Connective Tissue Growth Factor Modulates Adult β-Cell Maturity and Proliferation to Promote β-Cell Regeneration in Mice

Stimulation of endogenous -cell expansion could facilitate regeneration in patients with diabetes. In mice, connective tissue growth factor (CTGF) is expressed in embryonic -cells and in adult -cells during periods of expansion. We discovered that in embryos CTGF is necessary for -cell proliferation, and increased CTGF in -cells promotes proliferation of immature (MafA(-)) insulin-positive cells. CTGF overexpression, under nonstimulatory conditions, does not increase adult -cell proliferation. In this study, we tested the ability of CTGF to promote -cell proliferation and regeneration after partial -cell destruction. -Cell mass reaches 50% recovery after 4 weeks of CTGF treatment, primarily via increased -cell proliferation, which is enhanced as early as 2 days of treatment. CTGF treatment increases the number of immature -cells but promotes proliferation of both mature and immature -cells. A shortened -cell replication refractory period is also observed. CTGF treatment upregulates positive cell-cycle regulators and factors involved in -cell proliferation, including hepatocyte growth factor, serotonin synthesis, and integrin 1. Ex vivo treatment of whole islets with recombinant human CTGF induces -cell replication and gene expression changes consistent with those observed in vivo, demonstrating that CTGF acts directly on islets to promote -cell replication. Thus, CTGF can induce replication of adult mouse -cells given a permissive microenvironment.