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Connective tissue growth factor acts within both endothelial cells and beta cells to promote proliferation of developing beta cells.

ABSTRACT: Type 1 and type 2 diabetes result from an absolute or relative reduction in functional ?-cell mass. One approach to replacing lost ?-cell mass is transplantation of cadaveric islets; however, this approach is limited by lack of adequate donor tissue. Therefore, there is much interest in identifying factors that enhance ?-cell differentiation and proliferation in vivo or in vitro. Connective tissue growth factor (CTGF) is a secreted molecule expressed in endothelial cells, pancreatic ducts, and embryonic ? cells that we previously showed is required for ?-cell proliferation, differentiation, and islet morphogenesis during development. The current study investigated the tissue interactions by which CTGF promotes normal pancreatic islet development. We found that loss of CTGF from either endothelial cells or ? cells results in decreased embryonic ?-cell proliferation, making CTGF unique as an identified ? cell-derived factor that regulates embryonic ?-cell proliferation. Endothelial CTGF inactivation was associated with decreased islet vascularity, highlighting the proposed role of endothelial cells in ?-cell proliferation. Furthermore, CTGF overexpression in ? cells during embryogenesis using an inducible transgenic system increased islet mass at birth by promoting proliferation of immature ? cells, in the absence of changes in islet vascularity. Together, these findings demonstrate that CTGF acts in an autocrine manner during pancreas development and suggest that CTGF has the potential to enhance expansion of immature ? cells in directed differentiation or regeneration protocols.

SUBMITTER: Guney MA

PROVIDER: S-EPMC3174622 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Connective tissue growth factor acts within both endothelial cells and beta cells to promote proliferation of developing beta cells.

Guney Michelle A MA Petersen Christine P CP Boustani Andre A Duncan Matthew R MR Gunasekaran Uma U Menon Renuka R Warfield Courtney C Grotendorst Gary R GR Means Anna L AL Economides Aris N AN Gannon Maureen M

Proceedings of the National Academy of Sciences of the United States of America 20110829 37

Type 1 and type 2 diabetes result from an absolute or relative reduction in functional β-cell mass. One approach to replacing lost β-cell mass is transplantation of cadaveric islets; however, this approach is limited by lack of adequate donor tissue. Therefore, there is much interest in identifying factors that enhance β-cell differentiation and proliferation in vivo or in vitro. Connective tissue growth factor (CTGF) is a secreted molecule expressed in endothelial cells, pancreatic ducts, and e ...[more]

PMID: 21876171

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Project description:Endothelial progenitor cells (EPCs) play a vital role in endothelial repair following vascular injury by maintaining the integrity of endothelium. As EPCs home to endothelial injury sites, they may communicate with exposed vascular smooth muscle cells (VSMCs), which are subjected to cyclic stretch generated by blood flow. In this study, the synergistic effect of cyclic stretch and communication with neighboring VSMCs on EPC function during vascular repair was investigated. In vivo study revealed that EPCs adhered to the injury site and were contacted to VSMCs in the Sprague-Dawley (SD) rat carotid artery injury model. In vitro, EPCs were cocultured with VSMCs, which were exposed to cyclic stretch at a magnitude of 5% (which mimics physiological stretch) and a constant frequency of 1.25 Hz for 12 h. The results indicated that stretched VSMCs modulated EPC differentiation into mature endothelial cells (ECs) and promoted angiogenesis. Meanwhile, cyclic stretch upregulated the mRNA expression and secretion level of connective tissue growth factor (CTGF) in VSMCs. Recombinant CTGF (r-CTGF) treatment promoted endothelial differentiation of EPCs and angiogenesis, and increased their protein levels of FZD8 and β-catenin. CTGF knockdown in VSMCs inhibited cyclic stretch-induced EPC differentiation into ECs and attenuated EPC tube formation via modulation of the FZD8/β-catenin signaling pathway. FZD8 knockdown repressed endothelial differentiation of EPCs and their angiogenic activity. Wnt signaling inhibitor decreased the endothelial differentiation and angiogenetic ability of EPCs cocultured with stretched VSMCs. Consistently, an in vivo Matrigel plug assay demonstrated that r-CTGF-treated EPCs exhibited enhanced angiogenesis; similarly, stretched VSMCs also induced cocultured EPC differentiation toward ECs. In a rat vascular injury model, r-CTGF improved EPC reendothelialization capacity. The present results indicate that cyclic stretch induces VSMC-derived CTGF secretion, which, in turn, activates FZD8 and β-catenin to promote both differentiation of cocultured EPCs into the EC lineage and angiogenesis, suggesting that CTGF acts as a key intercellular mediator and a potential therapeutic target for vascular repair.

Dataset Information

Connective tissue growth factor acts within both endothelial cells and beta cells to promote proliferation of developing beta cells.

Publications

Connective tissue growth factor acts within both endothelial cells and beta cells to promote proliferation of developing beta cells.

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