Abstract
BackgroundPeripheral arterial disease (PAD) affects millions of people and compromises quality of life. Critical limb ischemia (CLI), which is the most advanced stage of PAD, can cause nonhealing ulcers and strong chronic pain, and it shortens the patients’ life expectancy. Cell-based angiogenic therapies are becoming a real therapeutic approach to treat CLI. Pericytes are cells that surround vascular endothelial cells to reinforce vessel integrity and regulate local blood pressure and metabolism. In the past decade, researchers also found that pericytes may function as stem or progenitor cells in the body, showing the potential to differentiate into several cell types. We investigated the gene expression profiles of pericytes during the early stages of limb ischemia, as well as the alterations in pericyte subpopulations to better understand the behavior of pericytes under ischemic conditions.MethodsIn this study, we used a hindlimb ischemia model to mimic CLI in C57/BL6 mice and explore the role of pericytes in regeneration. To this end, muscle pericytes were isolated at different time points after the induction of ischemia. The phenotypes and transcriptomic profiles of the pericytes isolated at these discrete time points were assessed using flow cytometry and RNA sequencing.ResultsIschemia triggered proliferation and migration and upregulated the expression of myogenesis-related transcripts in pericytes. Furthermore, the transcriptomic analysis also revealed that pericytes induce or upregulate the expression of a number of cytokines with effects on endothelial cells, leukocyte chemoattraction, or the activation of inflammatory cells.ConclusionsOur findings provide a database that will improve our understanding of skeletal muscle pericyte biology under ischemic conditions, which may be useful for the development of novel pericyte-based cell and gene therapies.
Highlights
Pericytes are cells that surround endothelial cells in the vascular system [1,2,3] and regulate the permeability, stability, and contractility of blood vessels [4, 5]
In angiogenesis that occurs during embryonic development, pericytes are recruited by endothelial cells via the PDGFRβ/PDGFβ, angiopoietin 1 (Ang1)/Tie2 and transforming growth factor-β (TGFβ) signaling pathways [1]
Some markers have been used to indicate a pericyte nature, including PDGFRβ, Nestin, Neuron glia antigen-2 (NG2), and CD146 [1]. These and other pericyte markers are expressed in mesenchymal stem/stromal cells (MSCs), which are widely used in clinical trials to treat various conditions due to their ability to differentiate into mature mesenchymal cells and secrete trophic and immunomodulatory molecules [10, 11]
Summary
Pericytes are cells that surround endothelial cells in the vascular system [1,2,3] and regulate the permeability, stability, and contractility of blood vessels [4, 5]. The expression of known pericyte markers can vary, depending on the tissue localization and the zonal effect of vascular structure (artery, capillary, or vein) [1]. These markers are transiently regulated by the physiological or pathological microenvironment [1]. Some markers have been used to indicate a pericyte nature, including PDGFRβ, Nestin, NG2, and CD146 [1] These and other pericyte markers are expressed in mesenchymal stem/stromal cells (MSCs), which are widely used in clinical trials to treat various conditions due to their ability to differentiate into mature mesenchymal cells and secrete trophic and immunomodulatory molecules [10, 11]. We investigated the gene expression profiles of pericytes during the early stages of limb ischemia, as well as the alterations in pericyte subpopulations to better understand the behavior of pericytes under ischemic conditions
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