title: Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: role of the pericardial fluid.
abstract: 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.
authors.affiliation: Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy. fe_limana@hotmail.com
authors.forename: Federica
authors.initials: F
authors.lastname: Limana
authors.forename: Chiara
authors.initials: C
authors.lastname: Bertolami
authors.forename: Antonella
authors.initials: A
authors.lastname: Mangoni
authors.forename: Anna
authors.initials: A
authors.lastname: Di Carlo
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.forename: David
authors.initials: D
authors.lastname: Mocini
authors.forename: Pina
authors.initials: P
authors.lastname: Iannelli
authors.forename: Roberta
authors.initials: R
authors.lastname: De Mori
authors.forename: Carlo
authors.initials: C
authors.lastname: Marchetti
authors.forename: Ombretta
authors.initials: O
authors.lastname: Pozzoli
authors.forename: Carlo
authors.initials: C
authors.lastname: Gentili
authors.forename: Antonella
authors.initials: A
authors.lastname: Zacheo
authors.forename: Antonia
authors.initials: A
authors.lastname: Germani
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
mesh_terms: 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
chemical_list: D025721:WT1 Proteins; D019009:Proto-Oncogene Proteins c-kit