RATIONALE: The regenerative capacity of the heart is markedly diminished shortly after birth, coinciding with overall withdrawal of cardiomyocytes from cell cycle. Consequently, the adult mammalian heart has limited capacity to regenerate after injury. The discovery of factors that can induce cardiomyocyte proliferation is, therefore, of high interest and has been the focus of extensive investigation throughout the past years. OBJECTIVE: We have recently identified C3orf58 as a novel hypoxia and Akt induced stem cell factor (HASF) secreted from mesenchymal stem cells, which can promote cardiac repair through cytoprotective mechanisms. Here, we tested the hypothesis that HASF can also contribute to cardiac regeneration by stimulating cardiomyocyte division and proliferation. METHODS AND RESULTS: Neonatal ventricular cardiomyocytes were stimulated in culture for 7 days with purified recombinant HASF protein. Compared with control untreated cells, HASF-treated neonatal cardiomyocytes exhibited 60% increase in DNA synthesis as measured by bromodeoxyuridine incorporation. These results were confirmed by immunofluorescence confocal microscopy showing a 50% to 100% increase in the number of cardiomyocytes in the mitotic and cytokinesis phases. Importantly, in vivo cardiac overexpression of HASF in a transgenic mouse model resulted in enhanced level of DNA synthesis and cytokinesis in neonatal and adult cardiomyocytes. These proliferative effects were modulated by a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway as revealed by the use of phosphoinositide 3-kinase -pathway-specific inhibitors and silencing of the Cdk7 gene. CONCLUSIONS: Our studies support the hypothesis that HASF induces cardiomyocyte proliferation via a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway. The implications of this finding may be significant for cardiac regeneration biology and therapeutics.
RATIONALE: The regenerative capacity of the heart is markedly diminished shortly after birth, coinciding with overall withdrawal of cardiomyocytes from cell cycle. Consequently, the adult mammalian heart has limited capacity to regenerate after injury. The discovery of factors that can induce cardiomyocyte proliferation is, therefore, of high interest and has been the focus of extensive investigation throughout the past years. OBJECTIVE: We have recently identified C3orf58 as a novel hypoxia and Akt induced stem cell factor (HASF) secreted from mesenchymal stem cells, which can promote cardiac repair through cytoprotective mechanisms. Here, we tested the hypothesis that HASF can also contribute to cardiac regeneration by stimulating cardiomyocyte division and proliferation. METHODS AND RESULTS:Neonatal ventricular cardiomyocytes were stimulated in culture for 7 days with purified recombinant HASF protein. Compared with control untreated cells, HASF-treated neonatal cardiomyocytes exhibited 60% increase in DNA synthesis as measured by bromodeoxyuridine incorporation. These results were confirmed by immunofluorescence confocal microscopy showing a 50% to 100% increase in the number of cardiomyocytes in the mitotic and cytokinesis phases. Importantly, in vivo cardiac overexpression of HASF in a transgenicmouse model resulted in enhanced level of DNA synthesis and cytokinesis in neonatal and adult cardiomyocytes. These proliferative effects were modulated by a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway as revealed by the use of phosphoinositide 3-kinase -pathway-specific inhibitors and silencing of the Cdk7 gene. CONCLUSIONS: Our studies support the hypothesis that HASF induces cardiomyocyte proliferation via a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway. The implications of this finding may be significant for cardiac regeneration biology and therapeutics.
Authors: Natalie Gude; John Muraski; Marta Rubio; Jan Kajstura; Erik Schaefer; Piero Anversa; Mark A Sussman Journal: Circ Res Date: 2006-07-13 Impact factor: 17.367
Authors: Stéphane Larochelle; Karl A Merrick; Marie-Emilie Terret; Lara Wohlbold; Nora M Barboza; Chao Zhang; Kevan M Shokat; Prasad V Jallepalli; Robert P Fisher Journal: Mol Cell Date: 2007-03-23 Impact factor: 17.970
Authors: Motoaki Sano; Yasukatsu Izumi; Katja Helenius; Masanori Asakura; Derrick J Rossi; Min Xie; George Taffet; Lingyun Hu; Robia G Pautler; Christopher R Wilson; Sihem Boudina; E Dale Abel; Heinrich Taegtmeyer; Fernando Scaglia; Brett H Graham; Anastasia Kralli; Noriaki Shimizu; Hirotoshi Tanaka; Tomi P Mäkelä; Michael D Schneider Journal: Cell Metab Date: 2007-02 Impact factor: 27.287
Authors: Mahasweta Girgenrath; Shawn Weng; Christine A Kostek; Beth Browning; Monica Wang; Sharron A N Brown; Jeffrey A Winkles; Jennifer S Michaelson; Norm Allaire; Pascal Schneider; Martin L Scott; Yen-ming Hsu; Hideo Yagita; Richard A Flavell; Jeffrey Boone Miller; Linda C Burkly; Timothy S Zheng Journal: EMBO J Date: 2006-11-23 Impact factor: 11.598
Authors: Jonathan T Butcher; Russell A Norris; Stanley Hoffman; Corey H Mjaatvedt; Roger R Markwald Journal: Dev Biol Date: 2006-10-04 Impact factor: 3.582
Authors: Eric M Morrow; Seung-Yun Yoo; Steven W Flavell; Tae-Kyung Kim; Yingxi Lin; Robert Sean Hill; Nahit M Mukaddes; Soher Balkhy; Generoso Gascon; Asif Hashmi; Samira Al-Saad; Janice Ware; Robert M Joseph; Rachel Greenblatt; Danielle Gleason; Julia A Ertelt; Kira A Apse; Adria Bodell; Jennifer N Partlow; Brenda Barry; Hui Yao; Kyriacos Markianos; Russell J Ferland; Michael E Greenberg; Christopher A Walsh Journal: Science Date: 2008-07-11 Impact factor: 47.728
Authors: Bernhard Kühn; Federica del Monte; Roger J Hajjar; Yuh-Shin Chang; Djamel Lebeche; Shima Arab; Mark T Keating Journal: Nat Med Date: 2007-07-15 Impact factor: 53.440