Abstract 761: Abnormal Differentiation of Multipotent Pulmonary Vascular Endothelial Precursors contributes to the Pathology of Pulmonary Arterial Hypertension
Niches for resident multipotent stem cells have been identified in many adult tissues including lung. The normal differentiation processes of these stem cells are likely disrupted by microenvironmental changes during pulmonary disease, programming their contribution to pathological remodeling at the expense of functional tissue regeneration. Two recent breakthroughs in understanding the pathogenesis of pulmonary arterial hypertension (PAH), the recognition of the potential role of stem cells to contribute to vascular remodeling and PDGF as a co-factor in disease progression have led us to assess the hypothesis that the lung side population (luSP) of stem cells contains endothelial precursors (EPC), which differentiate abnormally in response to PDGFB and contribute to pathogenic vascular remodeling characteristic of PAH. We therefore sought to identify a functional role in PAH using a murine model of hypobaric hypoxia induced PAH. We found that the introduction of luSP intravenously to mice prior to hypoxic exposure illustrated the ability of luSP to exacerbate the hypertensive response via increased right ventricular hypertrophy as well as systolic right ventricular pressures (0.306g p<0.0001; 36.1mmHg p<0.03) compared to chronic hypoxia alone (0.19g; 32.4mmHg; n=3). In addition, we identified the adult luSP in vitro as a novel source of resident lung vascular endothelial progenitors by FACS of collagenase digested, Hoechst 33342 and CD45 stained adult mouse lung cell suspensions. These freshly isolated luSP cells lacked expression of differentiated endothelial cell (EC) markers such as VeCadherin. In the presence of PDGFB the cells assume a hyperproliferative fibroblastâ€“like phenotype while untreated clonal populations expressed telomerase and differentiate to functional endothelial precursor cells EPC expressing VeCadherin, AcDiLDL uptake and angiogenic tube forming ability. These luSP-derived telomerase positive EPC also transdifferentiate to myofibroblasts in the presence of PDGFB. We have defined the presence of EPC as resident within the primitive adult lung SP, which are significantly affected during and contribute to the pathogenesis of PAH.