Oral Presentation 6th Australian Health and Medical Research Congress 2012

Endothelial progenitor cell differentiation: A role for peroxisome proliferator-activated receptor γ (#35)

Kate A Parham 1 2 3 4 , Wai Y Sun 1 3 4 5 , Stuart M Pitson 1 3 5 , Gabor Tigyi 6 , Claudine S Bonder 1 2 3 4 5
  1. Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia
  2. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
  3. Co-operative Research Centre for Biomarker Translation, La Trobe University, Melbourne, Victoria, Australia
  4. Centre for Stem Cell Research, Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia
  5. School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia, Australia
  6. University of Tennessee Health Science Center, University of Tennessee, Memphis, Tennessee, United States

Endothelial progenitor cells (EPCs) reside in the bone marrow and upon stimulation are mobilized, enter the circulation and travel to sites in need of new blood vessel development. Circulating EPCs can contribute to vasculogenesis in a paracrine manner or by differentiating into mature endothelial cells (ECs) to form the inner lining of the vasculature. Because EPCs are regulators of both physiological and pathological vasculogenesis these cells have become the target of close to 200 clinical trials aiming to control the biggest killers worldwide, cancer and cardiovascular disease. To this end, elucidation of factors involved in regulation of EPC differentiation is necessary. Transcription factors have been widely described as master switches for the determination of cell fate. Peroxisome proliferator-activated receptor-γ (PPARγ), a transcriptional member of the nuclear receptor super family, has been implicated in a number of vascular processes such as, vasoprotection, EPC proliferation, EPC migration and EPC survival.

This study aims to implicate PPARγ as a master regulator of EPC differentiation by assessing a correlation between PPARγ activity and EPC phenotype and function. Comparison of both endogenous PPARγ protein and mRNA revealed significantly elevated levels in human EPCs when compared to ECs. Importantly, PPARγ protein was shown to be primarily localised to the nucleus in EPCs, suggesting the presence of transcriptionally active PPARγ in the cell. In addition, pharmacological manipulation of PPARγ alters cell phenotype and cell function in Matrigel, a tube formation assay that mimics in vivo vasculogenesis. Herein, we also reveal a previously undescribed PPARγ regulatory complex in EPCs, with data suggesting that the bioactive second messenger, sphingosine-1-phosphate (S1P) plays a role in PPARγ gene regulation by binding to and activating PPARγ. Taken together, this new regulatory system controlling EPC phenotype and function may provide a new target for controlling aberrant vasculogenesis in disease.