Human islets show plasticity

Abstract

Nature reviews | Endocrinology In this proof-ofconcept study, the authors have shown that human islet cells exhibit plasticity in a new study published in Nature, Pedro Herrera and colleagues report that modified human α-cells and γ-cells can produce insulin, and when transplanted into a mouse model of diabetes mellitus, modified human α-cells can reverse symptoms of diabetes mellitus. this study provides evidence to suggest that the adaptive capacity of adult cells is greater than previously thought. in previous work, Herrera and his team investigated whether the adult pancreas can regenerate new insulin-producing cells. “we showed that in adult mice, after total β-cell ablation, new insulin-producing cells appear, and we identified these cells as naturally reprogrammed mature α-cells and δ-cells,” explains Herrera. in the present study, the team investigated whether human pancreatic cells are able to adapt in the same way mouse pancreatic cells can. they first sorted pancreatic cells from patients with diabetes mellitus and healthy donors by cell type, and focused on two of the non-insulin-producing cells, α-cells and γ-cells. “we knew that α-cells in mice upregulate several key β-cell transcription factors, such as PDX1 and MaFa, following β-cell ablation,” adds Herrera. “therefore, we decided to express these transcription factors in isolated purified labelled human α-cells and γ-cells.” the team then constructed transplantable β-cell-deficient islets from the modified islet cells. the authors found that when placed together in an islet the pancreatic cells expressed genes that are linked to insulin production. after 1 week, some of the cells in the pseudo-islets were secreting insulin in response to glucose. Finally, Herrera and colleagues transplanted the pseudo-islets of modified α-cells into a mouse model of diabetes mellitus. Following transplantation, the authors noted that the mice no longer expressed diabetic symptoms. when the team removed transplanted cells, the diabetic symptoms returned. Notably, the modified transplanted islets continued to secrete insulin for 6 months, revealing that insulin-producing α-cells display a stable functional phenotype. in this proof-of-concept study, the authors have shown that human islet cells can also exhibit plasticity. Herrera acknowledges that this discovery is in its early stages and so there is a lot of work to do before these findings reach the clinic. “we need to understand the molecular mechanisms behind the partial change of identity that allows the acquisition of a new function to fully differentiated and specialized cells,” concludes Herrera. “if we succeed, and find a way to target the non-β-cells in vivo, we then could imagine new innovative therapies to try to stimulate non-β-cell conversion towards insulin production.”