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An optimized protocol for efficient derivation of pancreatic islets from multiple human pluripotent stem cell lines

ABSTRACT: Future success of cell therapy for type 1 diabetes (T1D) relies on robust protocols for the differentiation of stem cells to pancreatic islets. However, currently established protocols generate stem cell-derived pancreatic islets (SC-islets) which contain non-endocrine cell populations and have immature functionality. Herein we report the development of a new protocol for the generation of potent SC-islets enriched in functional endocrine cells from multiple human pluripotent stem cell (hPSC) lines. We show that laminin-521 efficiently supports monolayer differentiation of 8 testes hPSC lines to endocrine progenitor (EP) stage. The efficiency was further improved by reducing the pancreatic progenitor (PP) stage. Importantly, we find that aggregation of EP reduces unwanted non-endocrine and proliferative cells. Subsequent suspension cultures generate SC-islets with strong in vitro glucose responsiveness, similar to human islets. Upon transplantation of 300 SC-islets into the anterior chamber of the eye of a diabetic mouse model, the SC-islets undergo further maturation in vivo and re-establish normal glycemic control. The SC-islets before and after transplantation are to a major extent free of non-endocrine cell populations. In conclusion, our robust differentiation protocol results in endocrine enriched and highly functional SC-islets that should be well suited for transplantation into patients with T1D.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270864 | GEO | 2026/03/27

REPOSITORIES: GEO

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Project description:Pancreatic islet transplantation as a cure for type 1 diabetes (T1D) cannot be scaled up due to a scarcity of human pancreas donors. In vitro expansion of beta cells from mature human pancreatic islets provides an alternative source of insulin-producing cells. The exact nature of the expanded cells produced by diverse expansion protocols, and their potential for differentiation into functional beta cells, remain elusive. We performed a large-scale meta-analysis of gene expression in human pancreatic islet cells, which were processed using three different previously described protocols for expansion and attempted re-differentiation. All three expansion protocols induced dramatic changes in the expression profiles of pancreatic islets; many of these changes are shared among the three protocols. Attempts at re-differentiation of expanded cells induce a limited number of gene expression changes. Nevertheless, these fail to restore a pancreatic islet-like gene expression pattern. Comparison with a collection of public microarray datasets confirmed that expanded cells are highly comparable to mesenchymal stem cells. Genes induced in expanded cells are also enriched for targets of transcription factors important for pluripotency induction. The present data increases our understanding of the active pathways in expanded and re-differentiated islets. Knowledge of the mesenchymal stem cell potential may help development of drug therapeutics to restore beta cell mass in T1D patients. Experiment Overall Design: In this study, we have tested three different protocols to expand human pancreatic islets in monolayer and after attempted maneuvers to re-differentiate the expanded cells back to islets. We have characterized the resulting cells in detail by performing microarray analyses with fresh pancreatic islets, expanded islet cells and re-differentiated cells. Genes modified by either of three protocols have 70 to 80% overlap with the genes changed by the other two protocols. Although there are promising changes in the right direction, none of the three protocols could achieve a return to a functional islet state. The expanded cells highly resemble Mesenchymal Stem Cells (MSC), and similar gene regulatory networks seem to be active in both cell types. On the other hand, the expanded islet cells are different from MSC in that they seem to retain activity of some islet gene modules. The current results highlight the importance of designing new strategies that take into account the MSC potential of expanded cells.

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An optimized protocol for efficient derivation of pancreatic islets from multiple human pluripotent stem cell lines

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