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Comparative Analysis of the Therapeutic Effects of Amniotic Membrane and Umbilical Cord Derived Mesenchymal Stem Cells for the Treatment of Type 2 Diabetes.

ABSTRACT: Type 2 diabetes mellitus (T2DM), one of the most common carbohydrate metabolism disorders, is characterized by chronic hyperglycemia and insulin resistance (IR), and has become an urgent global health challenge. Mesenchymal stem cells (MSCs) originating from perinatal tissues such as umbilical cord (UC) and amniotic membrane (AM) serve as ideal candidates for the treatment of T2DM due to their great advantages in terms of abundant source, proliferation capacity, immunomodulation and plasticity for insulin-producing cell differentiation. However, the optimally perinatal MSC source to treat T2DM remains elusive. This study aims to compare the therapeutic efficacy of MSCs derived from AM and UC (AMMSCs and UCMSCs) of the same donor in the alleviation of T2DM symptoms and explore the underlying mechanisms. Our results showed that AMMSCs and UCMSCs displayed indistinguishable immunophenotype and multi-lineage differentiation potential, but UCMSCs had a much higher expansion capacity than AMMSCs. Moreover, we uncovered that single-dose intravenous injection of either AMMSCs or UCMSCs could comparably reduce hyperglycemia and improve IR in T2DM db/db mice. Mechanistic investigations revealed that either AMMSC or UCMSC infusion could greatly improve glycolipid metabolism in the liver of db/db mice, which was evidenced by decreased liver to body weight ratio, reduced lipid accumulation, upregulated glycogen synthesis, and increased Akt phosphorylation. Taken together, these data indicate that the same donor-derived AMMSCs and UCMSCs possessed comparable effects and shared a similar hepatoprotective mechanism on the alleviation of T2DM symptoms.

SUBMITTER: Wang Z

PROVIDER: S-EPMC8749914 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMesenchymal stem cells (MSCs) have emerged as a promising regenerative tool, owing mainly to their multi-differentiation potential and immunosuppressive capacity. When compared with MSCs classically derived from the adult bone marrow (BM), MSCs of neonatal origins exhibit superior proliferation ability, lower immunogenicity, and possible lower incorporated mutation; hence, they are considered as an alternative source for clinical use. Several researches have focused on the biological differences among some neonatal MSCs cultured in serum-containing medium (SCM). However, since it has been reported that MSCs possess different biological characteristics when cultured in serum-free medium (SFM), these comparative studies in SCM cannot exactly represent the results under the serum-free Good Manufacturing Practice (GMP) standard.MethodsHere, MSCs were isolated from three neonatal tissues, namely amniotic membrane (AM), umbilical cord (UC), and chorionic plate (CP), from the same donor, and their morphologies, immunophenotypes, trilineage differentiation potentials, global gene expression patterns, and proliferation abilities were systematically compared under chemical-defined SFM.ResultsOur study demonstrated that these three neonatal MSCs exhibited a similar morphology and immunophenotypic pattern but various mesodermal differentiation potentials under SFM: amniotic membrane-derived MSCs showed a higher rate for osteogenic differentiation; chorionic plate-derived MSCs presented better adipogenic induction efficiency; and all these three neonatal MSCs exhibited similar chondrogenic potential. Moreover, by the analysis of global gene expression patterns, we speculated a possible higher proliferation ability of CP-MSCs in SFM, and we subsequently validated this conjecture.ConclusionsCollectively, these results suggest that MSCs of different neonatal origins possess different biological features in SFM and thus may represent an optimal choice for different clinical applications.

Project description:Mesenchymal stem cell (MSC) therapy is an innovative approach in diabetes due to its capacity to modulate tissue microenvironment and regeneration of glucose-responsive insulin-producing cells. In this study, we investigated the role of MSC-derived exosomes in pancreatic regeneration and insulin secretion in mice with streptozotocin-induced diabetes. Mesenchymal stem cells (MSCs) were isolated and characterized from umbilical cord blood (UCB). Exosomes were isolated and characterized from these MSCs. Diabetes was induced in male C57Bl/6 mice by streptozotocin (STZ; 40 mg/kg body weight, i.p.) for five consecutive days. The diabetic mice were administered (i.v.) with MSC (1 × 105 umbilical cord blood MSC cells/mice/day), their derived exosomes (the MSC-Exo group that received exosomes derived from 1 × 105 MSC cells/mice/day), or the same volume of PBS. Before administration, the potency of MSCs and their exosomes was evaluated in vitro by T cell activation experiments. After day 7 of the treatments, blood samples and pancreatic tissues were collected. Histochemistry was performed to check cellular architecture and β cell regeneration. In body weight, blood glucose level, and insulin level, cell proliferation assay was done to confirm regeneration of cells after MSC and MSC-Exo treatments. Hyperglycemia was also attenuated in these mice with a concomitant increase in insulin production and an improved histological structure compared to mice in the PBS-treated group. We found increased expression of genes associated with tissue regeneration pathways, including Reg2, Reg3, and Amy2b in the pancreatic tissue of mice treated with MSC or MSC-Exo relative to PBS-treated mice. MicroRNA profiling of MSC-derived exosomes showed the presence of miRs that may facilitate pancreatic regeneration by regulating the Extl3-Reg-cyclinD1 pathway. These results demonstrate a potential therapeutic role of umbilical cord blood MSC-derived exosomes in attenuating insulin deficiency by activating pancreatic islets' regenerative abilities.

Project description:BackgroundStem cell therapy provides great hope for patients with diabetes mellitus (DM). DM is a seriously alarming metabolic disease characterized by hyperglycemia and β cell dysfunction. Efficient novel therapeutic modalities to treat DM are indeed warranted. Stem cells (SC) derived from the umbilical cord specifically provide several advantages and unique characteristics being a readily available non-invasive source, with an additional credit for their banking potential. This meta-analysis study aims to provide a focused assessment for therapeutic efficacy of umbilical cord (UC)-derived SC-transplantation, namely Wharton's jelly mesenchymal stem cells (WJ-MSCs) and umbilical cord blood (UCB) for DM.MethodsThe clinical efficacy was evaluated based on glycemic control status (reflected on HbA1c%) and β cell function (reflected on C-peptide levels), as well as the daily insulin requirement in diabetic patients after receiving UC-derived SC-transplantation compared to baseline values. Moreover, we assessed these outcome measures in patients who received such intervention compared to those who did not receive it in randomized/non-randomized controlled clinical trials. We employed a random-effects model and standardized mean difference for this meta-analysis.ResultsEleven eligible clinical studies were included; WJ-MSCs (6 studies; 172 patients including 71 controls) and UCB (5 studies; 74 patients including 15 controls). WJ-MSCs significantly improved HbA1c% (pooled-estimate - 1.085; 95%CI (- 1.513, - 0.657); p < 0.001) and C-peptide levels (pooled-estimate 1.008; 95%CI (0.475, 1.541); p < 0.001), as well as the daily insulin-requirement (pooled-estimate - 2.027; 95%CI (- 3.32, - 0.733); p = 0.002). On the contrary, UCB was found to be uniformly ineffective; HbA1c% (pooled-estimate - 0.091, 95%CI (- 0.454, 0.271); p = 0.622), significantly deteriorated C-peptide levels (pooled-estimate - 0.789; 95%CI (- 1.252, - 0.325); p < 0.001) and daily insulin-requirement (pooled-estimate 0.916; 95%CI (0.247, 1.585); p = 0.007). All these observations remained consistent when we carried out sub-group meta-analysis for T1DM and T2DM and also when we compared patients who received WJ-MSCs or UCB to controls.ConclusionsThe results of our meta-analysis provide a clear evidence for the superior efficacy of WJ-MSCs over UCB in DM. This sheds lights on the importance to consider banking of WJ-MSCs together with the well-established routine UCB-banking, especially for those with family history of DM. Additionally, further clinical studies are required to investigate therapeutic efficacy of selected/enriched UCB-derived cell populations with immunomodulatory/regenerative potential in DM.

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Comparative Analysis of the Therapeutic Effects of Amniotic Membrane and Umbilical Cord Derived Mesenchymal Stem Cells for the Treatment of Type 2 Diabetes.

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