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- W4386864512 abstract "The unlimited expansion of human progenitor cells in vitro could unlock many prospects for regenerative medicine but it remains an important challenge as it requires the decoupling of the mechanisms supporting progenitor self-renewal and expansion from feed-forward mechanisms promoting their differentiation. The expansion of human pluripotent stem (hPS) cell derived pancreatic progenitors (PP) will accelerate the development of novel therapies for diabetes.We obtained mechanistic insights into the expansion requirements of PP cells and leveraged them to conduct a hypothesis-driven iterative search to identify conditions for the robust and unlimited expansion of hPS cell derived PP cells under GMP-compliant conditions. We show that the combined stimulation of specific mitogenic pathways, suppression of retinoic acid signaling and inhibition of selected branches of the TGFβ and Wnt signaling pathways are necessary for the effective decoupling of PP proliferation from differentiation. This enabled the selection of PDX1+/SOX9+/NKX6.1+ PP cells and their consistent, 2000-fold, expansion over ten passages and 40-45 days. Transcriptome analyses confirmed the stabilisation of PP identity and the effective suppression of differentiation. Using these conditions, PDX1+/SOX9+/NKX6.1+ PP cells, derived from different, both XY and XX, hPS cells lines, were enriched to nearly 90% homogeneity and expanded with very similar kinetics and efficiency. Furthermore, non-expanded and expanded PP cells, from different hPS cell lines, were differentiated in micropatterned wells into homogeneous islet-like clusters (SC-islets) with very similar efficiency. These clusters contained abundant β-cells of comparable functionality as assessed by glucose-stimulated insulin secretion assays.These findings established the signaling requirements to decouple PP proliferation from differentiation and allowed the consistent expansion of hPS cell derived PP cells. They will enable the establishment of large banks of PP cells derived under GMP conditions from diverse hPS cell lines. This will also streamline the generation of SC-islet clusters for further development of the differentiation process, diabetes research, personalized medicine and cell therapies." @default.
- W4386864512 created "2023-09-20" @default.
- W4386864512 date "2023-09-19" @default.
- W4386864512 modified "2023-09-27" @default.
- W4386864512 title "Reviewer #3 (Public Review): Regulation of multiple signaling pathways promotes the consistent expansion of human pancreatic progenitors in defined conditions" @default.
- W4386864512 doi "https://doi.org/10.7554/elife.89962.1.sa3" @default.
- W4386864512 hasPublicationYear "2023" @default.
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