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Cardiovascular Research 2007 76(1):119-131; doi:10.1016/j.cardiores.2007.05.013
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Copyright © 2007, European Society of Cardiology

Flk1+ cardiac stem/progenitor cells derived from embryonic stem cells improve cardiac function in a dilated cardiomyopathy mouse model

Shiro Babaa,*, Toshio Heikea, Momoko Yoshimotoa, Katsutsugu Umedaa, Hiraku Doia, Toru Iwasaa, Xue Linb, Satoshi Matsuokac, Masashi Komedab and Tatsutoshi Nakahataa

aDepartment of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
bDepartment of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
cDepartment of Physiology and Biophysics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

*Corresponding author. Tel.: +81 75 751 3295; fax: +81 75 752 2361. shibaba{at}kuhp.kyoto-u.ac.jp

Objectives Flk1+ cells derived from embryonic stem (ES) cells are known to differentiate into mesodermal lineages such as hematopoietic and endothelial cells. Here we demonstrate that they can develop into cardiomyocytes that support functional recovery in a dilated cardiomyopathy (DCM) C57/BL6 mouse model.

Methods Flk1+ and Flk1– cells were sorted at day 4 of differentiation, and cardiomyogenesis was assessed in vitro. Next, we transplanted these cells into the hearts of cardiomyopathy mice to assess improvement in cardiac function.

Results Flk1+ cells, but not Flk1– cells, isolated on day 4 after differentiation were efficiently converted into contractile cardiomyocytes. RT-PCR analysis and immunohistological assays demonstrated that contractile cells derived from Flk1+ cells in vitro expressed mature cardiac markers on day 10 after differentiation. Transplantation of sorted Flk1+ cells into DCM model mouse hearts improved cardiac function, as determined by echocardiography and cardiac catheterization. The in vivo differentiated Flk1+ cells expressed cardiac markers and had gap junctions, as demonstrated by immunohistochemistry. Furthermore, these cells generated ventricular type action potentials similar to those of adult ventricle.

Conclusion These results indicate that Flk1 is a good marker for sorting cardiac stem/progenitor cells which can differentiate into mature cardiomyocytes both in vitro and in vivo.

KEYWORDS Cell culture/isolation; Cell differentiation; Cell therapy; Cardiomyopathy


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