TY - JOUR
T1 - Stem cell differentiation requires a paracrine pathway in the heart
AU - Behfar, Atta
AU - Zingman, Leonid V.
AU - Hodgson, Denice M.
AU - Rauzier, Jean Michel
AU - Kane, Garvan C.
AU - Terzic, Andre
AU - Pucéat, Michel
PY - 2002/10
Y1 - 2002/10
N2 - Members of the transforming growth factor β1 (TGF-β) superfamily - namely, TGF-β and BMP2 - applied to undifferentiated murine embryonic stem cells up-regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription factors (Nkx2.5, MEF2C). Embryoid bodies generated from stem cells primed with these growth factors demonstrated an increased potential for cardiac differentiation with a significant increase in beating areas and enhanced myofibrillogenesis. In an environment of postmitotic cardiomyocytes, stem cells engineered to express a fluorescent protein under the control of a cardiac promoter differentiated into fluorescent ventricular myocytes beating in synchrony with host cells, a process significantly enhanced by TGF-β or BMP2. In vitro, disruption of the TGF-β/BMP signaling pathways by latency-associated peptide and/or noggin prevented differentiation of stem cells. In fact, only host cells that secrete a TGF-β family member induced a cardiac phenotype in stem cells. In vivo, transplantation of stem cells into heart also resulted in cardiac differentiation provided that TGF-β/BMP2 signaling was intact. In infarcted myocardium, grafted stem cells differentiated into functional cardiomyocytes integrated with surrounding tissue, improving contractile performance. Thus, embryonic stem cells are directed to differentiate into cardiomyocytes by signaling mediated through TGF-β/BMP2, a cardiac paracrine pathway required for therapeutic benefit of stem cell transplantation in diseased heart.
AB - Members of the transforming growth factor β1 (TGF-β) superfamily - namely, TGF-β and BMP2 - applied to undifferentiated murine embryonic stem cells up-regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription factors (Nkx2.5, MEF2C). Embryoid bodies generated from stem cells primed with these growth factors demonstrated an increased potential for cardiac differentiation with a significant increase in beating areas and enhanced myofibrillogenesis. In an environment of postmitotic cardiomyocytes, stem cells engineered to express a fluorescent protein under the control of a cardiac promoter differentiated into fluorescent ventricular myocytes beating in synchrony with host cells, a process significantly enhanced by TGF-β or BMP2. In vitro, disruption of the TGF-β/BMP signaling pathways by latency-associated peptide and/or noggin prevented differentiation of stem cells. In fact, only host cells that secrete a TGF-β family member induced a cardiac phenotype in stem cells. In vivo, transplantation of stem cells into heart also resulted in cardiac differentiation provided that TGF-β/BMP2 signaling was intact. In infarcted myocardium, grafted stem cells differentiated into functional cardiomyocytes integrated with surrounding tissue, improving contractile performance. Thus, embryonic stem cells are directed to differentiate into cardiomyocytes by signaling mediated through TGF-β/BMP2, a cardiac paracrine pathway required for therapeutic benefit of stem cell transplantation in diseased heart.
KW - Cardioblasts
KW - Cardiomyocytes
KW - Ischemic heart disease
KW - TGF-β
UR - http://www.scopus.com/inward/record.url?scp=0036793540&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036793540&partnerID=8YFLogxK
U2 - 10.1096/fj.02-0072com
DO - 10.1096/fj.02-0072com
M3 - Article
C2 - 12374778
AN - SCOPUS:0036793540
SN - 0892-6638
VL - 16
SP - 1558
EP - 1566
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -