Language
English
Publication Date
2-1-2025
Journal
Experimental & Molecular Medicine
DOI
10.1038/s12276-024-01380-2
PMID
39741186
PMCID
PMC11799530
PubMedCentral® Posted Date
1-1-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Human pluripotent stem cell-derived β-cells (SC-β-cells) represent an alternative cell source for transplantation in diabetic patients. Although mitogens could in theory be used to expand β-cells, adult β-cells very rarely replicate. In contrast, newly formed β-cells, including SC-β-cells, display higher proliferative capacity and distinct transcriptional and functional profiles. Through bidirectional expression modulation and single-cell RNA-seq, we identified SPOCK2, an ECM protein, as an inhibitor of immature β-cell proliferation. Human β-cells lacking SPOCK2 presented elevated MMP2 expression and activity, leading to β-integrin-FAK-c-JUN pathway activation. Treatment with the MMP2 protein resulted in pronounced short- and long-term SC-β-cell expansion, significantly increasing glucose-stimulated insulin secretion in vitro and in vivo. These findings suggest that SPOCK2 mediates fetal β-cell proliferation and maturation. In summary, we identified a molecular mechanism that specifically regulates SC-β-cell proliferation and function, highlighting a unique signaling milieu of SC-β-cells with promise for the robust derivation of fully functional cells for transplantation.
Keywords
Insulin-Secreting Cells, Humans, Cell Proliferation, Matrix Metalloproteinase 2, Animals, Mice, Signal Transduction, Cell Differentiation, Cells, Cultured, Stem-cell differentiation, Cell proliferation
Published Open-Access
yes
Recommended Citation
Blaszczyk, Katarzyna; Jedrzejak, Anna P; Ziojla, Natalia; et al., "SPOCK2 Controls the Proliferation and Function of Immature Pancreatic β-Cells Through MMP2" (2025). Faculty and Staff Publications. 4332.
https://digitalcommons.library.tmc.edu/baylor_docs/4332