Insulin-Producing Cells from Adult Human Bone Marrow Mesenchymal Stem Cells Control Streptozotocin-Induced Diabetes in Nude Mice

Abstract

Harvesting, expansion and directed differentiation of human bone marrow-derived mesenchymal stem cells (BM-MSCs) could provide an autologous source of surrogate β-cells that would alleviate the limitations of availability and/or allogenic rejection following pancreatic or islet transplantation. Bone marrow cells were obtained from three adult type 2 diabetic volunteers and 3 non-diabetic donors. After 3 days in culture, adherent MSCs were expanded for 2 passages. At passage 3, differentiation was carried out in a 3-staged procedure. Cells were cultured in a glucose-rich medium containing several activation and growth factors. Cells were evaluated in-vitro by flow cytometry, immunolabelling, Rt-PCR and human insulin and c-peptide release in responses to increasing glucose concentrations. One thousand cell-clusters were inserted under the renal capsule of diabetic nude mice followed by monitoring of their diabetic status. At the end of differentiation, ~5–10% of cells were immunofluorescent for insulin, c-peptide or glucagon; insulin and c-peptide were co-expressed. Nanogold immunolabelling for electron microscopy demonstrated the presence of c-peptide in the rough endoplasmic reticulum. Insulin-producing cells (IPCs) expressed transcription factors and genes of pancreatic hormones similar to those expressed by pancreatic islets. There was a stepwise increase in human insulin and c-peptide release by IPCs in response to increasing glucose concentrations. Transplantation of IPCs into nude diabetic mice resulted in control of their diabetic status for 3 months. The sera of IPC-transplanted mice contained human insulin and c-peptide but negligible levels of mouse insulin. When the IPCs-bearing kidneys were removed, rapid return of diabetic state was noted. BM-MSCs from diabetic and non-diabetic human subjects could be differentiated without genetic manipulation to form IPCs which, when transplanted, could maintain euglycaemia in diabetic mice for 3 months. Optimization of the culture conditions are required to improve the yield of IPCs and their functional performance.

Characterization of Insulin-Secreting Porcine Bone Marrow Stromal Cells Ex Vivo and Autologous Cell Therapy in Vivo

“…Direct reprogramming of pancreatic exocrine cells into b-like cells has been reported (64) by the same laboratory that more recently identified a liver-derived factor, betatrophin, that stimulated proliferation of residual b-cells in diabetic animals (63). A recent report has shown differentiation of human BMMSCs into islet-like cell clusters that expressed insulin, C-peptide, and glucagon, which restored euglycemia when transplanted into diabetic mice (25). STZ was administered on day 1.…”

VEGF gene transfected umbilical cord mesenchymal stem cells transplantation improve the lower limb vascular lesions of diabetic rats

“…MSCs are derived from many tissues, such as bone marrow (Gabr et al, 2013;Sun et al, 2007;Karnieli, Izhar-Prato, Bulvik, & Efrat, 2007), adipose tissue (Timper et al, 2006), umbilical cord or umbilical blood (Wang et al, 2011;Prabakar et al, 2012), fibroblasts (Tateishi et al, 2008), endometrium (Santamaria, Massasa, Feng, Wolff, & Taylor, 2011) and liver cells (Sapir et al, 2005). Human umbilical cord (hUC) is one of the richest tissues for MSCs.…”

Stem Cell versus Cancer and Cancer Stem Cell: Intricate Balance Decides Their Respective Usefulness or Harmfulness in the Biological System

“…However, emerging evidences suggest that adult stem cells may be more versatile than previously thought and able to create unrelated types of cells, either from the same or different germ layer. For instance, bone marrow stem cells may be able to create muscle cells, beta islet cells [32,33]. This research has led to early-stage clinical trials to test usefulness and safety in people.…”