title: A Shh coreceptor Cdo is required for efficient cardiomyogenesis of pluripotent stem cells.
abstract: Sonic hedgehog (Shh) signaling plays an important role for early heart development, such as heart looping and cardiomyogenesis of pluripotent stem cells. A multifunctional receptor Cdo functions as a Shh coreceptor together with Boc and Gas1 to activate Shh signaling and these coreceptors seem to play compensatory roles in early heart development. Thus in this study, we examined the role of Cdo in cardiomyogenesis by utilizing an in vitro differentiation of pluripotent stem cells. Here we show that Cdo is required for efficient cardiomyogenesis of pluripotent stem cells by activation of Shh signaling. Cdo is induced concurrently with Shh signaling activation upon induction of cardiomyogenesis of P19 embryonal carcinoma (EC) cells. Cdo-depleted P19 EC and Cdo(-/-) mouse embryonic stem (ES) cells display decreased expression of key cardiac regulators, including Gata4, Nkx2.5 and Mef2c and this decrease coincides with reduced Shh signaling activities. Furthermore Cdo deficiency causes a stark reduction in formation of mature contractile cardiomyocytes. This defect in cardiomyogenesis is overcome by reactivation of Shh signaling at the early specification stage of cardiomyogenesis. The Shh agonist treatment restores differentiation capacities of Cdo-deficient ES cells into contractile cardiomyocytes by recovering both the expression of early cardiac regulators and structural genes such as cardiac troponin T and Connexin 43. Therefore Cdo is required for efficient cardiomyogenesis of pluripotent stem cells and an excellent target to improve the differentiation potential of stem cells for generation of transplantable cells to treat cardiomyopathies.
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-Ro, Jangan-gu, Suwon, Gyunggi-do 440-746, Republic of Korea; Samsung Biomedical Research Institute, Suwon 440-746, Republic of Korea.
authors.forename: Myong-Ho
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-Ro, Jangan-gu, Suwon, Gyunggi-do 440-746, Republic of Korea; Samsung Biomedical Research Institute, Suwon 440-746, Republic of Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Leem
authors.affiliation: Department of Physiology, Sungkyunkwan University School of Medicine, 2066, Seobu-Ro, Jangan-gu, Suwon, Gyunggi-do 440-746, Republic of Korea; Samsung Biomedical Research Institute, Suwon 440-746, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-Ro, Jangan-gu, Suwon, Gyunggi-do 440-746, Republic of Korea; Samsung Biomedical Research Institute, Suwon 440-746, Republic of Korea.
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kang
authors.affiliation: Department of Physiology, Sungkyunkwan University School of Medicine, 2066, Seobu-Ro, Jangan-gu, Suwon, Gyunggi-do 440-746, Republic of Korea; Samsung Biomedical Research Institute, Suwon 440-746, Republic of Korea. Electronic address: hanacho@skku.edu.
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-Ro, Jangan-gu, Suwon, Gyunggi-do 440-746, Republic of Korea; Samsung Biomedical Research Institute, Suwon 440-746, Republic of Korea. Electronic address: kangj01@skku.edu.
authors.forename: Jong-Sun
authors.initials: JS
authors.lastname: Kang
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D018031:Connexin 43 / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D055786:Gene Knockout Techniques; D006321:Heart / Q000196:embryology*; D053823:Hedgehog Proteins / Q000819:agonists / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D038081:Organogenesis / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; D018031:Connexin 43; D053823:Hedgehog Proteins
keywords: Cardiomyocytes; Cardiomyogenesis; Cdo; Connexin 43; Sonic hedgehog; Stem cells