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Blood supply is fundamental for the survival of myocardial tissue, and the formation of an efficient vascular network is a prerequisite for blood flow. The paracrine function of MSCs, which is throughout the neovascularization process, including MSC mobilization, migration, homing, adhesion and retention, regulates angiogenesis and vasculogenesis through existing endothelial cells (ECs) and endothelial progenitor cells (EPCs). Additionally, MSCs have the ability to differentiate into multiple cell lineages and can be mobilized and migrate to ischemic tissue to differentiate into ECs, pericytes and smooth muscle cells in some degree, which are necessary components of blood vessels. These characteristics of MSCs support the view that these cells improve ischemic myocardium through angiogenesis and vasculogenesis. In this review, the results of recent clinical and preclinical studies are discussed to illustrate the processes and mechanisms of neovascularization in ischemic heart disease.<\/jats:p>","DOI":"10.3389\/fcvm.2021.633300","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T06:47:40Z","timestamp":1611643660000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":40,"title":["Neovascularization: The Main Mechanism of MSCs in Ischemic Heart Disease Therapy"],"prefix":"10.3389","volume":"8","author":[{"given":"Weili","family":"Shi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiqi","family":"Xin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yahui","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weihong","family":"Cong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keji","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nature10144","article-title":"Molecular mechanisms and clinical applications of angiogenesis","volume":"473","author":"Carmeliet","year":"2011","journal-title":"Nature."},{"key":"B2","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1136\/hrt.2009.180414","article-title":"Therapeutic angiogenesis for cardiovascular disease: biological context, challenges, prospects","volume":"97","author":"Zachary","year":"2010","journal-title":"Heart."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1161\/01.CIR.0000061911.47710.8A","article-title":"The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis","volume":"107","author":"Henry","year":"2003","journal-title":"Circulation."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2826","DOI":"10.1161\/01.CIR.0000132468.82942.F5","article-title":"Janus phenomenon: the interrelated tradeoffs inherent in therapies designed to enhance collateral formation and those designed to inhibit atherogenesis","volume":"109","author":"Epstein","year":"2004","journal-title":"Circulation."},{"key":"B5","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. 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