Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 8, Pages 2968-2981Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI93868
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Funding
- Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) [XDB19000000]
- National Science Foundation of China [91639302, 31625019, 91339104, 31271552, 31222038, 31571503, 31501172, 31601168, 81300340]
- Ministry of Science and Technology of China [2013CB945302, 2016YFC1300600, SQ2017YFSF080041]
- Youth Innovation Promotion Association of CAS [2015218]
- Key Project of Frontier Sciences of CAS [QYZDB-SSW-SMC003]
- International Cooperation Fund of CAS
- Shanghai Zhangjiang Stem Cell Research Project [ZJ2014-ZD-002]
- Shanghai Science and Technology Commission [14JC1407400, 16DZ2280800, 17ZR1449600, 17ZR1449800]
- Shanghai Yangfan Project [15YF1414000]
- Rising-Star Program [15QA1404300]
- China Postdoctoral Science Foundation [2015M581669, 2016T90387, 2016LH0042]
- President Fund of Shanghai Institutes for Biological Sciences (SIBS)
- Astrazeneca
- Boehringer Ingelheim
- Sanofi-SIBS fellowship
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The mechanisms that promote the generation of new coronary vasculature during cardiac homeostasis and after injury remain a fundamental and clinically important area of study in the cardiovascular field. Recently, it was reported that mesenchymal-to-endothelial transition (MEndoT) contributes to substantial numbers of coronary endothelial cells after myocardial infarction. Therefore, the MEndoT has been proposed as a paradigm mediating neovascularization and is considered a promising therapeutic target in cardiac regeneration. Here, we show that preexisting endothelial cells mainly beget new coronary vessels in the adult mouse heart, with essentially no contribution from other cell sources through cell-lineage transdifferentiation. Genetic-lineage tracing revealed that cardiac fibroblasts expand substantially after injury, but do not contribute to the formation of new coronary blood vessels, indicating no contribution of MEndoT to neovascularization. Moreover, genetic-lineage tracing with a pulse-chase labeling strategy also showed that essentially all new coronary vessels in the injured heart are derived from preexisting endothelial cells, but not from other cell lineages. These data indicate that therapeutic strategies for inducing neovascularization should not be based on targeting presumptive lineage transdifferentiation such as MEndoT. Instead, preexisting endothelial cells appear more likely to be the therapeutic target for promoting neovascularization and driving heart regeneration after injury.
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