Pericytes differentiate into smooth muscle cells through CXCL12 activation in hypoxia induced pulmonary hypertension




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Ke Yuan1,2, Wendy Zhang3, Elya A. Shamskhou1,2, Mark Orcholski1,2, Abinaya Nathan1,2, Stanley Qi4, Kristy Redhorse2,5, Mark Nicolls1 and Vinicio de Jesus Perez1,2

1Divisions of Pulmonary and Critical Care Medicine and Stanford Cardiovascular Institute, 2Cardiovascular Institution, 3Department of Genetics, School of Medicine, 4Department of Bioengineering, 5Dept of Biology, Stanford University

Background: Pericytes are specialized perivascular cells that directly interact with endothelial cells. They are also multipotent cells-like. Little is known regarding the contribution of pericytes to pulmonary vascular diseases such as pulmonary arterial hypertension (PAH), 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.

Materials and Methods: Transcriptome analysis was performed on human healthy and PAH pericytes and compared against healthy and PAH SMC. In order to trace pericyte lineage during hypoxia induced PH, we utilized fate mapping using the NG2-tdTomato(NG2-tdT) murine model which can selectively mark pericytes with red florescence. FACS was used to sort tdT positive cells followed by bulk and single cell RNA-seq analysis.

Results: Transcriptomic analysis demonstrated that genetic landscape of PAH pericytes was homologically similar to that of PAH SMCs. Analysis of NG2-tdT murine lung sections revealed that pericytes relocate from alveolar capillaries to the precapillary arterioles and expressed smooth muscle myosin heavy chain (SMMHC), a marker of mature SMCs. Bulk RNA-seq analysis of pericytes sorted from 21-day hypoxia revealed strong upregulation of cell motility related genes compared to normoxia. Further analysis using single cell RNA-seq revealed that pericytes under hypoxia can be distinguished into 8 different clusters. Among them, the SMC-like cluster was the most abundant and within this cluster, individual cells had elevated level of C-X-C motif chemokine 12 (CXCL12). Analysis of in both human PAH serum samples (N=83) and pericytes demonstrated a significant elevation in CXCL12. Moreover, overexpression of CXCL12 in healthy human lung pericytes produced a SMC like phenotype associated with greater contractility and reduced association to endothelial cells in matrigel tube formation assay.

Conclusion: Our results suggest that pericytes contribute to muscularization of distal precapillary vessels in response to hypoxia by differentiating into SMCs via a CXCL12 associated pathway. Our findings contribute to a better understanding of pericyte biology and identify pericytes as a potential therapeutic target in both hypoxia induced PH and PAH.

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