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Regulation of multiple signaling pathways promotes the consistent expansion of human pancreatic progenitors in defined conditions.
eLife 12:RP89962 (2024)
The unlimited expansion of human progenitor cells in vitro could unlock many prospects for regenerative medicine. However, it remains an important challenge as it requires the decoupling of the mechanisms supporting progenitor self-renewal and expansion from those mechanisms promoting their differentiation. This study focuses on the expansion of human pluripotent stem (hPS) cell-derived pancreatic progenitors (PP) to advance novel therapies for diabetes. We obtained mechanistic insights into PP expansion requirements and identified conditions for the robust and unlimited expansion of hPS cell-derived PP cells under GMP-compliant conditions through a hypothesis-driven iterative approach. 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 reproducible, 2000-fold, over 10 passages and 40-45 d, expansion of PDX1+/SOX9+/NKX6-1+ PP cells. Transcriptome analyses confirmed the stabilization 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 cell 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 microwells 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 GMP-produced PP cells derived from diverse hPS cell lines. This approach will streamline SC-islet production for further development of the differentiation process, diabetes research, personalized medicine, and cell therapies.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Developmental Biology ; Differentiation ; Hps Cells ; Human ; Islets ; Pancreas Progenitors ; Regenerative Medicine ; Signaling ; Stem Cells ; β-cells; Insulin-producing Cells; Growth-factor; Transcription Factor; Endocrine Development; Efficient Generation; Lineage Determinants; Beta-cells; In-vitro; Notch; Differentiation
ISSN (print) / ISBN
2050-084X
e-ISSN
2050-084X
Zeitschrift
eLife
Quellenangaben
Band: 12,
Artikelnummer: RP89962
Verlag
eLife Sciences Publications
Verlagsort
Sheraton House, Castle Park, Cambridge, Cb3 0ax, England
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute for Pancreatic Beta Cell Research (IPI)
Förderungen
Fibroblasts 'Theo'
Helmholtz Zentrum Mnchen
German Center for Diabetes Research (DZD)
German Research Foundation (DFG)
Helmholtz Zentrum Mnchen
German Center for Diabetes Research (DZD)
German Research Foundation (DFG)