Ubiquitous mesenchymal stem cells (MSCs) can be isolated from various tissues like umbilical cord, bone marrow, adipose tissue and placental tissues. However, to be considered as MSCs, they must meet specific requirements such as adherence to plastic, differentiation abilities towards bone, cartilage and fat lineage, presence/absence of peculiar surface markers. Some MSCs also express stemness markers of pluripotency like OCT4 and Nanog [
50]. Moreover, MSCs are characterized by high expansion potential and no tumorigenic risks [
47‐
51]. MSC have shown, both
in vitro and
in vivo, a strong immunomodulatory activity which may help avoiding post-transplant rejection. Immunomodulation is mediated by different mechanisms: secretions of soluble factors (e.g. prostaglandin E2 and IL-10), pathways activated by direct contact with T-cell or interaction with dendritic cells [
52]. Successful studies on human MSC differentiated into insulin producing cells were reported by Wu XH et al. [
53] who demonstrated the capacity of bone marrow mesenchymal stem cells (BM-MSCs) to transdifferentiate
in vitro into islet-like cells and transplanted the cells into streptozotocin-induced diabetic rat. Few years later in a similar attempt, Phadnis SM et al. failed to accomplish a sufficient
in vitro differentiation of BM-MSC, while achieved the amelioration of glycemia after injection of immature cells in diabetic mice, showing that pre-induced BM- MSCs (
in vitro) completed their maturation into endocrine pancreatic lineage and insulin producing cells
in vivo [
54]. Other studies describe protocols for generation of glucose-responsive insulin-producing islet-like clusters from accessible and abundant tissues like human adipose tissue (AD- MSCs) [
55,
56]; from Wharton’s jelly [
57],(WJ- MSCs), amniotic fluid (AF-MSCs) [
58] and umbilical cord blood (UCB-MSC) [
59]. Seeberg et al. have proposed to use mesenchymal stem cells from pancreas to produce beta-like cells, hypothesizing that the pancreatic origin would ease the induction process. Data have shown that MSCs isolated from adult human exocrine pancreatic tissue express the same cell surface antigens of MSCs derived from bone marrow, adipose tissue and umbilical cord blood, and the same ability to differentiate into mesodermic and endodermic cell lineages. Using a step-wise differentiation protocol they generated cells retaining a gene expression pattern (PDX1, Pax4 and ngn3) typical of beta cells [
60‐
62]. Recently, it was also showed by Cal et al. the safety and the moderate improvement of metabolic effects on insulin secretion of umbilical cord (UC) MSCs plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D) [
63].
However, it is important to remark the limitations observed using MSCs to derive insulin producing cells. First, C-peptide levels of differentiated cells were low and unlikely to sustain normoglycemia in diabetic mice, indicating the necessity to improve, qualitatively and quantitatively, the insulin producing cell mass. On this regard, the different germ layer derivation of MSCs hinders the definition of differentiation protocols for insulin producing cells [
12,
47]. Furthermore, MSCs clones display variable proliferation rates, which hamper the setting of standard protocols to obtain beta-like cells [
51‐
62].