title: Directed cardiomyogenesis of human pluripotent stem cells by modulating Wnt/β-catenin and BMP signalling with small molecules.
abstract: Cardiomyocytes derived from human pluripotent stem cells (PSCs) are a potential cell source for regenerative medicine, disease modelling and drug development. However, current approaches for in vitro cardiac differentiation of human PSCs are often time-consuming, heavily depend on expensive growth factors and involve the tedious formation of embryonic bodies whose signalling pathways are difficult to precisely modulate due to their complex microenvironments. In the present study, we report a new small molecule-based differentiation approach, which significantly promoted contracting cardiomyocytes in human PSCs in a monolayer format in as little as 7 days, in contrast with most traditional differentiation methods that usually take up to 3 weeks for cardiomyogenesis. This approach consists in activation of the Wnt/β-catenin signalling at day 0-1 with small molecule CHIR99021 (CH) followed by inhibition of bone morphogenetic protein (BMP) signalling at day 1-4 with DMH1 [termed as CH(0-1)/DMH1(1-4) treatment], a selective small molecule BMP inhibitor reported by us previously. Our study further demonstrated that the CH(0-1)/DMH1(1-4) treatment significantly promotes cardiac formation via mesoderm and mesoderm-derived cardiac progenitor cells without impacts on either endoderm or ectoderm differentiation of human PSCs. This rapid, efficient and inexpensive small molecule-based cardiomyogenic method may potentially harness the use of human PSCs in regenerative medicine as well as other applications.
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, U.S.A.
authors.forename: Jose S
authors.initials: JS
authors.lastname: Aguilar
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, U.S.A.
authors.forename: Aynun N
authors.initials: AN
authors.lastname: Begum
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, U.S.A.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Alvarez
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA 92354, U.S.A.
authors.forename: Xiao-bing
authors.initials: XB
authors.lastname: Zhang
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, U.S.A. Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, U.S.A.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Hong
authors.affiliation: College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, U.S.A. Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, U.S.A. jhao@westernu.edu.
authors.forename: Jijun
authors.initials: J
authors.lastname: Hao
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D024510:Muscle Development; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D019485:Bone Morphogenetic Proteins; C473711:Chir 99021; C583032:DMH1 compound; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011804:Quinolines
keywords: BMP; ESCs; Wnt/beta-catenin; cardiomyogenesis; iPSCs; small molecules and DMH1