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Diabetes mellitus (DM) is an alarming metabolic disease in which insulin secreting β-cells are damaged to various extent. Unfortunately, although currently available treatments help to manage the disease, however, patients usually develop complications, as well as decreased life quality and increased mortality. Thus, efficient therapeutic interventions to treat diabetes are urgently warranted. During the past years, mesenchymal stem cells (MSCs) have made their mark as a potential weapon in various regenerative medicine applications. The main fascination about MSCs lies in their potential to exert reparative effects on an amazingly wide spectrum of tissue injury. This is further reinforced by their ease of isolation and large ex vivo expansion capacity, as well as demonstrated multipotency and immunomodulatory activities. Among all the sources of MSCs, those isolated from umbilical cord-Wharton's jelly (WJ-MSCs), have been proved to provide a great source of MSCs. WJ-MSCs do not impose any ethical concerns as those which exist regarding ESCs, and represent a readily available non-invasive source, and hence suggested to become the new gold standard for MSC-based therapies. In the current review, we shall overview achievements, as well as challenges/hurdles which are standing in the way to utilize WJ-MSCs as a novel efficient therapeutic modality for DM.

BackgroundDiabetes mellitus is a devastating metabolic disease. Generation of insulin-producing cells (IPCs) from stem cells, especially from Wharton’s jelly mesenchymal stem cells (WJ-MSCs), has sparked much interest recently. Exendin-4 has several beneficial effects on MSCs and β cells. However, its effects on generation of IPCs from WJ-MSCs specifically have not been studied adequately. The purpose of this study was therefore to investigate how exendin-4 could affect the differentiation outcome of WJ-MSCs into IPCs, and to investigate the role played by exendin-4 in this differentiation process.MethodsWJ-MSCs were isolated, characterized and then induced to differentiate into IPCs using two differentiation protocols: protocol A, without exendin-4; and protocol B, with exendin-4. Differentiated IPCs were assessed by the expression of various β-cell-related markers using quantitative RT-PCR, and functionally by measuring glucose-stimulated insulin secretion.ResultsThe differentiation protocol B incorporating exendin-4 significantly boosted the expression levels of β-cell-related genes Pdx-1, Nkx2.2, Isl-1 and MafA. Moreover, IPCs generated by protocol B showed much better response to variable glucose concentrations as compared with those derived from protocol A, which totally lacked such response. Furthermore, exendin-4 alone induced early differentiation markers such as Pdx-1 and Nkx2.2 but not Isl-1, besides inducing late markers such as MafA. In addition, exendin-4 showed a synergistic effect with nicotinamide and β-mercaptoethanol in the induction of these markers.ConclusionsExendin-4 profoundly improves the differentiation outcome of WJ-MSCs into IPCs, possibly through the ability to induce the expression of β-cell markers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0374-4) contains supplementary material, which is available to authorized users.

Background Stem 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. Methods The 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. Results Eleven 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. Conclusions The 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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