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G-CSF Promotes the Proliferation of Developing Cardiomyocytes In Vivo and in Derivation from ESCs and iPSCs
Kenichiro Shimoji, Shinsuke Yuasa, Takeshi Onizuka, Fumiyuki Hattori, Tomofumi Tanaka, Mie Hara, Yohei Ohno, Hao Chen, Toru Egasgira, Tomohisa Seki, Kojiro Yae, Uichi Koshimizu, Satoshi Ogawa, Keiichi Fukuda
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Tokyo 160-8582, Japan Cardiology Division, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan Biomedical Research Laboratories, Asubio Pharma Co., Ltd., Tokyo 618-8513, Japan Corresponding author These authors contributed equally to this work
During a screen for humoral factors that promote cardiomyocyte differentiation from embryonic stem cells (ESCs), we found marked elevation of granulocyte colony-stimulating factor receptor (G-CSFR) mRNA in developing cardiomyocytes. We confirmed that both G-CSFR and G-CSF were specifically expressed in embryonic mouse heart at the midgestational stage, and expression levels were maintained throughout embryogenesis. Intrauterine G-CSF administration induced embryonic cardiomyocyte proliferation and caused hyperplasia. In contrast, approximately 50% of csf3r–/– mice died during late embryogenesis because of the thinning of atrioventricular walls. ESC-derived developing cardiomyocytes also strongly expressed G-CSFR. When extrinsic G-CSF was administered to the ESC- and human iPSC-derived cardiomyocytes, it markedly augmented their proliferation. Moreover, G-CSF-neutralizing antibody inhibited their proliferation. These findings indicated that G-CSF is critically involved in cardiomyocyte proliferation during development, and may be used to boost the yield of cardiomyocytes from ESCs for their potential application to regenerative medicine.
