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

Summary

SPOCK2 acts as an extracellular matrix brake on immature β-cell proliferation. Loss of SPOCK2 elevates MMP2 and activates β-integrin–FAK–c-JUN signaling, while exogenous MMP2 drives robust short- and long-term expansion of SC-β-cells with enhanced glucose-stimulated insulin secretion in vitro and in vivo. The work outlines a tractable pathway to expand functional SC-β-cells for transplantation.

Key Findings

• SPOCK2 is identified as an ECM inhibitor of immature β-cell proliferation using bidirectional modulation and scRNA-seq.
• SPOCK2 loss elevates MMP2 expression/activity, activating β-integrin–FAK–c-JUN signaling.
• Exogenous MMP2 induces pronounced short- and long-term expansion of SC-β-cells with improved GSIS in vitro and in vivo.

Clinical Implications

Enables pre-transplant expansion of SC-β-cells through SPOCK2 inhibition/MMP2 activation to improve graft yield and function; suggests careful evaluation of proliferation–maturation balance and off-target matrix remodeling.

Limitations

• Translational safety and durability of MMP2-mediated expansion not yet established in humans
• Potential off-target extracellular matrix remodeling requires careful assessment

Future Directions

Evaluate small-molecule or biologic modulators of the SPOCK2–MMP2–integrin axis, define maturation trajectories post-expansion, and test efficacy/safety in large-animal transplantation models.