TY - JOUR
T1 - SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2
AU - Blaszczyk, Katarzyna
AU - Jedrzejak, Anna P.
AU - Ziojla, Natalia
AU - Shcheglova, Ekaterina
AU - Szarafin, Karolina
AU - Jankowski, Artur
AU - Beamish, Christine A.
AU - Chmielowiec, Jolanta
AU - Sabek, Omaima M.
AU - Balasubramanyam, Ashok
AU - Patel, Sanjeet
AU - Borowiak, Malgorzata
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
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U2 - 10.1038/s12276-024-01380-2
DO - 10.1038/s12276-024-01380-2
M3 - Article
AN - SCOPUS:85213710023
SN - 1226-3613
JO - Experimental and Molecular Medicine
JF - Experimental and Molecular Medicine
M1 - 100466
ER -