| Summary: | Abstract Human embryonic stem (hES) cells have been around for more than two decades now. It was expected that hES/iPS (induced pluripotent stem) cells will quickly translate to the clinics to treat diabetic patients and to obtain gametes in vitro for infertile couples. However, there is no breakthrough yet in either of the fields although considerable progress has been made. Research efforts are ongoing to obtain an insight into the gene expression changes associated with directed differentiation of hES/iPS cells. Autologous bone marrow/cord blood mononuclear cells’ therapy has also failed to show any regenerative potential and only remains as a standard method of care for blood diseases. Only mesenchymal stem cells (MSCs) have shown promise in the clinics to alleviate diabetic symptoms. But MSCs are stromal cells with no regenerative properties; rather “paracrine providers”, pericytes/stromal cells, better known for their trophic, immuno-modulatory, and anti-inflammatory properties and thus best termed as mesenchymal stromal cells (MSCs). Autologus bone marrow cells enriched for hematopoietic stem cells have no potential to cross boundaries and transdifferentiate into other lineages including endodermal pancreatic cells. Endogenous, pluripotent, very small embryonic-like stem cells (VSELs) emerge as the most likely endogenous stem cell candidates to regenerate adult diabetic pancreas. Transplanted MSCs provide a healthy paracrine support required for endogenous/ resident VSELs to differentiate into acinar cells and islets in a diabetic pancreas to enable restoration of homeostasis. Our recently published study shows that VSELs exist and can be enriched from intact mouse pancreas as well as from the islets and increase in numbers in diabetic pancreas. Providing “regenerative pressure” by subjecting diabetic mice to partial pancreatectomy stimulated the VSELs to undergo differentiation into various cell types in an attempt to restore homeostasis. Double-blinded, placebo controlled clinical trials need to be undertaken to evaluate the efficacy of transplanting MSCs in diabetic patients with conviction since now underlying fine play of endogenous VSELs and niche providing MSCs has emerged.
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