Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: role of the pericardial fluid.
Stem cells expressing c-kit have been identified in the adult epicardium. In mice, after myocardial infarction, these cells proliferate, migrate to the injury site and differentiate toward myocardial and vascular phenotype. We hypothesized that, acutely after myocardial infarction, pericardial sac integrity and pericardial fluid (PF) may play a role on epicardial cell gene expression, proliferation and differentiation. Microarray analysis indicated that, in the presence of an intact pericardial sac, myocardial infarction modulated 246 genes in epicardial cells most of which were related to cell proliferation, cytoskeletal organization, wound repair and signal transduction. Interestingly, WT1, Tbx18 and RALDH2, notably involved in epicardial embryonic development, were markedly up-regulated. Importantly, coexpression of stem cell antigen c-kit and WT1 and/or Tbx18 was detected by immunohistochemistry in the mouse epicardium during embryogenesis as well as in adult mouse infarcted heart. Injection of human pericardial fluid from patients with acute myocardial ischemia (PFMI) in the pericardial cavity of non-infarcted mouse hearts, enhanced, epicardial cell proliferation and WT1 expression. Further, PFMI supplementation to hypoxic cultured human epicardial c-kit(+) cells increased WT1 and Tbx18 mRNA expression. Finally, insulin-like growth factor 1, hepatocyte growth factor and high mobility group box 1 protein, previously involved in cardiac c-kit(+) cell proliferation and differentiation, were increased in PFMI compared to the pericardial fluid of non ischemic patients. In conclusion, myocardial infarction reactivates an embryonic program in epicardial c-kit(+) cells; soluble factors released in the pericardial fluids following myocardial necrosis may play a role in this process.
Limana
Federica
F
Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy. fe_limana@hotmail.com
Bertolami
Chiara
C
Mangoni
Antonella
A
Di Carlo
Anna
A
Avitabile
Daniele
D
Mocini
David
D
Iannelli
Pina
P
De Mori
Roberta
R
Marchetti
Carlo
C
Pozzoli
Ombretta
O
Gentili
Carlo
C
Zacheo
Antonella
A
Germani
Antonia
A
Capogrossi
Maurizio C
MC
D000368:Aged; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D010490:Pericardial Effusion / Q000378:metabolism; D010496:Pericardium / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025721:WT1 Proteins / Q000378:metabolism
D025721:WT1 Proteins; D019009:Proto-Oncogene Proteins c-kit