Mesenchymal Stem Cells as Therapeutic Candidates for Halting the Progression of Diabetic Nephropathy

Table 1

Preclinical studies in rodents to test the potential of MSCs in DN.

MSC isolation/type of transplant	Model of DN and groups	Number of injections/route of delivery	Number of cells injected	Results	Reference
h-BM-MSCs,; xenotransplant	STZ-induced type 1 NOD/scid mice: normal, DN, DN + hMSC	Single dose,; intracardiac	2.5 × 10^6	DN + hMSC versus DN: ↑ pancreatic insulin content and islet cell number; ↓ renal macrophage infiltration; Improvement in renal histology	[45]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes C57BL/6 mice: DN + vehicle and DN + MSC	Single dose,; IV	0.5 × 10^6	DN + MSCs versus DN: ↓ blood glucose levels; ↓ albuminuria and glycosuria; Improvement in renal and -cell histology	[46]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes C57BL/6 mice: Control, DN + vehicle, DN + MSC	Two doses (interval of 20 days),; IV	0.5 × 10^6	DN + MSCs versus DN: ↓ albuminuria; Improvement in renal histology; No improvement in -cell function and histology	[47]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes Sprague-Dawley Rats: DN control, MSC, CSA, MSC + CSA (MSCA)	single dose, intracardiac	2 × 10^6	MSCA group versus DN: ↓ blood glucose levels; ↓ albuminuria; Improvement in renal mass index	[48]
ADMSCs, autologous	STZ-induced type 1 diabetes Sprague-Dawley Rats: Control non-diabetic, DN + vehicle, ADMSC + DN	Single dose,; IV	1 × 10^7	DN + ADMSCs versus vehicle: ↓ renal p-p-38, p-ERK and p-JNK; ↓ renal MDA and carbonyl protein; ↓ renal TNF-, IL-1, IL-6; ↓ renal MnSOD and CuZn-SOD	[49]
h-UCB-SCs, xenotransplant	STZ-induced type 1 diabetes Sprague-Dawley Rats: control, DN, DN + h-UCB-SC	Single dose,; IV	1 × 10^6	DN + h-UCB-SCs versus DN: ↓ blood glucose levels; ↓ albuminuria; ↓ renal fibronectin, -SMA; ↑ renal E-cadherin	[50]
h-UCB-SCs, xenotransplant	STZ-induced type 1 diabetes Sprague-Dawley Rats: control, DN, DN + h-UCB-SC	Single dose,; IV	5 × 10^5	DN + h-UCB-SCs versus DN: ↔ blood glucose levels; ↔ albuminuria; Improvement in renal histology; ↓ renal TGF-β1, -SMA; ↑ renal E-cadherin, BMP-7	[51]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes Sprague-Dawley Rats: Normal control, DN + MSC and DN + medium	Single dose, left renal artery	2 × 10^6	DN + MSCs versus DN + medium: ↔ blood glucose levels; ↓ kidney weight, kidney/body weight, creatinine clearance; ↓ albuminuria; Improvement in renal histology; ↑ renal nephrin, podocin, VEGF, BMP-7	[52]
BM-MSCs, allogeneic, UTDM	STZ-induced type 1 diabetes Sprague-Dawley Rats: Normal control, DN + PBS, DN + UTMD, DN + MSC, DN + MSC + UTMD	Single dose,; IV	1 × 10^6	MSC and MSC + UTMD versus DN and UTMD: ↓ blood glucose levels; ↑ plasma insulin; Attenuated β-cell damage; ↓ albuminuria; ↓ renal TGF-β1; ↑ renal synaptopodin, IL-10; After UTMD: MSC homing was increased to kidneys (~2x)	[53]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes Wistar Rats: Normal control, DN + vehicle, DN + MSC	2 doses; (1 week a part),; IV	2 × 10^6	DN + MSCs versus DN: ↓ blood glucose levels; ↓ albuminuria; ↓ creatinine clearance; Improvement in renal histology; ↓ renal MCP-1, ED-1, IL-1, IL-6, TNF-; ↑ renal HGF	[54]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes Wistar rats: DN, DN + MSC, DN + Insulin, DN + Probucol	2 doses; (1 week a part),; IV	2 × 10^6	DN + MSCs versus DN: ↓ blood glucose levels; ↓ albuminuria; ↓ creatinine clearance; ↓ kidney/body weight; Improvement in renal histology; ↓ renal fibronectin and collagen I; ↓ renal MDA content; ↓ renal TGF-β1; ↓ renal ROS fluorescence; ↑ renal SOD activity; ↓ cellular glucose uptake mediated by GLUT1 in kidneys	[55]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes albino rats: Control, DN, DN + PBS, DN + MSC	Single dose,; IV	1 × 10^6	DN + MSCs versus DN: ↓ blood glucose levels; ↓ albuminuria; ↓ body weight; ↓ serum creatinine and urea; ↑ renal VEGF and anti-apoptotic bcl2; ↓ renal TNF-α, pro-apoptotic Bax, TGF-; Improvement in renal histology	[56]
BM-MSCs, allogeneic	Normal control, DN + saline, DN + MSC	2 doses; (1 week a part),; IV	2 × 10^6	DN + MSCs versus DN: ↓ blood glucose levels; ↓ albuminuria; ↓ kidney/body weight; ↓ creatinine clearance; Improvement in renal histology; ↓ renal collagen I, collagen IV, -SMA, TGF-, P-smad3/smad2/3; ↑ renal E-cadherin, BMP7	[57]
BM-MSCs, allogeneic; SDF-1-loaded microbubbles	STZ-induced type 1 diabetes Sprague-Dawley Rats: Control, UTMD, UTMD + MSC	Single dose,; IV	1 × 10^6	Improvement in renal histology	[58]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes C57BL/6 mice: DN + vehicle, DN + MSC	Single dose,; IV	0.5 × 10^6	DN + MSCs versus DN: ↓ 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	[59]
BM-MSCs, allogeneic	STZ-induced type 1 diabetes Sprague-Dawley rats: control, DN, DN + MSC	Single dose,; IV	2 × 10^6	MSCs + DN versus DN: ↔ blood glucose levels; ↓ albuminuria; ↓ kidney weight; ↓ serum creatinine; ↓ renal PAI-1, TGF-1, Smad3	[60]

MSCs: mesenchymal stem cells; BM-MSC: bone marrow-derived MSCs; h-BM-MSC: human bone marrow-derived MSC; ADMSC: adipose-derived MSCs; h-UCB-SCs: human umbilical cord blood-derived stem cells; DN: diabetic nephropathy; STZ: streptozotocin; CSA: cyclosporine; PBS: phosphate buffered saline; IV: intravenous; -SMA: -smooth muscle actin; bFGF: basic fibroblast growth factor; BMP-7: bone morphogenic protein-7; EGF: epidermal growth factor; HGF: hepatocyte growth factor; MCP-1: monocyte chemoattractant protein-1; SDF-1: stromal derived factor-1; TGF-: transforming growth factor ; TNF-α: tumor necrosis factor-α; VEGF: vascular endothelial growth factor; IL: interleukin; SOD: superoxide dismutase; MDA: malondialdehyde; ROS: reactive oxygen species; UTMD: ultrasound-targeted microbubble destruction; PAI-1: plasminogen activator inhibitor-1.