SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2

Katarzyna Blaszczyk, Anna P. Jedrzejak, Natalia Ziojla, Ekaterina Shcheglova, Karolina Szarafin, Artur Jankowski, Christine A. Beamish, Jolanta Chmielowiec, Omaima M. Sabek, Ashok Balasubramanyam, Sanjeet Patel, Malgorzata Borowiak

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number100466
JournalExperimental and Molecular Medicine
DOIs
StateAccepted/In press - 2025

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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