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

doi:10.1016/j.cardiores.2007.05.013

Cardiovascular Research 2007 76(1):119-131; doi:10.1016/j.cardiores.2007.05.013

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

Shiro Baba^a^,*, Toshio Heike^a, Momoko Yoshimoto^a, Katsutsugu Umeda^a, Hiraku Doi^a, Toru Iwasa^a, Xue Lin^b, Satoshi Matsuoka^c, Masashi Komeda^b and Tatsutoshi Nakahata^a

^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) cellsare known to differentiate into mesodermal lineages such ashematopoietic and endothelial cells. Here we demonstrate thatthey can develop into cardiomyocytes that support functionalrecovery in a dilated cardiomyopathy (DCM) C57/BL6 mouse model.

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

Results Flk1⁺ cells, but not Flk1^– cells, isolated onday 4 after differentiation were efficiently converted intocontractile cardiomyocytes. RT-PCR analysis and immunohistologicalassays demonstrated that contractile cells derived from Flk1⁺cells in vitro expressed mature cardiac markers on day 10 afterdifferentiation. Transplantation of sorted Flk1⁺ cells intoDCM model mouse hearts improved cardiac function, as determinedby echocardiography and cardiac catheterization. The in vivodifferentiated Flk1⁺ cells expressed cardiac markers and hadgap junctions, as demonstrated by immunohistochemistry. Furthermore,these cells generated ventricular type action potentials similarto those of adult ventricle.

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

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

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