Adult muscle-derived stem cells engraft and differentiate into insulin-expressing cells in pancreatic islets of diabetic mice

Abstract

BackgroundPancreatic beta cells are unique effectors in the control of glucose homeostasis and their deficiency results in impaired insulin production leading to severe diabetic diseases. Here, we investigated the potential of a population of nonadherent muscle-derived stem cells (MDSC) from adult mouse muscle to differentiate in vitro into beta cells when transplanted as undifferentiated stem cells in vivo to compensate for beta-cell deficiency.ResultsIn vitro, cultured MDSC spontaneously differentiated into insulin-expressing islet-like cell clusters as revealed using MDSC from transgenic mice expressing GFP or mCherry under the control of an insulin promoter. Differentiated clusters of beta-like cells co-expressed insulin with the transcription factors Pdx1, Nkx2.2, Nkx6.1, and MafA, and secreted significant levels of insulin in response to glucose challenges. In vivo, undifferentiated MDSC injected into streptozotocin (STZ)-treated mice engrafted within 48 h specifically to damaged pancreatic islets and were shown to differentiate and express insulin 10–12 days after injection. In addition, injection of MDSC into hyperglycemic diabetic mice reduced their blood glucose levels for 2–4 weeks.ConclusionThese data show that MDSC are capable of differentiating into mature pancreatic beta islet-like cells, not only upon culture in vitro, but also in vivo after systemic injection in STZ-induced diabetic mouse models. Being nonteratogenic, MDSC can be used directly by systemic injection, and this potential reveals a promising alternative avenue in stem cell-based treatment of beta-cell deficiencies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0539-9) contains supplementary material, which is available to authorized users.

Islet-like clusters derived from skeletal muscle-derived stem/progenitor cells for autologous transplantation to control type 1 diabetes in mice

“…A number of studies reported that MSCs isolated from various sources, such as bone marrow [12,27], fat tissue [12,28], umbilical cord [13] and liver [29], could differentiate into insulin-producing cells. Recently, Mitutsova et al have shown that MDSPCs from mouse muscle can differentiate into pancreatic islet-like cells in vitro and in vivo [30]. In this study, we confirmed the potential of MDSPCs to form insulin-producing islet-like clusters in vitro and investigated the therapeutic potential of autologous transplantation with islet-like clusters on an STZ-induced diabetic mouse model.…”

“…The skeletal muscle tissues are known to present the stem/progenitor cells. Different populations of stem cells or progenitor cells derived from skeletal muscles have been shown and isolated based on their adhesion characteristic by pre-plating technique [14,19,30,34]. Previously, we have isolated the murine and human skeletal muscle-derived cells from the early pre-plate populations that possess satellite cell characteristics and cultured for myogenic differentiation [35].…”

“…Mitutsova et al [30] have shown that allogeneic transplantation of undifferentiated MDSPCs (pre-plating process, pp8) from adult mouse muscle by intraperitoneal injection reduced hyperglycaemia in an immunodeficient mouse STZ-induced diabetic model (STZ-treated NOD-scid mice) for 2-4 weeks. In the present study, we designed the method for autologous islet (islet-like cell clusters) transplantation to treat diabetes in a mouse model.…”

The role and therapeutic potential of stem cells in skeletal muscle in sarcopenia

“…They can be expanded in vitro for up to 30 passages while maintaining myogenic potential. Mitutsova et al [ 27 ] revealed that MDSCs could combat diabetes arising from pancreatic beta cell deficiency by investigating the effects of MDSCs on diabetic mouse models. The high survival rate and superior chondrogenic differentiation capacity of these cells make MDSCs plausible candidates for articular cartilage repair [ 20 ].…”

Advances and complications of regenerative medicine in diabetes therapy

“…Thus, various research groups have suggested proliferating ASCs in vitro (Gurusamy et al, 2018). Mitutsova et al (2017) have shown, that non-adherent muscle-derived adult stem cells (MDSCs) have the potential to differentiate into beta-cells during in vitro culturing. In their experiment a multipotent stem cell population isolated from adult skeletal muscle was able to form islet-like cell clusters.…”