Cardiac Progenitor Cell Recruitment Drives Fetal Cardiac Regeneration by Enhanced Angiogenesis

被引:8
作者
Zgheib, Carlos
Hodges, Maggie M.
Allukian, Myron W.
Xu, Junwang
Spiller, Kara L.
Gorman, Joseph H., III
Gorman, Robert C.
Liechty, Kenneth W.
机构
[1] Univ Colorado Denver, Sch Med, Dept Surg, Lab Fetal & Regenerat Biol, Anschutz Med Campus, Aurora, CO 80045 USA
[2] Colorado Childrens Hosp, Aurora, CO USA
[3] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA
[4] Univ Penn, Sch Med, Gorman Cardiovasc Res Grp, Philadelphia, PA 19104 USA
[5] Drexel Univ, Sch Biomed Engn Sci & Hlth Syst, Philadelphia, PA 19104 USA
关键词
ACUTE MYOCARDIAL-INFARCTION; DIFFERENTIAL GENE-EXPRESSION; HEART REGENERATION; TISSUE-REPAIR; MACROPHAGE HETEROGENEITY; ZEBRAFISH; MECHANISMS; MONOCYTE; FAILURE; INJURY;
D O I
10.1016/j.athoracsur.2017.05.040
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background. In contrast to adults, the fetal response to myocardial infarction (MI) is regenerative, requiring the recruitment of cardiac progenitor cells to replace infarcted myocardium. Macrophage contribution to tissue repair depends on their phenotype: M1 are proinflammatory and initiate angiogenesis; M2a are profibrotic and contribute to blood vessels maturation; and M2c are proremodeling and proangiogenesis. The goal of the present study was to expand on this work by examining cardiac progenitor cells recruitment, and the role of macrophages in promoting angiogenesis and cardiac regeneration in the fetal heart after MI. Methods. Fetal and adult sheep underwent MI and were sacrificed 3 or 30 days after MI. Some fetal hearts received stromal cell-derived factor-1 alpha-inhibitor treatment. The microvasculature was evaluated by micro-computed tomography, gene expression was evaluated by real-time polymerase chain reaction, and vessels counts were evaluated by immunohistochemistry. Results. Micro-computed tomography analysis showed restoration of microvasculature in fetal hearts after MI. Vascular endothelial growth factor-alpha increased, and the expression of tissue markers associated with the M1, M2a, and M2c macrophage phenotypes were elevated at day 3 after MI, but returned to baseline by 30 days after MI. In contrast, adult hearts after MI exhibited low vascular endothelial growth factor-alpha and persistent upregulation of all macrophage markers, consistent with prolonged inflammation, fibrosis, and remodeling. Inhibition of stromal cell-derived factor-1 alpha in fetal infarcts prevented angiogenesis, decreased vascular endothelial growth factor-alpha, and was associated with a sustained increase in M1, M2a, and M2c markers after MI. Conclusions. Changes in angiogenesis and macrophage phenotype-related gene expression after MI are important for the fetal regenerative response to MI and are mediated at least in part by cardiac progenitor cells recruitment. (C) 2017 by The Society of Thoracic Surgeons
引用
收藏
页码:1968 / 1976
页数:9
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