. 2021 Nov 15;13(11):12217–12227.

Table 1.

Characteristics, results, comments and outcomes of studies included in this review

No.	First author & Year of publication	Type of Metabolic Syndrome Cluster	Animal model & sample size (per group)	Type of Stem Cell, Dosage & Delivery Method	Parameters Observed	Results	Comments and Outcomes
1.	Lee Y. (2019) [1]	T2DM	BALB/c mice:	TMSCs	BW, IPGTT, Histology, Immunofluorescence, RT-PCR and ELISA (INS, CHOL, TGL).	After 10 weeks, treated mice reported,	TMCS successfully improved HFD-induced GLUC intolerance by enhancing INS secretion.
			▪ Male	▪ 2×10⁶ cells/mouse		▪ BW (↓)
			▪ 8 weeks old	▪ Once every 2 weeks for 10 weeks		▪ IPGTT (↑)
			▪ n=10	▪ IP injection		▪ INS (-)
2.	Cao M. (2015) [2]	T1DM	Nude mice:	Undifferentiated hFTM-PV or differentiated (EB-LCA and ILC)	BW, GLUC, INS and Mortality rate.	After 9 weeks, treated mice reported,	Transplantation of undifferentiated and differentiated (EB-LCA and ILCS) cells of hFTM-PV alleviated STZ-induced diabetes in mice.
			▪ Male	▪ Dosage not reported		▪ INS (↑)
			▪ 4-6 weeks old	▪ IP injection
			▪ n=8-16	▪ IP injection
3.	Villani V. (2014) [5]	T1DM	NOD/SCID mice:	AFSC	GLUC, INS, IHC, H&E, RT-PCR.	After 4 weeks, treated mice reported,	Transplantation of AFSC can treat insulin-dependent diabetes by protection and stimulation of endogenous β-cell regeneration.
			▪ Male	▪ 1×10⁶ cells/mouse		▪ GLUC (↓)
			▪ 4-6 weeks old	▪ Intracardiac injection		▪ INS (↑)
			▪ n=5-13	▪ Intracardiac injection		▪ INS (↑)
4.	Xiao N. (2013) [6]	T1DM	C57/BL6 mice:	UC-MSC and CB-MNCs	GLUC, H&E, IHC, PCR (human Alu).	After 5 weeks, treated mice with ratio 1:4 reported,	Co-transplantation of UC-MSC and CB-MNCs successfully reversed hyperglycaemia and effectively recovered pancreatic function in diabetic mice.
			▪ Female	▪ three groups (ratio of 1:1, 1:4 & 1:10)		▪ GLUC (↓)
			▪ 6-8 weeks old	▪ 1×10⁶ cells/mouse		▪ Pancreatic islets (↑)
			▪ n=8-10	▪ IV injection		▪ Pancreatic islets (↑)
5.	Bhansali S. (2015) [9]	T1DM	Wistar rats:	BM-MSC	BW, GLUC, IPGTT, H&E and IHC.	After 6 weeks, BrdU-labelled BM-MSCs confirmed localization in pancreas and treated rats reported,	Transplantation of BM-MSC corrected hyperglycaemia and stimulated pancreatic β-cell neogenesis.
			▪ Male	▪ 4.8×10⁶ cells/rat		▪ GLUC (↓)
			▪ n=6	▪ IV injection		▪ INS (↑)
			▪ n=6	▪ IV injection		▪ Pancreatic islets (↑)
6.	Kadam S. (2010) [10]	T1DM	BALB/C mice:	PD-MSC	BW, GLUC, IPGTT, INS and H&E.	After 15 days, treated mice showed,	Transplantation of undifferentiated PD-MSCs reversed STZ-induced hyperglycaemia and increased secretion of insulin by islets.
			▪ Male	▪ 1.5×10⁵ cells/mouse		▪ GLUC (↓)
			▪ 6-8 weeks old	▪ Intrapancreatic injection
			▪ n=5	▪ Intrapancreatic injection
7.	Zhou Y. (2015) [11]	T1DM	SD rat:	UC-MSC	BW, GLUC, INS, C-peptide, H&E, IHC, PCR, Western Blot.	After 42 days, hyperglycaemic progression halted by day 6 and treated rats reported,	Transplantation of UC-MSC exert trophic effects on β-cell survival by activating pancreatic P13K pathway and suspected to have been mediated by secreted IGF1.
			▪ Male	▪ 3×10⁶ cells/rat		▪ GLUC (↓)
			▪ 8 weeks old	▪ IV injection		▪ pAKT (↓)
			▪ n=8	▪ IV injection		▪ Pancreatic islets (↑)
8.	Maldonado M. (2017)[12]	T1DM	Kunming mice:	UCWJC	GLUC, C-peptide, IHC, Immunofluorescence, RT-PCR, Urine Assay.	After 11 weeks, UCWJC migrated to damaged organs and treated mice reported,	Transplantation of UCWJC normalized hyperglycaemia levels, promoted secretion of insulin from extrapancreatic cells and improved renal function.
			▪ Male	▪ 1×10⁷ cells/mouse		▪ GLUC (↓)
			▪ 10 weeks old	▪ IP injection		▪ C-peptide (↑)
			▪ n=10	▪ IP injection		▪ C-peptide (↑)
9.	Sun X. (2017) [13]	T2DM	SD rats:	UC-MSC	GLUC, INS, IPGTT, C-peptide, RT-PCR, Western Blot.	After 35 days, treated rats reported,	Transplantation of UC-MSC in diabetic rats inhibited NLRP3 inflammasome activation and decreased inflammatory cytokines, thus relieving insulin resistance of T2DM.
			▪ Male	▪ 3×10⁶ cells/rat		▪ GLUC (↓)
			▪ 8 weeks old	▪ IV injection		▪ INS (↓)
			▪ n=8	▪ IV injection		▪ IPGTT (↑)
10.	Murai N. (2017) [14]	T1DM	C57/BL6 mice:	BM-MSC	BW, GLUC, INS, Immunofluorescence, H&E, IHC.	After 28 days, intrapancreatic injection treated mice reported,	Transplantation of BM-MSC through intrapancreatic route reversed hyperglycaemia and restored BW. BM-MSC was absent in pancreas after 1 month, but effectively improved plasma INS levels and islet morphohistology.
			▪ Male	▪ 1×10⁶ cells/mouse		▪ GLUC (↓)
			▪ 7-9 weeks old	▪ Intrapancreatic or IV injection		▪ BW (↑)
			▪ n=11-14	▪ Intrapancreatic or IV injection		Meanwhile, IV injection did not present any significant changes.
11.	El-Hossary N. (2016) [15]	T1DM	Albino rats:	UC-MSC	BW, GLUC, H&E, Pancreatic Islet Measurement.	After 8 weeks, IV injection treated rats reported,	Transplantation of UC-MSC by IV route supported β-cell differentiation and proliferation in the pancreas, which alleviated hyperglycaemia and reduced further deterioration of the β-cell islets pathology.
			▪ Male	▪ 2×10⁶ cells/rat		▪ GLUC (↓)
			▪ 6-8 weeks old	▪ IP or IV injection		▪ BW (↑)
			▪ n=5-8			▪ Pancreatic islets (↑)
			▪ n=5-8			These changes were not observed in the IP injected rats.
12.	Yaochite JNU. (2016) [16]	T1DM	C57/BL6 mice:	T1DM derived BM-MSC and healthy BM-MSC	GLUC, INS, IPGTT, H&E, IHC, Cytokine level.	After 35 days, T1DM derived BM-MSC treated mice reported,	Transplantation of T1DM derived BM-MSC successfully reversed hyperglycaemia, improved β-cell mass, increased INS production and modulated pancreatic cytokine production.
			▪ Male	▪ 1×10⁶ cells/mouse		▪ GLUC (↓)
			▪ 10 weeks old	▪ intrasplenic injection		However, both groups
			▪ n=24			▪ INS (↑)
			▪ n=24			▪ Pancreatic islets (↑)
13.	Lee RH. (2006) [17]	T1DM	NOD/SCID mice:	BM-MSC	GLUC, INS, H&E, IHC, RT-PCR, Urine assay.	After 32 days, treated mice reported,	Transplantation of BM-MSC selectively home to β-cell islets and renal glomeruli of diabetic mice and had repairs tissues to restore physiological conditions and functions.
			▪ Male	▪ 2.5×10⁶ cells/mouse		▪ GLUC (↓)
			▪ 7-8 weeks old	▪ intracardial injection		▪ Urine volume (↓)
			▪ n=6-9			▪ BW (--)
						▪ INS (↑)
						▪ Pancreatic islets (↑)
14.	Lee H. (2017) [18]	PAH	SD rats:	UCB-MSC	Haemodynamics, BW, Organ weight, H&E, Wall thickness, Western Blot.	After 4 weeks, low-dose UC-MSCs was as competent as the high-dose in treated rats and reported,	Transplantation of low-dose and earlier treatment was as effective as high-dose UC-MSC in improving symptoms of PAH. Despite that, the dual or reversal treatment remains more effective as treatment for PAH.
			▪ Male	▪ High-dose: 3×10⁶ cells/rat		▪ Mean RV pressure (↓)
			▪ 6 weeks old	▪ Mid-dose: 1.5×10⁶ cells/rat		▪ Pulmonary pathology (↑)
			▪ n=5-6	▪ Low-dose: 3×10⁵ cells/rat		▪ Heart collagen-3 protein (↓)
			▪ n=5-6	▪ IV injection		▪ Heart collagen-3 protein (↓)
15.	Van Linthout S. (2017) [19]	Diabetic cardiomyopathy	SD rats:	PD-MSC	GLUC, IHC, Gene expression, Western Blot, Vascularization & Endothelial function.	After 13 days, treated rats reported high concentration of PD-MSC that was found in the LV pressure, lungs, kidney, pancreas and partially found in spleen. PD-MSC improved,	Transplantation of PD-MSC alleviated early symptoms of diabetic cardiomyopathy as seen by improved LV diastolic relaxation and relieved cardiomyocyte stiffness by increasing titin phosphorylation.
			▪ Male	▪ 1×10⁶ cells/rat		▪ vascularization (↑)
			▪ 8-9 weeks old	▪ IV injection		▪ cardiac inflammation (↓)
			▪ n=5-7			▪ endothelial function (↑)
			▪ n=5-7			▪ regulatory T-cells (↑)
16.	Zhang L. (2013) [20]	DN	SD rats:	ASC	BW, GLUC, CHOL, ALB, TGL, Urine analysis, H&E, IHC, Western Blot, RT-PCR.	After 32 weeks, treated rats reported,	Transplantation of repeated, systemic administration of ASC attenuated hyperglycaemia. Secretion of GDNF by ASCs may play an important role in amelioration of diabetic podocyte injury.
			▪ Male	▪ 5×10⁶ cells/rat		▪ ALB (↑)
			▪ 2 months old	▪ Once every 4 weeks for 32 weeks		▪ TGL (↑)
			▪ n=8-11	▪ IV injection		▪ CHOL (↓)
						▪ urinary protein excretion (↓)
						▪ Renal hypertrophy (↓)
17.	Lee H. (2015) [21]	PAH	SD rats:	UC-MSC	Organ weight, RV Pressure, Immunofluorescence, H&E, Western Blot, IHC, Cytokine and Gene expression.	After 3 weeks, treated rats reported,	Transplantation of UC-MSC alleviated symptoms of PAH as seen by the decreased pulmonary arteriole thickening and gene expression. This success may prove advantageous over chemical drugs for treatment of PAH.
			▪ Male	▪ 3×10⁶ cells/rat		▪ RV pressure (↑)
			▪ 6 weeks old	▪ IV injection		▪ Cardiac hypertrophy (↓)
			▪ n=16-24	▪ IV injection		▪ Expression of proteins and immunomodulatory metabolites (↓)
18.	Wu X. (2014) [22]	T1DM	BALB/c mice:	MBPC	BW, GLUC, INS, C-peptide, IPGTT, H&E, IHC, Immunofluorescence, RT-PCR.	After 42 days, treated mice reported,	Transplantation of MBPC efficiently reversed hyperglycaemia and restored islet structures. The MBPCs could stimulate β-cell regeneration and promote endogenous progenitor cell differentiation into β-cells. MBPC is easily isolated in a non-invasive manner.
			▪ Male	▪ 3×10⁵ cells/mouse		▪ BW (↑)
			▪ 8 weeks old	▪ IV injection		▪ GLUC (↓)
			▪ Sample size not reported			▪ Pancreatic Islets (↑)
			▪ Sample size not reported			▪ β-cell numbers (↑)

Symbols: (↑) = increase; (↓) = decrease; (--) = no changes. Abbreviations: T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus; PAH, Pulmonary artery hypertension; DN, Diabetic nephropathy; TMSC, Tonsil-derived mesenchymal stromal cells; EB, Embryoid body; ILC, Islet-like clusters; UC-MSC, Umbilical cord-derived mesenchymal stromal cells; UC-WJC, Umbilical cord Wharton’s Jelly Cells; UCB-MSC, umbilical cord blood-derived mesenchymal stromal cells; PD-MSC, placenta-derived mesenchymal stromal cells; CB-MNC, Cord blood mononuclear cells; MBPC, Menstrual blood progenitor cells; BM-MSC, Bone marrow mesenchymal stromal cells; ASC, Adipose-derived stem cells; BrdU, bromodeoxyuridine; SD, Sprague Dawley; STZ, streptozocin; MCT, Monocrotaline; HFD, high fat diet; NX, nephrectomy; NPH, neutral protamine Hagedorn; IP, intraperitoneal; IV, intravenous; BW, Body weight; GLUC, Glucose; INS, insulin; CHOL, cholesterol; TGL, triglyceride; ALB, Albumin; IPGTT, intraperitoneal glucose tolerance test; RT-PCR, Reverse transcription polymerase chain reaction; ELISA, Enzyme-linked immunosorbent assay; H&E, haemotoxylin-eosin; IHC, immunohistochemistry; RV, right ventricular; LV, left ventricular; GDNF, glial cell line-derived neurotrophic factor.