Perivascular Cell Differentiation in Tissue Remodeling and Fibrosis 344 views

Perivascular cells, or pericytes, are microvascular support cells which can be found in capillary beds in all tissues of the body. Pericytes are essential for vascular homeostasis, development, and wound healing. These cells maintain their local extracellular matrix (ECM) environment, ensuring the continuity of tissue form and thus tissue function. Given the right stimuli, pericytes can transdifferentiate into a variety of cell types both in vitro and in vivo, leading some to argue for their inclusion into a growing repertoire of stromal or mesenchymal stem cells. Several studies over the past decade have explored the possibility of perivascular contributions to myofibroblasts in fibrotic disease, but are limited by the difficulty in positively identifying a perivascular cell as it transitions from a quiescent to pro-fibrotic tissue remodeling phenotype. Here we investigated the effector cells of fibrotic disease, the myofibroblast, and ascertain the degree to which pericytes participate in myofibroblastic behaviors in a murine model of pulmonary fibrosis. A novel application of a murine pericyte lineage model allowed for the thorough quantitation and characterization of pericyte-derived myofibroblasts. We observed significant, substantial increases in contractile and matrix-secreting phenotypes, as well as the upregulation of tissue-remodeling gene families. Further analysis reveals a possible integrin-mediated mechanism for perivascular activation through active αvβ3 heterodimer. Exploration of pericyte response to bleomycin insult resulted in the discovery of several unique pericyte behaviors. A substantial population of pericytes express endothelial surface protein and mRNA, indicating a possible pericyte-endothelial transitional phenotype both in quiescent tissue and in tissue-remodeling disease. We also characterized the impact of stem cell factor KLF4 on perivascular cell transcript responses to lung injury, and found a large differential in expression profiles between KLF4 naïve and KLF4 knockout pericytes. In total, this work represents advances in our ability to study the pulmonary pericyte through the novel application of the reporter mouse in the bleomycin disease model, and significant improvements in our understanding of the mechanisms by which pericytes interact with fibroproliferative injury models.

PHD (Doctor of Philosophy)

English

2021-04-28