title: Three-Dimensional Adult Cardiac Extracellular Matrix Promotes Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
abstract: Pluripotent stem cell-derived cardiomyocytes (CMs) have great potential in the development of new therapies for cardiovascular disease. In particular, human induced pluripotent stem cells (iPSCs) may prove especially advantageous due to their pluripotency, their self-renewal potential, and their ability to create patient-specific cell lines. Unfortunately, pluripotent stem cell-derived CMs are immature, with characteristics more closely resembling fetal CMs than adult CMs, and this immaturity has limited their use in drug screening and cell-based therapies. Extracellular matrix (ECM) influences cellular behavior and maturation, as does the geometry of the environment-two-dimensional (2D) versus three-dimensional (3D). We therefore tested the hypothesis that native cardiac ECM and 3D cultures might enhance the maturation of iPSC-derived CMs in vitro. We demonstrate that maturation of iPSC-derived CMs was enhanced when cells were seeded into a 3D cardiac ECM scaffold, compared with 2D culture. 3D cardiac ECM promoted increased expression of calcium-handling genes, Junctin, CaV1.2, NCX1, HCN4, SERCA2a, Triadin, and CASQ2. Consistent with this, we find that iPSC-derived CMs in 3D adult cardiac ECM show increased calcium signaling (amplitude) and kinetics (maximum upstroke and downstroke) compared with cells in 2D. Cells in 3D culture were also more responsive to caffeine, likely reflecting an increased availability of calcium in the sarcoplasmic reticulum. Taken together, these studies provide novel strategies for maturing iPSC-derived CMs that may have applications in drug screening and transplantation therapies to treat heart disease.
authors.affiliation: 1 Department of Molecular Biology and Biochemistry, School of Biological Sciences , UC Irvine, Irvine, California.
authors.forename: Ashley H
authors.initials: AH
authors.lastname: Fong
authors.affiliation: 2 Department of Biomedical Engineering, The Henry Samueli School of Engineering , UC Irvine, Irvine, California.
authors.forename: Mónica
authors.initials: M
authors.lastname: Romero-López
authors.affiliation: 2 Department of Biomedical Engineering, The Henry Samueli School of Engineering , UC Irvine, Irvine, California.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Heylman
authors.affiliation: 2 Department of Biomedical Engineering, The Henry Samueli School of Engineering , UC Irvine, Irvine, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Keating
authors.affiliation: 3 Department of Chemical Engineering and Material Science, The Henry Samueli School of Engineering , UC Irvine, Irvine, California.
authors.forename: David
authors.initials: D
authors.lastname: Tran
authors.affiliation: 1 Department of Molecular Biology and Biochemistry, School of Biological Sciences , UC Irvine, Irvine, California.
authors.forename: Agua
authors.initials: A
authors.lastname: Sobrino
authors.affiliation: 1 Department of Molecular Biology and Biochemistry, School of Biological Sciences , UC Irvine, Irvine, California.
authors.forename: Anh Q
authors.initials: AQ
authors.lastname: Tran
authors.affiliation: 1 Department of Molecular Biology and Biochemistry, School of Biological Sciences , UC Irvine, Irvine, California.
authors.forename: Hiep H
authors.initials: HH
authors.lastname: Pham
authors.affiliation: 1 Department of Molecular Biology and Biochemistry, School of Biological Sciences , UC Irvine, Irvine, California.
authors.forename: Cristhian
authors.initials: C
authors.lastname: Fimbres
authors.affiliation: 1 Department of Molecular Biology and Biochemistry, School of Biological Sciences , UC Irvine, Irvine, California.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gershon
authors.affiliation: 2 Department of Biomedical Engineering, The Henry Samueli School of Engineering , UC Irvine, Irvine, California.|4 The Edwards Lifesciences Center for Advanced Cardiovascular Technology , UC Irvine, Irvine, California.
authors.forename: Elliot L
authors.initials: EL
authors.lastname: Botvinick
authors.affiliation: 5 Department of Biomedical Engineering, School of Engineering and Applied Science, Washington University in St. Louis , St. Louis, Missouri.
authors.forename: Steven C
authors.initials: SC
authors.lastname: George
authors.affiliation: 1 Department of Molecular Biology and Biochemistry, School of Biological Sciences , UC Irvine, Irvine, California.|2 Department of Biomedical Engineering, The Henry Samueli School of Engineering , UC Irvine, Irvine, California.|4 The Edwards Lifesciences Center for Advanced Cardiovascular Technology , UC Irvine, Irvine, California.
authors.forename: Christopher C W
authors.initials: CC
authors.lastname: Hughes
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D002417:Cattle; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000737:chemistry*; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D000943:Antigens, Differentiation