Table 1.

Preclinical studies in small and large animals to verify the therapeutic potential of MSCs in DKD.

MSC type	MSC source	Model of DKD and groups	Number of injections/route of delivery	Number of cells injected	Results	Ref
Xenogeneic	h-BM	STZ-induced DM1 in NOD/scid mice: control, DKD, DKD+hMSC	Single dose, intracardiac	2.5 × 106	DKD+hMSC versus DKD: ↑ Pancreatic insulin content and islet cell number ↓ Renal macrophage infiltration Improvement in renal histology	[98]
Syngeneic	BM	STZ-induced DM1 in C57BL/6 mice: DKD+vehicle and DKD+MSC	Single dose, IV	0.5 × 106	DKD+MSCs versus DKD: ↓ FBG ↓ Albuminuria and glycosuria Improvement in renal and β-cell histology	[99]
Syngeneic	BM	STZ-induced DM1 in C57BL/6 mice: control, DKD+vehicle, DKD+MSC	Two doses (20 days apart), IV	0.5 × 106	DKD+MSCs versus DKD: ↓ Albuminuria Improvement in renal histology No improvement in β-cell function and histology	[100]
Syngeneic	BM	STZ-induced DM1 in Sprague-Dawley rats: DKD, DKD+MSC, DKD+CSA, DKD+MSC+CSA (MSCA)	Single dose, intracardiac	2 × 106	MSCA group versus DKD: ↓ FBG ↓ Albuminuria Improvement in renal mass index	[101]
Autologous	AT	STZ-induced DM1 in diabetes Sprague-Dawley rats: control, DKD+vehicle, DKD+AT-MSC	Single dose, IV	1 × 107	DKD+AT-MSCs versus DKD: ↓ Renal p-p-38, p-ERK, and p-JNK ↓ Renal MDA and carbonyl protein ↓ Renal TNF-α, IL-1β, IL-6 ↓ Renal MnSOD and CuZn-SOD	[102]
Xenogeneic	h-UCB	STZ-induced DM1 in Sprague-Dawley rats: control, DKD, DKD+h-UCB-SC	Single dose, IV	1 × 106	DKD+h-UCB-SCs versus DKD: ↓ FBG ↓ Albuminuria ↓ Renal fibronectin, α-SMA ↑ Renal E-cadherin	[103]
Xenogeneic	h-UCB	STZ-induced DM1 in Sprague-Dawley rats: control, DKD, DKD+h-UCB-SC	Single dose, IV	5 × 105	DKD+h-UCB-SCs versus DKD: ↔ FBG ↔ Albuminuria Improvement in renal histology ↓ Renal TGF-β1, α-SMA ↑ Renal E-cadherin, BMP-7	[104]
Syngeneic	BM	STZ-induced DM1 in Sprague-Dawley rats: control, DKD+MSC, DKD+medium	Single dose, left renal artery	2 × 106	DKD+MSCs versus DKD+medium: ↔ FBG ↓ Kidney weight, kidney/body weight, creatinine clearance ↓ Albuminuria Improvement in renal histology ↑ Renal nephrin, podocin, VEGF, BMP-7	[105]
Syngeneic, UTDM	BM	STZ-induced DM1 in Sprague-Dawley rats: control, DKD+vehicle, DKD+UTMD, DKD+MSC, DKD+MSC+UTMD	Single dose, IV	1 × 106	DKD+MSC and DKD+MSC+UTMD versus DKD+vehicle and DKD+UTMD: ↓ FBG ↑ Plasma insulin Attenuated β-cell damage ↓ Albuminuria ↓ Renal TGF-β1 ↑ Renal synaptopodin, IL-10 ∗After UTMD: MSC homing was increased to kidneys (~2x)	[106]
Syngeneic	BM	STZ-induced DM1 in Wistar rats: control, DKD+vehicle, DKD+MSC	2 doses (1 week apart), IV	2 × 106	DKD+MSCs versus DKD: ↓ FBG ↓ Albuminuria ↓ Creatinine clearance Improvement in renal histology ↓ Renal MCP-1, ED-1, IL-1β, IL-6, TNF-α ↑ Renal HGF	[107]
Syngeneic	BM	STZ-induced DM1 in Wistar rats: DKD, DKD+MSC, DKD+insulin, DKD+probucol	2 doses (1 week apart), IV	2 × 106	DKD+MSCs versus DKD: ↓ FBG ↓ Albuminuria ↓ Creatinine clearance ↓ Kidney/body weight Improvement in renal histology ↓ Renal fibronectin, collagen I, TGF-β1, MDA content, ROS fluorescence ↑ Renal SOD activity ↓ Cellular glucose uptake mediated by GLUT1 in kidneys	[108]
Syngeneic	BM	STZ-induced DM1 in albino rats: control, DKD, DKD+vehicle, DKD+MSC	Single dose, IV	1 × 106	DKD+MSCs versus DKD: ↓ FBG ↓ Albuminuria ↓ Body weight ↓ Serum creatinine and urea ↑ Renal VEGF and antiapoptotic bcl2 ↓ Renal TNF-α, proapoptotic Bax, TGF-β Improvement in renal histology	[109]
Syngeneic	BM	STZ-induced DM1 in Wistar rats: control, DKD+vehicle, DKD+MSC	2 doses (1 week apart), IV	2 × 106	DKD+MSCs versus DKD: ↓ FBG ↓ Albuminuria ↓ Kidney/body weight ↓ Creatinine clearance Improvement in renal histology ↓ Renal collagen I, collagen IV, α-SMA, TGF-β, P-smad3/smad2/3 ↑ Renal E-cadherin, BMP-7	[47]
Syngeneic	BM ∗SDF-1-loaded microbubbles	STZ-induced DM1 in Sprague-Dawley rats: DKD+vehicle, DKD+UTMD, DKD+UTMD+MSC-SDF-1	Single dose, IV	1 × 106	DKD+UTMD+MSC-SDF-1 versus DKD: Improvement in renal histology ↑ MSC engraftment with SDF-1 (7-fold versus control and 1.6-fold versus UTDM)	[110]
Syngeneic	BM	STZ-induced DM1 in C57BL/6 mice: DKD+vehicle, DKD+MSC	Single dose, IV	0.5 × 106	DKD+MSCs versus DKD: ↓ Kidney ↓ Kidney/body weight ↓ Serum creatinine, urea, and plasma cystatin C ↓ Renal collagen I and fibronectin ↓ Renal tubular apoptotic index, ROS total, lipid peroxidation, oxidative protein damage, F4/80-positive cells ↑ Renal nephrin, tubular Ki67 proliferation index ↑ Plasma bFGF, EGF, HGF, IL-6, and IL-10 Improvement in renal histology	[111]
Syngeneic	AT	STZ-induced DM1 in Sprague-Dawley rats: control, DKD, DKD+vehicle, DKD+MSC	Single dose, IV	1 × 107	DKD+MSCs versus DKD: Improvement in renal histology ↓ Kidney apoptosis (TUNEL, ↓ Bax and ↑ Bcl2), expression of Wnt1, Wnt3a, Snail, active β-catenin ↑ Renal klotho	[49]
Syngeneic	BM	STZ-induced DM1 in Sprague-Dawley rats: control, DKD, DKD+MSC	Single dose, IV	2 × 106	DKD+MSC versus DKD: ↔ FBG ↓ Albuminuria ↓ Kidney weight ↓ Serum creatinine ↓ Renal PAI-1, TGF-β1, Smad3	[112]
Xenogeneic	h-BM (DM1 and normal individuals)	STZ-induced DM1 in C57BL/6 mice: DKD+DM1-MSC, DKD+control MSC, DKD+vehicle	Single dose, intrasplenic	1 × 106	DKD+MSC versus DKD: ↓ FBG (~70% of mice) ↑ Serum insulin Improvement in glucose tolerance test Improvement in pancreatic inflammation (↓ IL-2 and INF-γ) and β-cell function	[113]
Xenogeneic (Lewis and SD-Tg rats -> C57BL/6J and C57BL/6-Tg mice)	BM	STZ-induced DM1 and HFD-induced DM2 in C57BL/6J and C57BL/6-Tg mice: Control, STZ+vehicle, STZ+MSC, STZ+MSC-CM Control, HFD+vehicle, HFD+MSC, HFD+MSC-CM	STZ model: 2 doses (4 weeks apart) HFD model: 4 doses (2 weeks apart) IV	1 × 104 MSC/body weight	STZ model: STZ+MSC and STZ+CM-MSC versus STZ+vehicle Improvement in renal histology ↓ FBG: all groups versus control ↓ Renal TNF-α, ICAM-1, p-p38-MAPK ↑ Renal ZO-1, megalin HFD model: HFD+MSC and HFD+CM-MSC versus HFD+vehicle Improvement in renal histology ↓FBG: all groups versus control; HFD-MSC versus HFD-vehicle ↓ Renal TNF-α, ICAM-1, TGF-β ↑ Renal ZO-1, megalin	[50]
Syngeneic	BM	STZ-induced DM1 in albino Wistar rats: control, DM, DKD, DM+MSC, DKD+MSC	Single dose, IV	1 × 106	MSC-treated versus nontreated: ↓ Serum creatinine, urea, uric acid ↓FBG ↑ Serum insulin ↓ Albuminuria ↓ Serum TGF-β, FGF-2, PDGF ↔ Serum AGEs ↑ Serum HO-1 activity ↓ Renal IL-8, MCP-1	[114]
Syngeneic (from each model of diabetic and control rats)	BM+treatment with UCB extracts preinfusion	STZ-induced DM1 in Sprague-Dawley rats and C57BL/6 mice; DM2 in OLETF diabetic rats: control, STZ or OLEFT, STZ+MSC, OLEFT+MSC	Four doses (2 weeks apart), IV	1 × 104 MSC/body weight	MSC-treated versus nontreated: ↔ FBG ↔ Albuminuria ↔ Renal histology MSC+UCB extract-treated versus nontreated: ↔ FBG ↓ Albuminuria Improvement in renal histology	[115]
Syngeneic	BM+treatment with melatonin preinfusion	STZ-induced DM1 in Wistar rats: control, DKD, DKD+MSC, DKD+MSC+melatonin	Single dose, IV	1 × 106	DKD+MSCs versus DKD (effects intensified with melatonin): ↑ Renal SOD, Beclin-1 ↓ Renal TGF-β	[116]
Syngeneic	BM	STZ-induced DM1 in Sprague-Dawley rats: control, DKD+vehicle, DKD+MSC	Four doses (1-2 weeks apart), IV	5 × 106	DKD+MSCs versus DKD: ↑ Rat survival ↓ Serum urea ↓ Albuminuria ↓ Renal TGF-β1, fibronectin, ICAM-1, MCP-1, CD68, TNF-α, IL-6, IL-1β ↓ Serum IL-1α, IL-1β, IL-6, IFNγ Improvement in renal histology	[52]
Syngeneic	BM+transfection with miR-124a	STZ-induced DM1 in Sprague-Dawley rats: control, MSC, DKD, DKD+MSC with miR124a mimics, inhibitors, and negative control	Single dose, IV	3 × 106	DKD+MSCs versus DKD: ↔ FBG ↔ Albuminuria MSC+miR124a: ↑ Renal nephrin, podocin, CD2AP, Bcl-2 ↓ Renal TGF-β1, collagen I and III, caspase-3, Bax	[45]
Xenogeneic (human -> monkeys)	BM	STZ-induced DM1 in cynomolgus monkeys (Macaca fascicularis) treated with insulin glargine and glulisine+acute ischemia-reperfusion injury: control, DKD, DKD+MSC	Single dose; intra-arterial (suprarenal aorta)	5 × 106 cells/kg	DKD+MSCs versus DKD: ↔ Serum creatinine, urea, TNF-α, IFN-γ ↔ Albuminuria ↔ Urinary NGAL, GST-α, and TIMP-1 Improvement in renal histology (↓ necrosis)	[117]
Syngeneic	Amniotic liquid (adenovirus SIRT3 overexpression)	db/db mice: wild type, control, DKD+adenovirus control, DKD+adenovirus-SIRT3	Single dose, intraparenchymal	3 × 106	DKD versus DKD+SIRT3: ↓ Body weight ↓ FBG, serum insulin, C-peptide, glucagon, HbA1c ↓ Serum creatinine, urea ↓ Serum TNF-α, IL-6, MCP-1 ↓ Systolic blood pressure ↓ Albuminuria ↓ Kidney weight, oxidative stress, collagen I/III/IV deposition, MMP9, TGF-β Improvement in renal histology	[118]
Syngeneic	BM	STZ-induced DM1 in Sprague-Dawley rats: control, DKD+vehicle, DKD+MSC, DKD+MSC+WRW4 (1 mg/kg), DKD+LXA4 (10 mg/kg), DKD+LXA4+WRW4	Two doses (1 week apart), IV	5 × 106	DKD+MSCs versus DKD: ↑ Rat survival ↔ FBG ↓ Serum creatinine and urea ↓ Glycosuria, albuminuria ↑ Renal LXA4 ↓ Renal TGF-β1, p-SMAD2/3 ↓ Serum TNF-α, IL-6, IL-8, IFN-γ (LXA4 treatment exhibited similar findings when compared to MSC, which was abrogated by WRW4 treatment)	[48]
Allogeneic (from CAG-EGFP.SD-Tg rats)	AT	Spontaneously diabetic Torii (SDT) fatty rats (SDT.Cg-Lepfa/JttJcl)+unilateral nephrectomy: control; DKD+MSC suspension via IV route; DKD+MSC sheets transplanted directly into the kidney	Single dose, IV or cell sheets transplanted directly into the kidney	6 × 106/ml via IV route and cell sheets	DKD+cell sheets versus DKD+MSC via IV route and DKD: ↓ Albuminuria, proteinuria, and urinary L-FABP, KIM-1, IL-6 Improvement in renal histology DKD+cell sheets and DKD+MSC via IV route versus DKD: ↓ Urinary podocalyxin and TNF-α	[90]
Xenogeneic (human -> macaques)	UCB	STZ-induced DM1 in rhesus macaques+high-fat and high-salt diet (for 2 years): control; DKD; DKD+MSC	4 doses (2 weeks apart), IV	2 × 106/kg	DKD+MSCs versus DKD: ↓ FBG, insulin requirement ↓ Serum creatinine and BUN ↑ eGFR ↓ Albuminuria ↓ Renal IL-1β, IL-16, TNF-α, CTGF, SGLT2 ↑ Renal IL-6 ↓ Serum IFN-γ, TNF-α, IL-1β, IL-5, IL-12p70, IL-15, IL-16 Improvement in renal histology	[44]
Xenogeneic (human -> mice)	UCB	Unilateral nephrectomy+STZ-induced DM1 in CD1 mice	3 doses (4 weeks apart), IV	5 × 105	DKD+MSCs versus DKD: ↔ Serum glucose ↓ Serum creatinine and BUN ↓ Albuminuria ↓ Renal mRNA desmim, α-SMA, Fn1, Kim-1, NGAL, MCP-1, VCAM-1, ICAM-1, IL-1b, TNF-α, IL-6, iNOS ↑ Renal mRNA arginine 1 Improvement in renal histology	[53]

MSCs: mesenchymal stem cells; BM-MSC: bone marrow-derived MSCs; h-BM-MSC: human bone marrow-derived MSC; AT-MSC: adipose tissue-derived MSCs; h-UCB-SCs: human umbilical cord blood-derived stem cells; MSC-CM: MSC-conditioned medium; DM: diabetes mellitus; DKD: diabetic kidney disease; AGEs: advanced glycation end products; BMP-7: bone morphogenic protein-7; CSA: cyclosporine; EGF: epidermal growth factor; FBG: fasting blood glucose; bFGF: basic fibroblast growth factor; Fn1: fibronectin-1; GST-α: glutathione S-transferase-α; HFD: high-fat diet; HGF: hepatocyte growth factor; HO-1: heme-oxygenase-1; ICAM-1: intercellular adhesion molecule-1; iNOS: inducible nitric oxide synthase; IL: interleukin; IFN-γ: interferon-γ; IV: intravenous; KIM-1: kidney injury molecule-1; LETO: Long-Evans Tokushima Otsuka rats; L-FABP: liver-type fatty acid binding protein; LXA4: lipoxin A4; MDA: malondialdehyde; miR: microRNA; MCP-1: monocyte chemoattractant protein-1; MMP: matrix metalloproteinase; NGAL: neutrophil-gelatinase associated lipocalin; OLETF: Otsuka Long-Evans Tokushima Fatty diabetic rats; PAI-1: plasminogen activator inhibitor-1; PDGF: platelet-derived growth factor; ROS: reactive oxygen species; SDF-1: stromal-derived factor-1; SIRT3: sirtuin 3; SOD: superoxide dismutase; α-SMA: α-smooth muscle actin; STZ: streptozotocin; TGF-α: transforming growth factor α; TGF-β1: transforming growth factor β1; TIMP-1: tissue inhibitor metalloproteinase-1; TNF-α: tumor necrosis factor-α; UTMD: ultrasound-targeted microbubble destruction; VCAM-1: vascular cell adhesion molecule-1; VEGF: vascular endothelial growth factor; ZO-1: zonula occludens-1.