Strategies to Improve the Safety of iPSC-Derived β Cells for β Cell Replacement in Diabetes

Abstract

Allogeneic islet transplantation allows for the re-establishment of glycemic control with the possibility of insulin independence, but is severely limited by the scarcity of organ donors. However, a new source of insulin-producing cells could enable the widespread use of cell therapy for diabetes treatment. Recent breakthroughs in stem cell biology, particularly pluripotent stem cell (PSC) techniques, have highlighted the therapeutic potential of stem cells in regenerative medicine. An understanding of the stages that regulate β cell development has led to the establishment of protocols for PSC differentiation into β cells, and PSC-derived β cells are appearing in the first pioneering clinical trials. However, the safety of the final product prior to implantation remains crucial. Although PSC differentiate into functional β cells in vitro, not all cells complete differentiation, and a fraction remain undifferentiated and at risk of teratoma formation upon transplantation. A single case of stem cell-derived tumors may set the field back years. Thus, this review discusses four approaches to increase the safety of PSC-derived β cells: reprogramming of somatic cells into induced PSC, selection of pure differentiated pancreatic cells, depletion of contaminant PSC in the final cell product, and control or destruction of tumorigenic cells with engineered suicide genes.

Preservation of β-Cells as a Therapeutic Strategy for Diabetes

“…Researchers are developing techniques to eliminate any remaining undifferentiated stem cells to minimize the risk of tumor formation. Additionally, immunomodulatory approaches are being investigated to reduce the immune response and prevent rejection of the transplanted cells [32].…”

Developments in endoderm and pancreatic β-cell differentiation from human pluripotent stem cells

“…The risk of immune rejection necessitates the continuous use of immunosuppressants, which are gradually improving. However, these can lead to a variety of side effects, including immunosuppressive infections [16,76]. If the side effects of immunosuppression outweigh the benefits of improved glycemic control or those of insulin administration, these therapies become less effective and more challenging to use, necessitating alternative therapeutic approaches to evade immune responses.…”

Cryopreservation of engineered tissues and organoids

“…Given that β cells are particularly vulnerable to hypoxia due to their exceptionally high oxygen requirements [19], methods for protecting the transplanted β-cell mass from hypoxia are crucial to ensure maximal therapeutic effects. Furthermore, the transplantation of live cells raises safety concerns as they may develop into tumors or trigger severe immune responses [20][21][22]. To guarantee the safe administration of these novel therapeutic modalities, it is of the utmost importance to develop methods for precise control over the cells.…”