nascent nephron and the collecting duct. Based on transcriptional analyses, the cortical stroma is predicted to be the main source of HGF in the embryonic kidney, whereas its receptor, MET, is expressed in the collecting duct epithelium. Thus, support exists for a mechanism whereby stromal HGF triggers epithelial-to-mesenchymal transition of the collecting duct, which makes it receptive to invasion by the nascent nephron epithelium. A caveat to this hypothesis is that loss of anastomosis between nascent nephrons and collecting ducts has not been reported in Hgf-null mice, and the working hypothesis that must be tested in future work is that multiple redundant ligands promote activation of epithelial-to-mesenchymal transition pathways in the collecting duct epithelium.

Corticomedullary patterning

Following MET, the lumenized renal vesicle forms a comma-shaped and then an S-shaped body. Although several studies have characterized the proximal–distal patterning of the renal vesicle and S-shaped body^95–98, the mechanisms by which proximal–distal polarity is initially established remains poorly understood. A growing body of evidence, particularly from kidney organoid models, suggests that the stroma has a crucial role in orchestrating higher order patterning^99–103. In particular, a 2022 study demonstrated that co-culturing of induced pluripotent stem cell (iPSC)-derived nephron epithelia and UB lineages achieved NPC and UB crosstalk and enhanced the quality of resulting assembloids¹⁰³. However, the resulting structures remained highly disorganized. Only when the researchers included primary stromal progenitor cells with these assembloids were they able to reproduce a complex kidney structure with a peripheral progenitor niche surrounding internally differentiated nephrons and a clear cortical–medullary axis¹⁰³.

Vascular patterning

In addition to the epithelia, the kidney possesses a highly complex vascular network that is integrated with the epithelium throughout the organ. Abundant evidence from other model systems supports a role for mural cells in the regulation of endothelial differentiation and patterning. Growing evidence supports a similar role in the developing kidney^104–106. The embryonic vasculature in kidneys where all stroma has been ablated is thicker than that of wild-type kidneys and ectopically present in the most outer regions of the cortex, cortical to the NPCs, indicative of unrestricted and unstructured endothelial growth¹⁰⁴. As described below, targeted genetic studies are beginning to reveal more nuanced roles.

Netrin 1 (NTN1) is a member of a family of secreted proteins with similarity to laminin. Netrins have primarily been described as having roles in neuronal pathfinding. Stromal ablation of Ntn1 using a Foxd1cre driver resulted in smaller kidneys with defects in arterial patterning and branching, reduced VSMC coverage, and ectopic expression of smooth muscle-related genes such as Acta2 and Cnn1 around the cortex. Ntn1 mutants also demonstrated downregulation of Klf4, which is required for maintaining VSMCs in a mesenchymal state by preventing the SMC transcription factors myocardin (MYOCD) and serum response factor (SRF) from binding to CArG boxes and activating SMC gene expression^106–109. Ablation of Klf4 from stromal progenitors led to decreased arterial branching and ectopic expression of SMC genes at the kidney periphery; however, the defects in renal artery patterning were not as pronounced as in the Ntn1 mutants, suggesting that stromal Ntn1 is necessary for the proper development and patterning of blood vessels and the migration, function and survival of endothelial cells, in part via regulation of stromal Klf4 (Fig. 5a).

Fig. 5 | — a, PBX1 inhibits PDGFRβ expression within stromal progenitors to prevent the premature differentiation of smooth muscle cells (SMCs) and vascular smooth muscle cells (VSMCs) during nephrogenesis. Within the FOXD1⁺ stromal progenitors, NTN1 and KLF4 maintain SMC progenitors by inhibiting SRF and MYOCD to prevent ectopic SMC differentiation. Under normal conditions, once FOXD1⁺ progenitors undergo differentiation and the expression of FOXD1, PBX1 and NTN1 disappears (FOXD1⁻, PBX1⁻, NTN1⁻, as shown in the lower panel), SRF and MYOCD activate the transcription of SMC genes, which then respond to PDGFRβ or other growth factors to ensure proper patterning and differentiation of SMC and VSMCs during angiogenesis. However, genetic deletion of netrin or PBX1 from FOXD1⁺ stromal progenitors (right-hand side) results in the premature differentiation of SMCs and VSMCs, which are inappropriately localized to the cortex rather than distributed throughout the tissue. This premature and ectopic differentiation of SMCs and VSMCs impairs the proper development and patterning of the vasculature. b, Angiogenesis is regulated by stromal–endothelial signalling crosstalk. PDGF–PDGFRβ signalling during pericyte recruitment ensures proper pericyte coverage of the vasculature. c, YAP–TAZ and TIE2–angiopoietin 2 (ANGPT2) signalling during sprouting angiogenesis promotes proliferation at the sprouting front and junction stabilization through cytoskeletal rearrangement via ANGPT2 –TIE2, VE-cadherin, and VEGF–VEGFR signalling. d, Stromal cell-derived factor 1 CXCL12 (also known as SDF1) signalling via CXCR4 or CXCR7 during pericyte detachment and rearrangement facilitates vasculature stabilization during vascular remodelling. e, NOTCH3 signalling promotes proper VSMC differentiation and recruitment to the vasculature. f, Pericytes can also modulate vascular tone to regulate renal blood flow by responding to agents such as angiotensin II, endothelin 1, Rho kinase activity and nitric oxide (NO) resulting in pericyte contraction or dilation which adjusts blood vessel diameter. NPCs, nephron progenitor cells; UB, ureteric bud. Created in BioRender. A. Fusco (2025).

The TALE transcription factor PBX1 is expressed in both the NPCs and broadly throughout the renal stroma in the developing kidney. Conditional ablation of Pbx1 from the stroma using the Foxd1cre driver resulted in premature differentiation of the stroma into PDGFRβ⁺ mural cells¹⁰⁵, resulting in the premature depletion of Foxd1⁺ stromal progenitor cells. PBX1 promotes the self-renewal and maintenance of skeletal and haematopoietic stem cells over their differentiation^105,110,111, suggesting that it may have a similar role in the kidney stromal progenitors. The ectopic and premature expression of PDGFRβ permitted premature association of mural-like cells with the developing vascular bed, resulting in a threefold increase in arterial branching. Mutant mice exhibited increased ratios of blood urea nitrogen to creatinine, suggesting that the increased arterial branching caused a drop in blood flow rate and decreased glomerular filtration pressure¹⁰⁵. Deletion of one Pdgfrb allele was sufficient to rescue the phenotype of Pbx1 mutants, suggesting that PBX1 repression of PDGFRβ spatially and temporally restricts VSMC differentiation and arterial patterning to prevent non-productive angiogenesis leading to improper blood flow and kidney dysfunction (Fig. 5a). Somewhat surprisingly, although the Foxd1-expressing progenitor population was prematurely lost in Pbx1 mutants, UB branching morphogenesis and nephrogenesis were not affected.

The role of PDGFB–PDGFRβ ligand–receptor pairing in endothelial–mesenchymal crosstalk has been relatively well defined and reviewed elsewhere^112–118. During vascular development, secretion of PDGFB by endothelial cells at angiogenic sprouts recruits pericytes that express PDGFRβ (Fig. 5b). Once recruited, secretion of PDGFB also stimulates the proliferation, maturation and co-migration of associated pericytes and VSMCs with the endothelium. Additionally, PDGFB secreted by the glomerular endothelium acts on mesangial precursors to stimulate the differentiation of mesangial cells and formation of the glomerular tufts. Ablation of PDGFB or PDGFRβ leads to neonatal lethality as a consequence of severe vascular malformations, including decreased pericyte recruitment and VSMC differentiation, leading to vessel dilation and leakage as well as an absence of mesangial cells and resulting in defects in glomerular tuft formation and aneurysmatic glomeruli^{115,119–124}.

The above-described vascular patterning defects highlight the importance of endothelial cell proliferation, migration and interaction with their surrounding environments through the integration of key signalling pathways. VEGF signalling can promote the activity of YAP–TAZ signalling, which induces a transcriptional programme to drive the expression of genes involved in cytoskeletal organization and migration that is required for angiogenesis^125–127. YAP–TAZ activity also regulates sprouting angiogenesis by promoting stretch-induced proliferation and rearrangements of endothelial cells (Fig. 5c). During sprouting angiogenesis, YAP and TAZ are sequestered away from the nucleus at stable junctions that require less junctional turnover, but at the sprouting front, YAP and TAZ relocate to the nucleus where they increase VE-cadherin turnover to maintain junctional integrity and prevent haemorrhages^127–130. YAP and TAZ can regulate the expression of angiopoietin (ANGPT) 2 (Angpt2), which has a role in vessel destabilization and remodelling of the sprouting front¹³¹.

The ANGPT–TIE2 system provides signals from the surrounding pericytes and VSMCs to control vascular remodelling (via Angpt2) and maturation to quiescent endothelia (via Angpt1). TIE-2 is a receptor tyrosine kinase that is expressed by vascular endothelial cells and its ligands, ANGPT1 and ANGPT2, are important for the development of microvessels. Angpt1 is expressed in stromal cells that surround the developing vasculature, including differentiated pericytes, VSMCs, fibroblasts and monocytes where it is has a proposed role in vasculature stabilization through the recruitment of interstitial mural cells that support the newly formed vasculature^132,133 (Fig. 5c). ANGPT2 is thought to act antagonistically to ANGPT1 to facilitate vascular remodelling as angiogenesis progresses. Ablation of Angpt1 or Tie2 weakens the association of endothelial cells with the surrounding mural cells and ECM, and leads to disorganization of large and small vessels, and uneven coverage of VSMCs, supporting a role for ANGPT1 in mural cell recruitment and distribution^{122,134–141}.

Stromal cell-derived factor 1 (SDF1) (also known as C-X-C motif chemokine 12 (CXCL12)) is a chemoattractant cytokine that is expressed in stromal cells, podocytes and blood vessels. SDF1 signalling through its receptor CXCR4 has a critical role in recruiting vascular progenitor cells to facilitate blood vessel formation during angiogenesis and vasculogenesis^142,143 (Fig. 5d). Indeed, SDF1-secreting stromal cells localize around CXCR4⁺ early nephron components and blood vessels in the embryonic kidney and are required for renal vascular development¹⁴². Additionally, a second receptor, CXCR7, fine tunes cell migration and differentiation by scavenging SDF1 to generate local SDF1 gradients and thereby modulate SDF1–CXCR4 signalling^144–146. Deletion of Cxcl12 or Cxcr4 in mice results in defective blood vessel formation, vascular patterning, glomerular capillary development, and a reduction in mesangial cells. SDF1 has also been postulated to have a role in regulating pericyte detachment during vascular remodelling by modifying the pericyte response to PDGFB expression. Although interesting, interpretation of these outcomes is complicated by the broad expression of Cxcl12 across multiple cell types. Indeed, ablation of Cxcl12 from the endothelium partially recapitulates the phenotype observed in Cxcl12-null embryos.

Ephrins and their receptors (Ephs) are membrane-bound proteins that signal through direct cell-to-cell contact to direct proper pericyte and SMC orientation and coverage during vascular development. Several Ephs and ephrins are expressed in multiple cell types in the embryonic mouse kidney. Knockout of Efnb2 (which encodes ephrin B2) specifically in mural cells using a PDGFRβ-Cre driver led to defects in vascular formation in multiple organ systems. Within the kidney, only simplified, immature glomeruli formed^147,148. This result suggests a role for ephrin signalling in glomerular capillary formation, perhaps mediated by mesangial cells.

Notch signalling also has a crucial role in development of renal vasculature by regulating the spatial organization and patterning of blood vessels through crosstalk with other key pathways such as those regulated by VEGF and PDGFRβ (Fig. 5e). NOTCH3 regulates arterial differentiation and the maturation of VSMCs but not endothelial cells, and mutations in Notch3 are associated with CADASIL — a syndrome characterized by stroke and dementia with VSMC dysfunction that sometimes has renal involvement^149–153. At least in the embryonic kidney, Notch3 mRNA seems to be enriched in the stroma (T.J.C., unpublished data), providing further support for a role of stroma in vascular patterning and disease.

In addition to their roles in nephrogenesis, YAP and TAZ also have critical roles in the specification of unique subsets of stromal cells. Although phosphorylated (inactive) YAP is found predominantly in the cytoplasm of cells in the nephrogenic zone, non-phosphorylated (active) YAP is enriched in the nuclei of pericytes in the region of proximal tubules⁸⁶. Stromal specific co-ablation of YAP and TAZ (using Foxd1cre) resulted in death within 48 h of birth. Embryonic kidneys showed signs of interstitial oedema in the cortex beginning around E15.5, coinciding with the onset of renal filtration. Characterization of the vasculature of the mutants showed a failure to form fenestrations within the peritubular capillaries, which presumably led to an accumulation of filtrate in the interstitial spaces and subsequent oedema.

In the adult organ, pericytes modulate vascular tone and permeability in response to factors produced by the endothelium, such as ANGII, endothelin 1 and nitric oxide (Fig. 5f). Such signalling results in contraction or relaxation of pericytes, which induces contraction or dilation of the associated blood vessel. These effects directly affect renal blood flow and have secondary effects on renal filtration^154,155. Pericytes have also been shown to regulate blood flow in the renal medulla where their contractility is dependent on Rho kinase (ROCK) activity. In a model of ischaemia–reperfusion-induced acute kidney injury, treatment with the ROCK inhibitor hydroxyfasudil during reperfusion was able to reduce kidney injury by preventing a decline in medullary perfusion¹⁵⁶. It is interesting to note that many of the factors involved in regulating vascular tone are expressed in the embryonic endothelium and pericytes¹⁵⁷ (T.J.C., unpublished data). However, the role(s) of these factors in kidney endothelial differentiation and patterning are unknown.

Growth and morphogenesis

Although the initial stages of kidney development are directed by branching morphogenesis and MET, the ultimate form of the organ is dependent on the integrated proliferation and morphogenesis of the different cellular lineages. Available evidence suggests that at least some of the growth factors that direct these processes come from the adjacent stroma.

Fibroblast growth factors (FGFs) have diverse roles in cell migration, proliferation, differentiation, metabolism, tissue repair and survival across organs. Along with other growth factors, FGFs direct tissue patterning and morphogenesis by establishing spatially restricted and tissue-specific signalling gradients that regulate various signalling cascades to coordinate cell migration and organization (Fig. 6a). In mice, 18 FGFs signal through FGF receptors. Renal development relies primarily on FGFs 1, 2, 5, 7, 8, 9, 10 and 20 along with receptors FGFR1, FGFR2 and FGFRL1 (reviewed elsewhere¹⁵⁸). Fgf7 is expressed in the renal stroma surrounding the ureter but is not detectable in the kidney itself, at least at the time points that have been examined^159,160. Kidneys of Fgf7-null mice are small, with ~30% fewer nephrons than in wild-type littermates. Adults have been described to have a ‘thin papilla’ with fewer epithelia and cuboidal morphology¹⁶¹. In ex vivo studies, continuous exposure of embryonic kidney cultures to high levels of FGF7 delayed differentiation of UBs into collecting duct epithelia^161,162.

Fig. 6 | — The processes of growth and morphogenesis are regulated by FGF and WNT crosstalk between stroma and epithelia starting around embryonic day 11.5 (E11.5), and continue throughout branching events until nephrogenesis ceases around postnatal day 3 (P3). a, FGF7 and FGF10 are secreted by FOXD1⁺ stromal cells, and bind to their receptor FGFR2 on epithelial cells to promote ureteric bud (UB) branching, epithelial proliferation and survival. These events stimulate SHH expression within the UB and subsequently activate Smoothened (SMO) in stromal cells to induce the production of BMP4 — ultimately creating a feedback loop that modulates FGF and BMP signalling to maintain a balance between proliferation and branching. b, In response to FGF and SHH signalling, WNT4 and WNT9b promote nephron induction, whereas WNT5a and BMP4 suppress ectopic branching to control the number and spatial organization of branch points. WNT7b expression in the UB promotes maturation and elongation of the collecting ducts and also influences stromal proliferation and differentiation through interactions with SHH. NPCs, nephron progenitor cells; RV, renal vesicle; WD, Wolffian duct.

The cells that stroma-derived FGF7 signals to are unknown. FGF7 receptors are expressed in the NPCs and UB tips (FGFR1) and collecting ducts (FGFR2)¹⁶⁰. Global deletion of Fgfr1 results in embryonic lethality prior to onset of kidney development. Deletion of Fgfr1 and Fgfr2 from the WDs using a Hoxb7cre driver led to reduced branching and proliferation of the UB, a phenotype resembling that of Fgf7-null mice. However, deletion of Fgfr1 and Fgfr2 using Pax3cre (which is active in the NPCs and stroma) led to complete loss of the MM and arrested UB growth at E11.5 (ref. 158). Of note, Pax3cre is active in the TBX18⁺ stroma surrounding the WD, as well as FOXD1⁺ stroma¹⁶³. Moreover, ablation of Fgfr2 in renal stroma with a Foxd1cre driver or in NPCs with a Six2Cre driver did not result in kidney defects. By contrast, Tbx18cre-mediated deletion of Fgfr2 resulted in aberrant ureter formation, suggesting that the TBX18⁺ stroma may be a major site of FGF signal transduction. Tbx18Cre-Fgfr2 mutants also had impaired ureteral insertion into the bladder and vesicoureteral reflux¹⁵⁸, suggesting that FGFR2 signalling in the stroma surrounding the WD restricts UB induction, perhaps through induction of Bmp4 expression during early embryonic development (~E10.5).

WNT signalling regulates distinct developmental events within specific subdomains of the developing kidney¹⁶⁴. Wnt7b is expressed within the collecting duct network (except for the UB tips) and is critical for regulating the formation of the renal medulla through canonical signalling between the epithelia and adjacent stroma (Fig. 6b). Ablation of Wnt7b from the collecting ducts using a Hoxb7cre driver resulted in failed formation of the medulla and decreased expression of the canonical WNT pathway components LEF1 and Axin2 in the adjacent interstitium¹⁶⁴. Levels of LEF1 and Axin2 were unaltered in other populations, including the renal vesicles and UB tips. Ablation of the WNT signalling transducer β-catenin from the interstitium using the Foxd1cre driver also led to failed development of the medulla and loss of stromal LEF1 and Axin2 expression¹⁶⁴. These defects were primarily attributed to deficiencies in cell proliferation both within the stroma and the epithelia. How deletion of β-catenin in the stroma non-autonomously led to defects in proliferation of the adjacent epithelia (collecting ducts and loops of Henle) is not clear but it was noted that the stromal expression of other WNT ligand transcripts, including Wnt4 and Wnt5a, was lost or reduced in the mutants. Additional studies have suggested that β-catenin is necessary and sufficient to promote formation of a specific subclass of medullary stroma^165,166. An attractive model is that WNT7b from the collecting ducts promotes the specification of a specific population of stroma that produces non-canonical Wnts that reciprocally signal back to the collecting ducts to stimulate their growth and/or morphogenesis.

Perturbation of TGFβ signalling in the stroma by inactivation of the signalling intermediate Smad4 using Foxd1cre increased the proliferation of medullary stroma with a concomitant increase in WNT signalling markers, such as LEF1 and Axin2 (ref. 167), suggesting that WNT and TGFβ work antagonistically to ensure that medullary stroma proliferation reaches but does not exceed a target number in the neonatal organ. Specification of this target cell number through communication between the proliferating stroma and adjacent epithelium would be a logical mechanism for proportional growth of the medulla, but this mechanism is yet to be defined.

In addition to its expression in the renal vesicles, WNT4 is expressed within the differentiating medullary stroma^168,169 where it has a role in the formation of a transient population of SMCs within the embryonic medullary stroma, which disappear shortly after birth^170,171. Wnt4-deficient embryos lack α-SMA-positive medullary stromal cells in part due to a failure to activate Bmp4 expression. Supplementation of cultured, Wnt4-deficient embryos with BMP4 or WNT4 led to a robust rescue of α-SMA-positive cells¹⁷⁰.

As mentioned above, expression of Wnt4, Wnt5a and Wnt11 in the medullary stroma is lost upon stroma-specific deletion of β-catenin^164,172. These ‘non-canonical’ WNTs produced by the stroma may direct morphogenesis of the adjacent epithelia (collecting ducts and loop of Henle), explaining the phenotype of these Foxd1cre-Ctnnb1 mutants. Interestingly, ablation of the Hedgehog pathway antagonist, Patched 1 (Ptch1), from the stroma led to decreased nephron endowment and an excess of Wnt5a-expressing stroma¹⁷³. Deletion of Wnt5a levels in stromal Ptch1-knockout mice (that is, in Foxd1cre;Ptch1;Wnt5a knockouts) improved nephron numbers. The mechanism by which ectopic Hedgehog signalling and Wnt5a regulates nephron number is not clear, but ablation of Smoothened, a component of the Hedgehog signal transduction cascade, from the stroma results in small, mispatterned kidneys with reduced nephron endowment and expansion of the NPC population, perhaps due to a defect in MET¹⁷⁴. This result is somewhat puzzling. Although the Hedgehog ligands, Ihh and Shh, are both expressed in the kidney, only ablation of Shh has a mutant phenotype¹⁷⁵. Shh is primarily expressed in the medullary collecting ducts and ureter whereas Ihh is expressed in the proximal tubules. Examination of pathway activity suggests that the Hedgehog pathway is only active in medullary stroma. How defects in the medullary stroma affect the cortical nephrons is unclear. It is possible that low-level Hedgehog activity (perhaps mediated by Ihh) is present in the cortical stroma, but this has not been demonstrated.

Differentiation and growth of the ureter

One of the best characterized examples of stromal–epithelial crosstalk during development comes from the nascent ureter and its surrounding smooth muscle progenitors^176–178. Given the focus of this Review on intrarenal stroma, we only briefly describe this process here.

The ureteric smooth muscle forms from a population of stromal cells that surrounds the nascent ureter. The ureteric epithelium provides secreted factors including WNTs^170,171,179 and Hedgehog proteins¹⁸⁰, which activate their signal transduction cascades within the adjacent stromal cells to direct the processes of differentiation and proliferation. Reciprocally, the stroma produces BMP4 and FGFs that signal both autonomously and non-autonomously to regulate proliferation of the stroma and differentiation of the adjacent epithelium¹⁸¹. Although the proliferation of ureteric SMC progenitors is seemingly required for ureter growth, it is not required for ureteric differentiation.

SMC progenitors express a number of transcription factors that are involved in various aspects of SMC growth (TSHZ3 (ref. 182)), survival (SIX1 (refs. 183–185)) and differentiation (TBX18 (refs. 54,186,187) and SOX9 (ref. 188)). Some of these factors may establish the competence of the stromal cells to respond to ligands and/or to differentiate into SMCs whereas the expression of others is regulated by the ligands themselves. For instance, both SOX9 and TBX18 require Wnt–β-catenin activity for their expression in the SMC precursors and they are both necessary for proper growth.

Mechanobiology and tissue stiffness

Studies over the past few years have demonstrated that tissue development, maintenance and disease can be influenced by biomechanical signalling¹⁸⁹. Factors that influence the biomechanical properties of tissues include hydrostatic pressure, fluid shear stress, cell adhesion and ECM composition or elasticity. We have long known that naive mesenchymal stem cells are highly sensitive to matrix elasticity for lineage specification. For example, stem cells grown on soft matrices that mimic brain microenvironments become neurogenic, whereas stem cells grown on stiffer matrices that mimic muscle become myogenic¹⁹⁰. Efforts to improve stem cell-based tissue engineering and regeneration protocols are now focused on methods to reproduce ECM-mediated stimuli in organoid model systems based on our understanding of the influence of mechanical properties on renal cell behaviour in vitro. Standard plastic culture dishes are markedly stiffer than bone or kidney, and when cultured on plastic, primary renal proximal tubules collapse into monolayer cells that spontaneously dedifferentiate and proliferate¹⁹¹. However, when cultured in soft Matrigel (which contains laminin and collagen type IV resembling the basement membrane that surrounds the proximal tubules in vivo) proximal tubules retain their tubular morphology and differentiated state. Moreover, studies of human-derived renal stem cells cultured on collagen-1-coated hydrogels of variable stiffness demonstrated that cell proliferation, migration, spreading and focal adhesion assembly mediated by ROCK activity increased with increasing matrix stiffness, resulting in the differentiation of cells towards a podocyte lineage¹⁹². These studies support the idea that differences in the stiffness of the ECM can have a profound impact on the differentiation of renal cells. Given that the stromal fibroblasts are a primary source of ECM in the kidney, it is reasonable to speculate that the stroma creates specialized microenvironments with specific ECM compositions and stiffness that are required for the differentiation and maintenance of adjacent epithelia.

The variability of ECM compositions in vivo has prompted the development of engineered ECM that can be tailored to cell or tissue-specific needs, and the use of microfabricated scaffolding substrates that can reproduce the physical and architectural features of ECM (reviewed elsewhere¹⁹³). Despite considerable progress with in vitro models, quantification of regional differences in embryonic tissue stiffness is yet to be fully characterized in vivo, in part owing to lack of experimental tools. A 2024 study described the use of microindentation to quantify tissue-level regional differences in the mechanical properties of embryonic mouse kidneys, demonstrating that the cortical zone of the embryonic kidney exhibits greater stiffness than the medullary zone¹⁹⁴. These findings align with in vitro work demonstrating improved maintenance of progenitor cells in stiff ECM over soft ECM^190–192. High resolution mapping of the biomechanical properties of the embryonic kidney combined with single-cell analyses should facilitate assessment of regional differences in the expression of various growth factors and ECM components that drive differential stiffness and provide critical guidance for the improvement of tissue engineering and regeneration models^166,195.

Modelling of stromal heterogeneity

As described above, the different roles of the stroma in kidney development are in part dependent on the different identities of the stromal cells and their neighbours. Even Foxd1-expressing progenitors give rise to at least four different cell types (fibroblasts, mural cells, SMCs and capsule cells), but within those categories, further heterogeneity exists. scRNA-seq of E18.5 Foxd1cre-derived cells identified 17 unique transcriptional clusters¹⁶⁶. Further characterization revealed distinct anatomical domains along the cortical–medullary axis that correlated with nephron and vascular patterning and may foreshadow the distinct anatomical zones of the adult organ¹⁶⁶ (Fig. 7), and suggested further heterogeneity within the fibroblast and pericyte subclasses. This stromal heterogeneity may create unique microenvironments that regulate or coordinate the development of adjacent epithelia and endothelia during development; however, the mechanism by which this level of transcriptomic and spatial heterogeneity arises is unclear.

Fig. 7 | — a, When the first ureteric bud (UB) branching event occurs at embryonic day 11.5 (E11.5), two distinct populations of stroma can be detected: the FOXD1⁺ and TBX18⁺ populations. b, By E13.5, comma-shaped bodies (CSB) and S-shaped bodies (SSB) have begun to form after the initiation of mesenchymal-to-epithelial transition, and there are at least three distinct populations of stroma: the FOXD1⁺ progenitors, the FOXD1-derived stroma that surrounds the CSB and SSB, and the TBX18⁺ ureteric stroma. c, At E18.5 there are seven anatomically distinct populations of stroma along the cortical–medullary axis as defined by in situ hybridization analyses¹⁶⁶. These populations can be depicted by their spatial correlation to different segments of the nephron and their uniquely expressed genes. CD, collecting duct; NPCs, nephron progenitor cells.

One possibility is that this heterogeneity is associated with the cortical–medullary osmotic gradient of the kidney; however, this hypothesis has not been experimentally addressed and one can only speculate on potential cause–effect relationships. In one scenario, cortical–medullary patterning of stroma could be established by the osmotic gradient. Although intriguing, this possibility seems unlikely as the kidney epithelium that helps establish the osmotic gradient is not mature until some time after birth in mice, whereas the interstitial patterning is present in the embryonic organ. The alternative scenario, in which the cortical–medullary patterning of the stroma influences patterning of the nephron seems more likely. Another possible explanation for stromal patterning is that it is triggered by cues from cells of the nephron and/or vasculature. This hypothesis also seems unlikely as the above-described genetic studies demonstrate that stromal heterogeneity is not simply a reflection of epithelial and/or endothelial heterogeneity. On the contrary, they demonstrate the importance of distinct stromal subpopulations for proper development and maintenance of the renal epithelia and endothelia. A similar role for stroma has been identified in the developing gut tube where regionalized signals produced by the adjacent mesodermal fibroblasts (stroma) are necessary for patterning the nascent structure into distinct organs¹⁹⁶. A third possible explanation for stromal patterning is that the stromal progenitors are predestined to form distinct stromal subpopulations. A similar mechanism has been proposed for the patterning of the vertebrate embryonic limb along its proximal–distal axis¹⁹⁷. Some support for this model is provided by the above-described scRNA-seq study¹⁶⁶, which demonstrated that molecular heterogeneity exists within the FOXD1 population itself, and suggested that rather than representing a single multipotent progenitor cell type, the FOXD1-expressing population may comprise three or four limited potency progenitors. It is tempting to speculate that the different types of stromal cells (fibroblasts, capsule, mural cells and SMCs) arise from distinct progenitor pools with limited potential. However, if this is the case, the origin of heterogeneity within each of these subclasses is unclear. Given the location of FOXD1 progenitors at the outer edge of the cortex on the opposite side of the collecting duct tip from the nascent nephron, it is difficult to imagine how different stromal subpopulations locate adjacent to their spatially associated nephron segment or vessel as the tissue undergoes morphogenesis. A more intuitive model is that initially, the stroma autonomously patterns into a small number of lineages (for example, smooth muscle, fibroblast and mural cells or nephrogenic, cortical and medullary cells). Then, as the parenchyma develops, interactions with the renal parenchyma (that is, the epithelia and endothelia) and perhaps between the different stromal cell types further refines, remodels and reinforces this patterning.

The scenario that seems most likely is a combination of the different models proposed above. It is possible that limited potency progenitors differentiate into precursors of the major stromal cell types (for example, smooth muscle, fibroblast and mural cells or nephrogenic, cortical and medullary cells), which influence the initial steps of epithelial and endothelial differentiation and patterning. Feedback from the adjacent parenchyma may then serve to further pattern the stroma into distinct populations that reciprocally signal back to maintain the functional state of their neighbours. Further insights into this question will require more extensive analyses of stromal heterogeneity at different time points and in relation to nephron and endothelial pattern. It will also require investigation of stromal heterogeneity and patterning in mutant mice that lack various epithelial or endothelial cell types and of stromal–parenchymal interactions in organoids in which different cell types can be recombined.

Given the critical roles of different stromal populations in the proper formation of epithelial and endothelial tubules of the kidney, it seems clear that any attempt to engineer renal tissue needs to consider the stroma. Multiple protocols have been established to generate renal organoids from iPSCs. Gene expression analyses have indicated that these organoids represent a fetal stage of kidney development, and we would therefore expect them to display stromal heterogeneity characteristic of the developing kidney. However, single cell analyses have so far clustered kidney organoid interstitial cells into only a few clusters, suggesting that the cell type repertoire is incomplete. Indeed, whether organoids formed using any of the current protocols include a true FOXD1⁺ stromal progenitor in their cellular repertoire is unclear. Given the demonstrated roles for the stroma in the growth and differentiation of both the epithelia and endothelia, it seems plausible that defects in epithelial differentiation, the lack of a clearly identifiable cortical–medullary axis, and failure to maintain endothelial cells in organoids grown under static conditions may result from a failure to induce sufficient stromal heterogeneity with current protocols. In support of this hypothesis, inclusion of a FOXD1⁺ progenitor cell in organoid protocols greatly improved the pattern and differentiation of epithelia¹⁰³. These observations suggest that the development of differentiation protocols with appropriate stromal representation should be a priority. Signalling pathways and transcriptional regulators characteristic of individual stromal subtypes as identified by single-cell transcriptomics could provide a framework for the in vitro differentiation of stromal cells; however, given the distinct molecular requirements of epithelia, endothelia and stroma, one single protocol for all kidney cell types and lineages may be unrealistic. Instead, researchers may need to develop protocols that promote the formation of different lineages and then combine them together to form multilineage organoids, or so-called assembloids. In support of this approach, a 2024 study that combined renal and endothelial organoids achieved a level of maturation across multiple cell types that surpassed that previously seen in organoids derived from a single cell source¹⁹⁸.

Implications for the adult kidney

A growing body of evidence suggests that, similar to the embryo, considerable heterogeneity exists in the interstitium of adult mouse and human kidney. Several different stromal cell types — including glomerular and extraglomerular mesangial cells, VSMCs, EPO-producing fibroblasts, ureteric SMCs, renal capsule cells and various resident immune cells — are readily distinguishable both morphologically and molecularly, and have distinct functions. However, scRNA-seq studies have suggested that there may be additional, as-yet unappreciated, heterogeneity within the fibroblast and pericyte populations similar to observations in the embryo, raising questions about the functional relevance of stromal heterogeneity in the adult. Some potential roles are obvious. Although perhaps less so than in the embryo, the ECM of the adult kidney is complex and heterogeneous^199,200. As in the embryo, adult fibroblasts and pericytes are likely to be a major source of ECM structural proteins and modifying enzymes that are necessary for maintaining the organ scaffold during tissue homeostasis and repair, and contributing to the pathological ECM that forms fibrotic scars after injury. Thus, it seems reasonable to think that the molecular heterogeneity of stromal cells will at a minimum match that of the ECM under homeostatic conditions and in response to injury.

The major sources of myofibroblasts after injury are stromal fibroblasts and/or pericytes²⁰¹. Some data suggest cell-type specificity within the stromal cells that give rise to myofibroblasts. For example, GLI1-expressing cells, which are a subset of the adult stroma, give rise to a disproportionate number of myofibroblasts after injury, suggesting that this population of cells may contain a myofibroblast progenitor²⁰². However, that study also identified αSMA-positive myofibroblasts that were not derived from GLI1⁺ cells, suggesting that GLI1⁺ cells are not the only source of myofibroblasts. Whether many or all stromal cells can form myofibroblasts or whether myofibroblasts arise from a limited population(s) of progenitors remains unknown.

Although less well studied, a growing body of evidence suggests that the adult renal stroma contributes to tissue repair and maintenance. Ablation of GLI1-expressing stromal cells in the adult kidney leads to vascular rarefaction and epithelial cell injury²⁰², supporting an essential role for stroma in tissue maintenance. A separate study showed that Pdgfrb-expressing stromal cells are necessary for the repair of the proximal tubules after ischaemic and obstructive injuries²⁰³. Similar to fibroblasts and pericytes in other organs, the renal interstitial cells produce various trophic factors, growth factors, cytokines and small molecules that probably create unique molecular niches that influence the growth, maintenance and survival of the adjacent parenchyma (epithelia and endothelia), and response to injury^204–206. A heterogeneous stromal population may be required to provide unique trophic factors for the maintenance and repair of different adult cell types.

Of note, the stroma has long been theorized to be a critical regulator of renal physiology. In 1991, Lemley and Kriz wrote “The interstitium of the kidney is not a simple passive space in which the “true” functional units—nephrons and vessels—are embedded. Rather, it mediates and in fact modulates almost all exchange among the tubular and vascular elements of the renal parenchyma”⁹. Although this theory was primarily formulated on the basis of morphological observations, it has been validated by experimental evidence. As just one example, deletion of AT1Rs from SMCs leads to reduced levels of sodium transporters in adjacent epithelia²⁰⁷, indicting that stromal cell signalling to epithelia regulates their basic physiological functions. It is almost certain that additional signalling, biomechanical and physical roles for the stroma in renal physiology exist, which raises the interesting possibility that stromal cells may be a driver of evolutionary change in the kidney. As organisms have evolved to fill distinct ecological niches, the kidney has evolved to meet physiological demands. The expanded renal papilla found in desert rodents is frequently described as a mechanism to meet the need for water reabsorption in arid environments, whereas the absence of a papilla in freshwater beavers is thought to be an adaptation to an environment in which water conservation is not required. These extreme variations are observed in kidneys from species within the same phylogenetic order²⁰⁸. Given the demonstrated roles for the stroma in directing the specification, differentiation and growth of the different nephron segments as well as their physiological function, it seems plausible that changes in stromal patterning and/or signalling drive the evolution of this organ. Insights into the stromal heterogeneity and differences in gene expression at the single-cell level across different rodent species that exhibit variations in kidney anatomy, such as those described above, may provide clues into the role of stromal cells in promoting these morphological adaptations.

Another interesting possibility is that stromal cells may contribute to the metabolic health of the parenchyma. Studies of neural glia have shown that they can act as both a source and a sink for metabolites to maintain neuronal health^209,210. In line with this theory, lactate produced by the proximal tubules can promote proliferation and formation of myofibroblasts in adjacent fibroblasts^211,212. Further examination of interactions between stromal cells and epithelial metabolism in the normal and diseased kidney is warranted.

Conclusions and future directions

As we describe above, the stroma exhibits many different roles in kidney development and available evidence points to potential roles in the adult organ. Although some stromal populations such as the mesangium, the EPO-producing fibroblasts and renin-producing cells have been quite extensively studied, the ontogeny, dynamics and function of the stromal population as a whole are poorly understood. In our opinion, the available studies form a convincing framework to propose that stromal cells are the essential fourth component of the kidney that is required for the development and function of the nephron, collecting duct and vasculature. In this regard, the renal stroma again demonstrates similarities with neural glia. Glia are the non-neuronal and non-endothelial cells — that is, the stroma — of the nervous system. Neuroanatomists have assigned specific names to glial cell types including oligodendrocytes, Schwann cells, astrocytes and microglia, and this classification has been essential to defining the roles of these stromal subtypes in neuronal development, homeostasis and injury repair. We believe that cementing the functional relevance of kidney stromal subpopulations through further investigations will enable the development of a nomenclature similar to that used in neurobiology that will clarify the functional distinctions between stromal subpopulations in the kidney.

Certainly, the available literature raises more questions than it answers. Perhaps the most obvious revolve around understanding the nature of stromal–parenchymal interactions. As described above, specific interactions between stroma and adjacent parenchymal cells are required for healthy kidney development. The diversity of functions in regulating various developmental processes suggests that there may be a wide variety of stromal–parenchymal interactions that have not yet been discovered. Single-cell omics data are expected to provide a rich source of new leads that may take the field to the next level of resolution in terms of the identification and pathway analysis of specific stromal and parenchymal subtypes. However, accurate predictions of stromal parenchymal interactions require knowledge of the precise spatial relationships between the different stromal cell types and their associated parenchyma. Emerging spatial transcriptomic studies have provided some insights but more detailed studies are essential¹⁵⁷. Of note, the stroma produces more than just ligands and receptors. The stroma is a source of small molecules, metabolites, ECM (and ECM modifiers), all of which contribute to the microenvironment in which the parenchyma is formed and maintained. As more information on the diversity of stromal parenchymal interactions emerges, modelling of molecular interactions, perhaps using artificial intelligence-based approaches, will generate testable hypotheses.

A deeper understanding of the transcriptome and phenotype of stromal cells from single-cell omics studies will also enable the development of tools for cell type-specific manipulation of distinct subpopulations. The generation of fluorescent reporters, Cre recombinases and/or inducible mouse lines that are specific for distinct stromal subpopulations is essential to provide higher genetic resolution. In addition to facilitating genetic manipulation, the ability to generate and isolate pure populations of stroma will enable investigators to generate renal assembloids to test the functions of specific stromal cell populations. As described above, insights into the power of such an approach have been demonstrated using assembloids created from the co-culture of stromal and renal epithelial progenitors¹⁰³. Similar studies using specific stromal subtypes in combination with epithelial progenitors is an obvious next step.

Tools that can label stromal subpopulations will also provide insights into the fates of these subpopulations in the adult kidney. Available evidence suggests that the adult stroma is heterogeneous; however, it is unknown whether the identities and spatial organization of these subpopulations are conserved from the embryonic kidney. Embryonic subpopulations may give rise to specific adult subpopulations, but they may also be transitory. If transitionary, it will be of interest to determine at what point the transitory populations are lost, whether their loss coincides with the maturation of epithelial subtypes, and the identities of the subpopulations that replace them.

The development of a new generation of subpopulation-specific genetic tools will also enable studies of the physiological function of the adult stroma. Studies that have identified essential roles for interstitial cells in the maintenance of adult kidney tissue^202–204, argue strongly for further research to deepen our understanding of the roles of diverse stromal subpopulations in kidney physiology and repair.

Improved understanding of the identities and dynamics of stromal subpopulations will also shed light on the role of the stroma in human disease. Although stromal cell dysregulation in the form of myofibroblast conversion and ultimately fibrosis has been well documented as a consequence of parenchymal injury, to our knowledge no reports have yet described a primary causal role for stromal cells in human kidney disease. Use of single-cell omics to characterize the dynamic changes in stromal composition in human kidney disease coupled with hypothesis testing in mouse models with the use of genetic tools that can target specific subpopulations will enable investigation of the role of stromal subtypes in progression of kidney disease, and potentially lead to the identification of new therapeutic targets.

Key points.

The kidney stroma is a heterogeneous population of vascular mural cells, fibroblasts, smooth muscle and leukocytes that arise from at least three unique cellular lineages.
The different stromal cell types produce a wide array a signalling proteins, small molecules and metabolites, extracellular matrix and hormones that create regional microenvironments in the kidney.
Studies using genetic mouse models and kidney organoids have revealed essential roles for the stroma in the development of nephrons and the vasculature.
Growing evidence indicates that the stroma of the adult organ is as diverse as that of the embryo, suggesting that it might have essential roles in tissue maintenance, repair and disease progression.
The development of new tools is expected to uncover additional roles for the stroma in both the embryonic and adult organ.

Footnotes

Competing interests

The authors declare no competing interests.

Peer review information Nature Reviews Nephrology thanks Sunder Sims-Lucas and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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PERMALINK

The kidney stroma in development and disease

Alexandria N Fusco

Leif Oxburgh

Thomas J Carroll

Abstract

Introduction

Fig. 1 |. Stromal cells along the cortical–medullary axis of the kidney.

Stromal cells of the kidney

Fibroblasts

Vascular mural cells

Smooth muscle

Tissue-resident macrophages

Cells of the renal capsule

Origin of the stroma

Fig. 2 |. Lineage tracing of stromal progenitors.

The roles of the stroma in development

Table 1 |.

Ureteric bud branching

Fig. 3 |. Signalling from the stroma during ureteric bud induction and branching morphogenesis.

Mesenchymal-to-epithelial transition

Fig. 4 |. Signals from the stroma induce mesenchymal-to-epithelial transition in a subset of nephron progenitor cells.

Corticomedullary patterning

Vascular patterning

Fig. 5 |. Vascular patterning is regulated by stromal PBX1 and NTN1 signalling.

Growth and morphogenesis

Fig. 6 |. Regulation of nephrogenesis by FGF and WNT.

Differentiation and growth of the ureter

Mechanobiology and tissue stiffness

Modelling of stromal heterogeneity

Fig. 7 |. Stromal populations during embryonic development.

Implications for the adult kidney

Conclusions and future directions

Key points.

Footnotes

References

ACTIONS

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