title: The use of aggregates of purified cardiomyocytes derived from human ESCs for functional engraftment after myocardial infarction.
abstract: Embryonic stem cells (ESCs) have the capacity to undergo directed differentiation into contracting cardiomyocytes. Therefore, functional cardiomyocytes derived from human embryonic stem cells (hESC-CMs) are potential candidates for cellular cardiomyoplasty to regenerate the myocardium after infarction. However, the directed differentiation of hESCs induces not only contracting cardiomyocytes but also other cell types. Thus, a risk of teratoma formation and oncologic transformation exists following the transplantation of hESC-CMs containing other cell lineages. In addition, the transplantation of hESC-CMs into the infarcted myocardium limits therapeutic efficacy due to low viability and poor engraftment. In this study, we established an efficient preparation method to obtain pure contracting cardiomyocytes from hESCs. We also developed a delivery system to achieve enhanced viability and a functional connection with the host myocardium after transplantation in a myocardial infarction model. A serum-free medium was used to obtain pure contracting cardiomyocytes from other cell lineages after the cardiac differentiation of hESCs. Aggregates of purified hESC-CMs were formed, and then the expression of cardiomyocyte-specific markers and the viability of the aggregated CMs were examined in hypoxic conditions. In addition, we determined whether the viability of the hESC-CMs and their ability to engraft with the host myocardium could be enhanced by transplanting them as aggregates in a myocardial infarction model. The therapeutic efficacy of the cardiomyocytes was examined by immunohistochemical analyses as well as physiological analyses of left-ventricular function. We found that the transplantation of contracting hESC-CM aggregates improved their survival and function in infarcted rat hearts in comparison to the transplantation of dissociated cells. Our method using hESC-CMs can be considered an effective strategy for clinical applications without critical barriers.
authors: Stem Cell Research Laboratory, CHA Stem Cell Institute, CHA University, Seoul, South Korea.
authors: Sung-Hwan
authors: SH
authors: Moon
authors: Department of Orthopedic Surgery, Korea University Ansan Hospital, Ansan, South Korea.
authors: Sun-Woong
authors: SW
authors: Kang
authors: Stem Cell Research Laboratory, CHA Stem Cell Institute, CHA University, Seoul, South Korea.
authors: Soon-Jung
authors: SJ
authors: Park
authors: CHA Bio & Diostech Co., Ltd., Seoul, South Korea.
authors: Daekyeong
authors: D
authors: Bae
authors: Laboratory of Cardiovascular Physiology and Ion Channel Signaling, Department of Physiology, Seoul National University College of Medicine, Seoul, South Korea.
authors: Sung Joon
authors: SJ
authors: Kim
authors: Laboratory of Cardiovascular Physiology and Ion Channel Signaling, Department of Physiology, Seoul National University College of Medicine, Seoul, South Korea; Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Daejeon, South Korea.
authors: Hyang-Ae
authors: HA
authors: Lee
authors: Laboratory of Cardiovascular Physiology and Ion Channel Signaling, Department of Physiology, Seoul National University College of Medicine, Seoul, South Korea.
authors: Kyung Soo
authors: KS
authors: Kim
authors: CHA Bio & Diostech Co., Ltd., Seoul, South Korea.
authors: Ki-Sung
authors: KS
authors: Hong
authors: Department of Animal Biotechnology, College of Animal Bioscience and Technology, Konkuk University, Seoul, South Korea.
authors: Jong Soo
authors: JS
authors: Kim
authors: Department of Animal Biotechnology, College of Animal Bioscience and Technology, Konkuk University, Seoul, South Korea.
authors: Jeong Tae
authors: JT
authors: Do
authors: Division of Cardiology, Department of Internal Medicine, Kwandong University College of Medicine, Myongji Hospital Cardiac Center, Seoul, South Korea.
authors: Ki Hyun
authors: KH
authors: Byun
authors: Stem Cell Research Laboratory, CHA Stem Cell Institute, CHA University, Seoul, South Korea; CHA Bio & Diostech Co., Ltd., Seoul, South Korea. Electronic address: stemchung@gmail.com.
authors: Hyung-Min
authors: HM
authors: Chung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D058732:Embryoid Bodies / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects; D033581:Stem Cell Transplantation; D014463:Ultrasonography
chemical_list: D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free