Unraveling the interplay between inflammation and stem cell mobilization or homing: Implications for tissue repair and therapeutics

ABSTRACT

Inflammation and stem cell mobilization or homing play pivotal roles in tissue repair and regeneration. This review explores their intricate interplay, elucidating their collaborative role in maintaining tissue homeostasis and responding to injury or disease. While examining the fundamentals of stem cells, we detail the mechanisms underlying inflammation, including immune cell recruitment and inflammatory mediator release, highlighting their self-renewal and differentiation capabilities. Central to our exploration is the modulation of hematopoietic stem cell behavior by inflammatory cues, driving their mobilization from the bone marrow niche into circulation. Key cytokines, chemokines, growth factors, and autophagy, an intracellular catabolic mechanism involved in this process, are discussed alongside their clinical relevance. Furthermore, mesenchymal stem cell homing in response to inflammation contributes to tissue repair processes. In addition, we discuss stem cell resilience in the face of inflammatory challenges. Moreover, we examine the reciprocal influence of stem cells on the inflammatory milieu, shaping immune responses and tissue repair. We underscore the potential of targeting inflammation-induced stem cell mobilization for regenerative therapies through extensive literature analysis and clinical insights. By unraveling the complex interplay between inflammation and stem cells, this review advances our understanding of tissue repair mechanisms and offers promising avenues for clinical translation in regenerative medicine.

INTRODUCTION

Inflammation in itself is not to be considered as a disease but as a salutary operation consequent to some violence or some disease [1]. It is closely linked with nearly every human ailment [2]. Inflammation serves as a crucial defense mechanism against pathogens and tissue damage, orchestrated by a complex interplay of immune cells, cytokines, and chemokines. It is characterized by a series of events including vasodilation, increased vascular permeability, and leukocyte recruitment to the site of injury or infection [3]. Adult stem cells, on the other hand, possess remarkable self-renewal and differentiation capabilities, contributing to tissue homeostasis, repair, and regeneration [4,5]. The mobilization or homing of stem cells, the process by which stem cells are released from their niche into circulation or injury sites, plays a pivotal role in tissue repair, particularly in response to inflammatory stimuli [6,7].

INFLAMMATION: A FUNDAMENTAL PROCESS IN THE IMMUNE SYSTEM

Inflammation, a conserved process marked by activating immune and nonimmune cells to safeguard the host against bacteria, viruses, toxins, and infections, can be categorized into acute and chronic phases. Acute inflammation is usually rapid and self-limiting, whereas chronic inflammation endures over an extended period, potentially resulting in tissue damage and organ dysfunction [8,9]. Chronic inflammation is associated with numerous diseases, including ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, nonalcoholic fatty liver disease, autoimmune disorders, and neurodegenerative conditions [10]. Injury and infection-triggered inflammatory responses can be detected through two distinct modes of recognition [11] [Figure 1]. First, tissue damage leads to the release of intracellular proteins such as heat-shock proteins, the transcription factor high mobility group box 1 (HMGB1), extracellular adenosine triphosphate (eATP), histone, and mitochondrial peptides bearing the N-formyl group characteristic of prokaryotic proteins, eliciting an inflammatory response [12,13,14,15,16]. Second, microbes and their shed or secreted products are sensed through the binding of their conserved molecular constituents to soluble receptors such as complement, mannose-binding protein, and bacterial cell wall components such as lipopolysaccharide, which in turn bind to cell-surface receptors such as toll-like receptor (TLR) family members [17,18]. The inflammatory response recruits various immune cells, including neutrophils, macrophages, and lymphocytes, to the site of inflammation in a tightly regulated manner. Cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (ILs), along with chemokines, orchestrate leukocyte trafficking and activation, aiding in the clearance of pathogens and damaged cells [17,18]. Furthermore, it is now understood that inflammation can occur independently of infection or tissue injury. Cells experiencing senescence or stress, such as endoplasmic reticulum (ER), mitochondrial, or osmotic stress, activate the NOD-like receptor family and pyrin domain-containing 3 (NLRP3) inflammasome and produce inflammatory cytokines [11,19,20]. Furthermore, a key player in the complex landscape of inflammation is the NLRP3 inflammasome, a protein complex that modulates inflammatory responses and has been implicated in various diseases.

Figure 1.

Schematic illustration showing the two types of inflammatory responses: injury-triggered and infection-triggered. Both inflammatory reactions involve recruiting immune cells to clear damaged cells or pathogens

NLRP3 INFLAMMASOME

Inflammasomes, first proposed by Martinon et al., 2002 [21], are protein complexes containing caspase-1 that positively regulate the inflammation and are associated with various diseases such as diabetes, Alzheimer’s disease, gout, and atherosclerosis [22,23,24,25,26]. The NLRP3 inflammasome is among the most studied inflammasome members [23,24,26]. It consists of NLRP3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and pro-caspase-1 [27,28]. Activation of the NLRP3 inflammasome involves two steps: priming and activation. In the priming signal, pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) bind to TLRs, activating the NF-κB pathway. This activation results in increased expression of inflammasome-related molecules such as pro-IL1β, pro-IL-18, and NLRP3 [29,30]. In the activation signal, the NLRP3 inflammasome assembles and activates through three main mechanisms: ion flux (potassium channels, chloride channels, or calcium signaling), mitochondrial dysfunction, and lysosomal disruption [29,30]. After activation, the inflammasome-activated caspase-1 cleaves pro-IL-1β, pro-IL-18, and gasdermin D, leading to the secretion of IL-1β and IL-18 [31,32] and induction of inflammatory programmed cell death-pyroptosis [29] [Figure 2].

Figure 2.

Schematic illustration showing the activation pathway of the NLRP3 inflammasome. The NLRP3 inflammasome, a protein complex crucial for inflammation, involves NLRP3, ASC, and pro-caspase-1. Activation occurs in two steps: priming and activation. Priming involves pathogen-associated molecular patterns or damage-associated molecular patterns binding to toll-like receptors, activating the NF-κB pathway, and increasing pro-interleukin (IL)-1β, pro-IL-18, and NLRP3 expression. Activation involves ion flux, mitochondrial dysfunction, and lysosomal disruption, leading to the assembly of the inflammasome. Activated caspase-1 then cleaves pro-IL-1β, pro-IL-18, and gasdermin D, resulting in IL-1β and IL-18 secretion and pyroptosis

STEM CELLS: BASICS AND TYPES

In contrast to the intricate regulatory pathways of inflammasomes, stem cells offer a promising avenue in regenerative medicine. Stem cells, characterized by their remarkable plasticity, play pivotal roles in tissue repair and regeneration. Understanding their dynamics and potential therapeutic applications requires a grasp of their fundamental properties. Stem cells are undifferentiated cells capable of both self-renewal and differentiation into specialized cell types. Hematopoietic stem cells (HSCs) give rise to all blood cell lineages, whereas mesenchymal stem cells (MSCs) have the potential to differentiate into various mesenchymal lineages including adipocytes, osteoblasts, and chondrocytes [33,34]. These multipotent stem cell populations reside in specialized niches within tissues, maintaining tissue homeostasis and responding to injury or inflammation by proliferating and differentiating into required cell types for tissue repair [35] [Table 1].

Table 1.

Comparison of hematopoietic stem cells and mesenchymal stem cells

Aspect	HSCs	MSCs
Origin and location	Originate in bone marrow	Found in bone marrow and various tissue (e.g., adipose tissue, umbilical cord blood)
Differentiation ability	Give rise to all blood cell types	Differentiate into nonhematopoietic cell types (e.g., bone, cartilage, muscle, and fat)
Function	Primarily involved in blood cell production	Exhibit immunomodulatory properties; contribute to tissue repair and regeneration
Response to inflammation or injury	Mobilize from bone marrow to peripheral blood; participate in tissue repair	Actively respond to inflammation; secrete anti-inflammatory cytokines; promote tissue healing; modulate immune responses
Clinical application	Used in HSCT	Investigated for therapeutic potential in various conditions; enhance HSCT outcomes when combined with HSC infusion

MSCs: Mesenchymal stem cells, HSCs: Hematopoietic stem cells, HSCT: Hematopoietic stem cell transplantation

HEMATOPOIETIC STEM CELLS AND THE BONE MARROW NICHE

HSCs reside in the bone marrow niche. The existence of a niche or microenvironment was proposed in 1978 by Schofield [36]. He suggested that stem cells are associated with other tissue-resident cells that prevent stem cell differentiation and maintain self-renewal. Niche is composed of endothelial cells and mesenchymal stromal progenitor cells. The interactions between niche cells and HSCs are associated with adhesion, self-renewal, mobilization, and homing [37,38]. The following ten molecules on the surface of niche cells (N-cadherin, soluble kit ligand, angiopoietin, stromal cell-derived factor 1 [SDF-1, also called CXCL12], vascular cell adhesion molecule-1 [VCAM-1], ICAM-1,2,3, thrombopoietin, osteopontin [OPN], E-selectin, and P-selectin) are responsible for the interaction with the surface receptors (N-cadherin, c-kit, tie2, CXC chemokine receptor-4 [CXCR4], very late antigen-4 [VLA-4], LFA-1, MPL, α and β integrin [CD44], E-selectin ligand-1, and P-selectin glycoprotein ligand-1) on the HSCs, respectively [38]. Niche cells also can provide noncellular ligands such as fibronectin, laminin, collagen, OPN, and hyaluronan for cell adhesion between HSCs and niche cells [39]. Besides endothelial cells and mesenchymal stromal progenitor cells, there are a variety of cells such as macrophages, neutrophils, osteoblasts, and megakaryocytes regulated by sympathetic nerves and complement components that maintain the bone marrow’s hemostasis [40,41].

THE INTERPLAY BETWEEN INFLAMMATION AND HEMATOPOIETIC STEM CELL MOBILIZATION

Inflammation exerts profound effects on stem cell dynamics, influencing their mobilization from the bone marrow into circulation. During inflammation, cytokines and chemokines such as granulocyte colony-stimulating factor (G-CSF, also known as filgrastim), granulocyte-macrophage CSF, and SDF-1 are upregulated, promoting the release of stem cells from the bone marrow niche [42]. In addition, inflammatory signals can directly modulate the behavior of stem cells, enhancing their migratory and homing capacities to sites of injury or inflammation [43]. This orchestrated mobilization of stem cells plays a crucial role in tissue repair and regeneration, contributing to the replenishment of damaged cell populations and the restoration of tissue function [44].

Beyond the regulation by circadian rhythms [45], HSCs will mobilize to the peripheral blood in responses to systemic or local inflammation, intensive exercise, hypoxia, and tissue/organ injuries in steady-state conditions [6,46,47,48,49]. Accumulated studies revealed that G-CSF or plerixafor (also known as AMD3100) can activate neutrophils in the bone marrow, and then, the activated neutrophils will release some DAMPs such as HMGB1, eATP, DNA, and hyaluronan fragments [50,51,52]. These DAMPs will be recognized by mannan-binding lectin, which then activates complement system through MBL-associated serine proteinase. The activated complement C5a then lyses erythrocytes and releases sphingosine-1-phosphate into the peripheral blood to attract the HSCs mobilized from the bone marrow [40,50,53,54]. Recent studies have reported that the NLRP3 inflammasome is involved in G-CSF and AMD3100-triggered HSC mobilization in mice. Additionally, the administration of the NLRP3 inflammasome activator nigericin, or the activation mediators IL-1β and IL-18, induces HSC mobilization in mice [55,56,57,58]. Mice deficient in caspase-1 and Nlrp3 are poor mobilizers in response to G-CSF and AMD3100 [59]. In clinical settings, proinflammatory cytokine levels (interferon-gamma, IL-22, and TNF-α) correlate positively with G-CSF-triggered HSC mobilization [60]. All these evidence demonstrated that innate immunity plays an important role in HSC mobilization.

Moreover, in addition to influencing stem cell mobilization, inflammatory signals secreted by recruited immune cells also suppress Notch activation in tissue-resident stem cells such as airway stem cells. This process promotes stem cell plasticity and their differentiation into alveolar cells [61,62]. These findings underscore the intricate interplay between inflammation and stem cell dynamics, wherein inflammatory cues mobilize stem cells and shape their fate and function in tissue repair and regeneration processes.

AUTOPHAGY AND HEMATOPOIETIC STEM CELL MOBILIZATION

Transitioning to another facet of stem cell regulation, autophagy emerges as a critical intracellular mechanism with implications in immunity and inflammation [63,64,65]. Recent studies have elucidated a mutual regulation between inflammasomes and autophagy [66,67,68]. Autophagy is initiated by the formation of a double membrane called autophagosome-sequestered malfunctioning components [69,70]. The autophagosome fuses with lysosome to become the autolysosome and degrades all unwanted cytosolic constituents [69,70]. Autophagy is initiated by the autophagy-related protein 1 (Atg1)-Atg13 protein complex. The class III phosphoinositide 3-kinase-Beclin 1 complex is the key for the nucleation step [71]. Elongation of the isolation membrane is mediated by two ubiquitin-like conjugation systems (coordination by several Atg proteins, such as Atg3 and Atg5-12) [72,73]. Autophagy plays important roles in cell survival, immunity, development, cancer, and adaptation to starvation [74,75]. Evidence also showed that autophagy is important for hematopoietic system and Atg7^−/− mice developed severe anemia, lymphopenia, and atypical myeloproliferation resembling human myelodysplastic syndrome [72,76,77]. In addition, autophagy also plays an important role in hematopoietic cell differentiation [78,79], including erythroid cell terminal differentiation, especially in reticulocyte maturation [80,81,82,83] and megakaryocyte differentiation [84], and is also required for the maintenance of quiescence and stemness of HSCs [85,86,87]. Notably, G-CSF-induced neutrophil and HSC mobilization is impaired in Atg7^−/− or Atg5^−/− mice, suggesting a crucial role for autophagy in this process [88]. Autophagy-related genes also increase expression in both neutrophils and HSCs of mice and humans after G-CSF stimulation [88]. Furthermore, G-CSF has been shown to mobilize regulatory T-cells (Tregs) from the bone marrow to the peripheral blood and induce autophagy for the survival of Tregs [89,90]. These cells are heterogeneous immunosuppressive T-cells that maintain tolerance after HSC transplantation (HSCT) [91]. Understanding autophagy’s role in HSC mobilization holds promise for improving HSCT protocols and promoting tolerance of graft-versus-host diseases after HSCT.

MESENCHYMAL STEM CELL HOMING IN RESPONSE TO INFLAMMATION

Transitioning to another aspect of stem cell behavior, MSCs exhibit remarkable homing capabilities in response to inflammation. MSCs can be isolated from various tissues, including bone marrow [92], adipose tissue [93], umbilical cord tissue [94], placenta [95], umbilical cord [96], peripheral blood [97], and skin [98]. Among these, bone marrow MSCs, adipose-derived MSCs, and umbilical cord MSCs are the most frequently studied. Compared to the other two MSC types, adipose-derived MSCs are readily available and collected noninvasively, making adipose tissue an ideal source for MSCs [99]. For clinical treatments, MSCs can be sourced endogenously or exogenously. Regardless of their origin, MSCs preferentially home to injury or tumor sites under the influence of inflammatory and chemotactic factors, which promote angiogenesis, regeneration, immunomodulation, anti-inflammatory, and antitumor effects [100,101,102,103]. Therapeutic MSC administration can be performed systemically or site specifically; thus, MSC homing can be divided into nonsystemic and systemic [Figure 3]. In nonsystemic homing, MSCs injected locally near the target tissue are recruited to the injury site by sensing chemokines released from injured or inflamed tissue [104]. In systemic homing, MSCs are administered locally or recruited endogenously into the circulation first. They then go home to the injury site akin to leukocytes, following four subsequent steps [101,103,104]. Initially, adhesion molecules such as VLA-4 (also known as α4β1-integrin) on the surface of MSCs bind to VCAM-1 on endothelial cells, promoting adhesion and activating between MSCs and endothelial cells [105,106]. Several reports have demonstrated that damaged tissues or inflammatory sites express various inflammatory cytokines such as IL-1β and IL-6, as well as growth factors such as epidermal growth factor and fibroblast growth factor. These factors bind to receptors on MSC surfaces, facilitating the rolling, capture, and adhesion of MSCs at the target site [107]. For instance, stromal cell-derived factor 1 (SDF-1) significantly increases after cardiac ischemia, and the recruitment of MSCs expressing CXCR4 toward the SDF-1 gradient plays a crucial role in tissue recovery [108]. The SDF-1/CXCR4 interaction between SDF-1 and CXCR4 regulates MSC homing, and strategies have been developed to modify MSCs to express more CXCR4 before transplantation for cardiac repair [109]. Subsequently, matrix metalloproteinases (MMP-9 and MMP-2), released by inflammatory cells or MSCs, degrade the two major components of basement membranes – collagen and gelatin, enabling transendothelial migration of MSCs [110,111]. Finally, chemotactic factors such as platelet-derived growth factors and insulin-like growth factor-1 guide MSCs to the injured or inflamed sites [103]. Several inflammatory mediators (such as TNF-α) or chemokines are produced throughout the homing process, contributing to the formation of a chemotactic gradient that aids in recruiting MSCs to the injury site [101]. Recent studies have reported that MSCs interact with platelets in the blood and are involved in the migration of MSCs both in vitro and in vivo [107,112,113,114].

Figure 3.

Schematic illustration showcasing mesenchymal stem cell (MSC) homing, depicting two pathways: nonsystemic homing and systemic homing. In nonsystemic homing, MSCs are injected locally near the target tissues. Conversely, MSCs navigate to the injury site or tumor in systemic homing through four subsequent steps: adhesion, facilitating rolling and capture, transendothelial migration, and homing to the injury site. In both modes of MSC homing, recruitment to the injury site is facilitated by the sensing of chemokines

GRANULOCYTE COLONY-STIMULATING FACTOR TRIGGERED HEMATOPOIETIC STEM CELL MOBILIZATION

While MSC homing highlights the body’s intrinsic repair mechanisms, another vital therapeutic approach involves the mobilization of HSCs. The administration of G-CSF has been widely used clinically to mobilize HSCs for HSCT in the treatment of hematopoietic diseases such as sickle cell anemia, thalassemia, and hematological malignancies [115,116,117,118,119,120,121,122]. In addition, G-CSF, which stimulates the production of granulocytes, has been used since 1988 to treat cytopenia following chemotherapy, as well as neutropenia caused by nonchemotherapy-related idiosyncratic drug reactions or diseases [123,124]. G-CSF also aids in mobilizing granulocytes for transfusions and contributes to treating congenital or acquired bone marrow failure [125]. Furthermore, G-CSF has demonstrated neuroprotective and cardioprotective effects and has been used in numerous clinical trials for the treatment of conditions such as spinal cord injury, carbon monoxide poisoning, nonarteritic anterior ischemic optic neuropathy, and myocardial infarction [126,127,128,129]. The administration of G-CSF is associated with a range of side effects, including musculoskeletal pain, bone pain, splenomegaly, thrombocytopenia, and drug hypersensitivity reactions [123,130,131,132].

STEM CELL RESILIENCE

In addition to their therapeutic mobilization, stem cell resilience is crucial in understanding their utility. Resilience is the dynamic process by which individuals adapt and maintain their functionality amid various challenges or stressors [133,134]. Stem cells play a crucial role in tissue homeostasis by replenishing damaged or senescent cells, thereby supporting tissue integrity and preserving organ function [135]. Their inherent regenerative potential enables them to participate in tissue repair and regeneration following injury, disease, or physiological stress [136]. Moreover, stem cells exert immunomodulatory effects by regulating inflammatory responses, modulating immune cell function, and promoting tissue repair and regeneration [33]. In addition, they offer neuroprotective effects through diverse mechanisms, including neurotrophic factor secretion, promoting neuronal survival, and modulation of inflammatory reactions. This multifaceted resilience of stem cells underscores their significance in maintaining overall tissue health and function [137]. In clinical trials, MSCs have been used to treat several neurodegenerative diseases, including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. All MSC treatments have demonstrated safety and early promising signs of efficacy [138,139,140,141]. HSCs have also been employed in clinical trials for multiple sclerosis therapy, showing an increase in the percentage of regulatory T-cells and suppression of inflammation [138,142,143].

CLINICAL IMPLICATIONS AND THERAPEUTIC POTENTIAL

Dysregulated inflammation and impaired stem cell mobilization or homing are associated with various pathological conditions including cardiovascular diseases, neurodegenerative disorders, and autoimmune diseases [144,145,146,147]. Therapeutic strategies to modulate inflammation and enhance stem cell mobilization are promising for treating these conditions. Administering inflammatory factors such as G-CSF has been widely used clinically to mobilize HSCs for HSCT. Beyond neurodegenerative diseases, MSCs have demonstrated effectiveness in alleviating various conditions. They mitigate inflammatory bowel disease by modulating inflammatory cytokines within the inflamed gut in clinical trials [148,149]. Additionally, they ameliorate spinal cord injury by improving motor function in the lower limbs and bladder compliance [150,151,152,153]. In addition, MSCs have been shown to safeguard renal function by diminishing serum creatinine and blood urea nitrogen levels, thereby mitigating acute renal injury through various mechanisms such as anti-inflammation, anti-apoptosis, angiogenesis anti-oxidative stress, and anti-fibrosis [154,155]. Furthermore, MSC transplantation has demonstrated improvements in quality of life, functional outcomes, and pain relief for patients with heart failure or knee osteoarthritis [150,156,157,158,159,160] [Table 2]. Moreover, emerging strategies, such as cell-based therapies incorporating MSCs alongside HSCT, aim to enhance hematopoietic reconstitution and address graft-versus-host diseases with ongoing exploration through clinical trials [161]. However, challenges such as optimizing the efficacy and safety of stem cell-based therapies and understanding the long-term consequences of modulating inflammation warrant further investigation.

Table 2.

Comparison of clinical implication and disease condition between granulocyte colony-stimulating factor, hematopoietic stem cells, and mesenchymal stem cells

Treatment	Clinical implication	Disease condition	Reference
G-CSF (filgrastim)	Stimulates production of granulocytes	Cytopenia, neutropenia, and cancer	[123,124,125]
HSCs	Differentiates into various blood cell types	Various hematological disorders (e.g., sickle cell anemia, thalassemia, and hematological malignancies)	[115,116,117,118,119,120,121,122]
MSCs	Immunomodulation, tissue repair, and regeneration	Diverse human diseases (e.g., neurodegenerative diseases, inflammatory bowel disease, acute renal injury, heart failure, and knee osteoarthritis)	[138,139,140,141,148,149,150,151,152,153,154,155,156,157,158,159,160]

MSCs: Mesenchymal stem cells, HSCs: Hematopoietic stem cells, G-CSF: Granulocyte colony-stimulating factor

CONCLUSION

Inflammation and stem cell mobilization or homing are intricately linked processes essential for tissue homeostasis, repair, and regeneration. Understanding the mechanisms underlying their interplay provides insights into the development of novel therapeutic strategies for a wide range of diseases and conditions. Further research into elucidating the complex crosstalk between inflammation and stem cells will undoubtedly uncover new avenues for therapeutic intervention and enhance our ability to harness the regenerative potential of stem cells.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Financial support and sponsorship

This work was supported by a research funding from the Ministry of Science and Technology, Taiwan (MOST 103-2320-B-320-006, MOST 103-2321-B-320-001, MOST105-2633-B-320-001, MOST105-2311-B-320-001-MY3, MOST106-2633-B-320-001, MOST108-2311-B-320-001, and MOST109-2311-B-320-001), Buddhist Tzu Chi Medical Foundation (TCMMP104-06, TCMMP108-04, and TCMMP111-01), and Buddhist Tzu Chi General Hospital, Hualien, Taiwan (TCRD106-42, TCRD108-55, TCRD110-61, TCRD111-082, TCRD112-054, and TCRD113-055).

Conflicts of interest

Dr. Hsin-Hou Chang, an editorial board member at the Tzu Chi Medical Journal, had no role in the peer review process or the decision to publish this article. The other authors declared no conflicts of interest in writing this article.