**5. Promise and challenges of stem cell derived islet cell transplant- can it become a clinical reality?**

People who are insulin dependent require multiple insulin injections, sometimes with an insulin pump, coupled with regular blood glucose monitoring. Diabetes management has improved with the availability of modified insulin's, each with peaks of activity at varying times and conditions. Transplantation of cadaveric islets coupled with immune suppression has been impressive results leading to insulin independence in patients with Type 1 Diabetes. But again there is not a perfect balance between the available donors populations compared to diabetic load. Continuous availability of beta cells to the patients at an appropriate timelines is the need of the hour in any country. This can be made a reality with the use of pluripotent stem cells, to produce a virtually unlimited and uniform supply of human islet-like clusters by directed differentiation can solve many issues.

Stem cells, being undifferentiated, are capable of self-renewal, and can virtually produce any tissue or organ [73–78]. Stem cells can be broadly classified on the basis of their origin as embryonic stem cells (ESCs), fetal stem cells (FSCs), adult stem cells (ASCs), and induced pluripotent stem cells (iPSCs). The iPSCs and ESCs are pluripotent stem cells (PSCs), while ASCs are unipotent or oligopotent [79–81].

Human-induced PSCs (iPSCs) and human embryonic stem cells (ESCs), serve as a reproducible source of human cells even at early developmental stages owing to their potential of forming any cell type in the adult body [82–84]. From a viewpoint of preservation of β-cells through islet protection and regeneration, the humaninduced PSCs (iPSCs), hematopoietic stem cells (HSCs), human cord blood-derived multipotent stem cells (CB-SCs), and MSCs are being used. Additionally, stem cells are capable of re-establishing peripheral tolerance towards β-cells by remodeling of immune responses alongside inhibition of autoreactive T-cell function [85, 86]. Stem cells have the potential to increase islet mass owing to their capability of differentiation to β-cells-like organoids. They inhibit the immune responses of T cell and Th1 cells through TGF-β and inflammatory pathways, and thus reconstitute immunotolerance. Type 1 diabetes being an autoimmune disease is featured by activated immune cells which target and destroy pancreatic β-cells. Thus stem cell therapy for treating T1DM should take into account the stem cell's immunomodulatory properties of and also its capability of differentiation into insulin-producing cells.

Nevertheless, challenges demanding resolution are plenty, like the ethical problem in using autologous and allogeneic stem cells to preserve the β-cells' function. Even though research focused on stem cell-derived β-cell replacement is gaining momentum year by year, enormous effort on the interventions with stem cell transplantation is required in the future to aid in achieving remission of T1DM by β-cell replacement.
