부산대학교 도서관

Pericytes are specialized perivascular cells that directly interact with endothelial cells in capillaries. They are also multipotent cells that can give rise to different cell lineages when exposed to specific environmental stimuli. Little is known regarding the contribution of pericytes to pulmonary vascular diseases such as pulmonary hypertension (PH), a disorder associated with abnormal vascular remodeling of microvessels secondary to smooth muscle cell (SMC) accumulation. It is also unclear whether the overabundant SMCs are of pericyte-origin and what underlying mechanisms drive that transition. In the pulmonary vasculature of PH patients, pericytes assume SMC morphology, express both SMC and pericyte markers, and display higher rates of proliferation, motility and contractility. In addition, gene patterns comparing PH pericytes to PH SMCs were more homologically similar than healthy pericytes to healthy SMCs by transcriptomic analysis. In order to trace pericyte lineage during hypoxia induced PH, we utilized fate mapping using the NG2tdTomato murine model which can selectively mark pericytes with red fluorescence. After mice were exposed to hypoxia at various time points, lungs were extracted, sliced, and stained by different cell markers. Pericytes from this murine model were sorted and tested by RNA-seq and single cell RNA-seq under hypoxic conditions. We found that pericytes left the lung parenchyma near alveolar capillaries and accumulated at distal vessels at hypoxia day 7. They continued to approach larger vessels at hypoxia day 14. At hypoxia day 21, pericytes attached to large arteries and also expressed mature smooth muscle myosin heavy chain (Fig 1). RNA-seq revealed that cell motility related genes were upregulated. Moreover, single cell RNA-seq identified that pericytes underwent unique differentiation states and composed a mixture of eight different cellular clusters after hypoxia. Among them, the SMC-like cluster was the most abundant. Our results suggest that pericytes contribute to muscularization of distal precapillary vessels in response to hypoxia by differentiating into SMCs. Our findings contribute to a better understanding of pericyte biology and identify pericytes as a potential therapeutic target in PH. [ABSTRACT FROM AUTHOR]