TY - JOUR
T1 - Reprogramming of human fibroblasts toward a cardiac fate
AU - Nam, Young Jae
AU - Song, Kunhua
AU - Luo, Xiang
AU - Daniel, Edward
AU - Lambeth, Kaleb
AU - West, Katherine
AU - Hill, Joseph A.
AU - Di Maio, J. Michael
AU - Baker, Linda A.
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
PY - 2013/4/2
Y1 - 2013/4/2
N2 - Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including GATA binding protein 4, Hand2, T-box5, and myocardin, and twomicroRNAs,miR-1 andmiR-133, activated cardiacmarker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4-11 wk, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of nonmyocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-likemyocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach.
AB - Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including GATA binding protein 4, Hand2, T-box5, and myocardin, and twomicroRNAs,miR-1 andmiR-133, activated cardiacmarker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4-11 wk, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of nonmyocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-likemyocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach.
KW - Cardiogenesis
KW - Cell fate specification
KW - Phenotypic switching
KW - Regeneration
UR - http://www.scopus.com/inward/record.url?scp=84875848994&partnerID=8YFLogxK
U2 - 10.1073/pnas.1301019110
DO - 10.1073/pnas.1301019110
M3 - Article
C2 - 23487791
AN - SCOPUS:84875848994
SN - 0027-8424
VL - 110
SP - 5588
EP - 5593
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -