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

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. The human body has a limited ability to regenerate insulin-producing cells, which are crucial for managing diabetes. Researchers are exploring ways to create these cells from stem cells in the lab. This study focuses on understanding how to make these lab-grown cells more effective and plentiful. The researchers used a type of cell called SC-β-cells, derived from human stem cells to study how they grow and function. They discovered that a protein called SPOCK2 plays a role in controlling the growth of these cells. By reducing SPOCK2 levels, they found that the cells grew better and produced insulin more effectively. The study suggests that manipulating SPOCK2 and using proteins like MMP2 can help expand the number of functional insulin-producing cells. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.