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Castro-Gutiérrez, R.* ; Shilleh, A.H.* ; Barra, J.M.* ; Williams, S.P.M.* ; Nedumaran, B.* ; Triolo, T.M.* ; Hebrok, M. ; Russ, H.A.*

Physical and biochemical determinants of endocrine fate in 3D suspension culture based stem cell-derived β-cell differentiation.

Cells 15:1600 (2026)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
Efficient and reproducible generation of functional stem cell-derived β cells (sBC) remains a major challenge for basic research and cell replacement therapy, partly due to incomplete understanding of endocrine induction during differentiation and challenges with clinical scale-up. Here, we dissect the individual contributions of commonly used endocrine differentiation factors on pancreatic progenitor maintenance, endocrine commitment, and hormone subset generation in a scalable 3D differentiation system. We demonstrated that starting pluripotent stem cell cluster size is a critical determinant for downstream sBC generation. We also verify that a commonly employed combination of endocrine induction molecules efficiently drives endocrine lineage commitment but yields limited β-cell generation. Detailed analysis of the effects of individual endocrine induction molecules revealed distinct effects: EGF or KGF preserved NKX6.1+ progenitors without induction of endocrine differentiation; Notch or BMP inhibition robustly induced endocrine marker expression but concurrently reduced NKX6.1 expression, resulting in predominant generation of glucagon-expressing cells; retinoic acid, thyroid hormone (T3), or TGFβ inhibition maintained high NKX6.1 levels while also promoting efficient insulin+ endocrine differentiation. These findings indicate NKX6.1 protein maintenance as a key determinant of human β-cell generation and show that endocrine differentiation factors exert divergent effects on lineage progression.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Endocrine System ; Enteroendocrine Cell ; Progenitor Cell ; Stem Cell ; Cellular Differentiation ; Hormone ; Progenitor ; Induced Pluripotent Stem Cell; In-vitro; Pancreatic Progenitors; Maturation; Neurogenin3; Nkx6.1
ISSN (print) / ISBN 2073-4409
e-ISSN 2073-4409
Journal Cells
Quellenangaben Volume: 15, Issue: 17, Pages: , Article Number: 1600 Supplement: ,
Publisher MDPI
Publishing Place Basel
Institute(s) Institute for Diabetes und Organoid Technology (IDOT)
Grants Pathway to Stop Diabetes Initiator Award by ADA
National Institutes of Health
Thomas H. Maren Research Excellence Postdoctoral Award by UF
Advanced Postdoctoral Fellowship