Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells

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		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		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		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		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		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		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		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		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		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		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		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		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		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		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		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		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		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		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	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		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	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		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		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		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)	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		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		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	/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	/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		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.