RATIONALE: Direct reprogramming of fibroblasts into cardiomyocytes is a novel strategy for cardiac regeneration. However, the key determinants involved in this process are unknown. OBJECTIVE: To assess the efficiency of direct fibroblast reprogramming via viral overexpression of GATA4, Mef2c, and Tbx5 (GMT). METHODS AND RESULTS: We induced GMT overexpression in murine tail tip fibroblasts (TTFs) and cardiac fibroblasts (CFs) from multiple lines of transgenic mice carrying different cardiomyocyte lineage reporters. We found that the induction of GMT overexpression in TTFs and CFs is inefficient at inducing molecular and electrophysiological phenotypes of mature cardiomyocytes. In addition, transplantation of GMT infected CFs into injured mouse hearts resulted in decreased cell survival with minimal induction of cardiomyocyte genes. CONCLUSIONS: Significant challenges remain in our ability to convert fibroblasts into cardiomyocyte-like cells and a greater understanding of cardiovascular epigenetics is needed to increase the translational potential of this strategy.
RATIONALE: Direct reprogramming of fibroblasts into cardiomyocytes is a novel strategy for cardiac regeneration. However, the key determinants involved in this process are unknown. OBJECTIVE: To assess the efficiency of direct fibroblast reprogramming via viral overexpression of GATA4, Mef2c, and Tbx5 (GMT). METHODS AND RESULTS: We induced GMT overexpression in murine tail tip fibroblasts (TTFs) and cardiac fibroblasts (CFs) from multiple lines of transgenic mice carrying different cardiomyocyte lineage reporters. We found that the induction of GMT overexpression in TTFs and CFs is inefficient at inducing molecular and electrophysiological phenotypes of mature cardiomyocytes. In addition, transplantation of GMT infected CFs into injured mouse hearts resulted in decreased cell survival with minimal induction of cardiomyocyte genes. CONCLUSIONS: Significant challenges remain in our ability to convert fibroblasts into cardiomyocyte-like cells and a greater understanding of cardiovascular epigenetics is needed to increase the translational potential of this strategy.
Authors: Linda W van Laake; Robert Passier; Jantine Monshouwer-Kloots; Arie J Verkleij; Daniel J Lips; Christian Freund; Krista den Ouden; Dorien Ward-van Oostwaard; Jeroen Korving; Leon G Tertoolen; Cees J van Echteld; Pieter A Doevendans; Christine L Mummery Journal: Stem Cell Res Date: 2007-08-17 Impact factor: 2.020
Authors: Zongjin Li; Andrew Lee; Mei Huang; Hyung Chun; Jaehoon Chung; Pauline Chu; Grant Hoyt; Phillip Yang; Jarrett Rosenberg; Robert C Robbins; Joseph C Wu Journal: J Am Coll Cardiol Date: 2009-04-07 Impact factor: 24.094
Authors: Kazu Kikuchi; Jennifer E Holdway; Andreas A Werdich; Ryan M Anderson; Yi Fang; Gregory F Egnaczyk; Todd Evans; Calum A Macrae; Didier Y R Stainier; Kenneth D Poss Journal: Nature Date: 2010-03-25 Impact factor: 49.962
Authors: Thomas Vierbuchen; Austin Ostermeier; Zhiping P Pang; Yuko Kokubu; Thomas C Südhof; Marius Wernig Journal: Nature Date: 2010-01-27 Impact factor: 49.962