Document Detail


Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells.
MedLine Citation:
PMID:  23461462     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Despite preclinical studies demonstrating the functional benefit of transplanting human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) into damaged myocardium, the ability of these immature cells to adopt a more adult-like cardiomyocyte (CM) phenotype remains uncertain. To address this issue, we tested the hypothesis that prolonged in vitro culture of human embryonic stem cell (hESC)- and human induced pluripotent stem cell (hiPSC)-derived CMs would result in the maturation of their structural and contractile properties to a more adult-like phenotype. Compared to their early-stage counterparts (PSC-CMs after 20-40 days of in vitro differentiation and culture), late-stage hESC-CMs and hiPSC-CMs (80-120 days) showed dramatic differences in morphology, including increased cell size and anisotropy, greater myofibril density and alignment, sarcomeres visible by bright-field microscopy, and a 10-fold increase in the fraction of multinucleated CMs. Ultrastructural analysis confirmed improvements in the myofibrillar density, alignment, and morphology. We measured the contractile performance of late-stage hESC-CMs and hiPSC-CMs and noted a doubling in shortening magnitude with slowed contraction kinetics compared to the early-stage cells. We then examined changes in the calcium-handling properties of these matured CMs and found an increase in calcium release and reuptake rates with no change in the maximum amplitude. Finally, we performed electrophysiological assessments in hESC-CMs and found that late-stage myocytes have hyperpolarized maximum diastolic potentials, increased action potential amplitudes, and faster upstroke velocities. To correlate these functional changes with gene expression, we performed qPCR and found a robust induction of the key cardiac structural markers, including β-myosin heavy chain and connexin-43, in late-stage hESC-CMs and hiPSC-CMs. These findings suggest that PSC-CMs are capable of slowly maturing to more closely resemble the phenotype of adult CMs and may eventually possess the potential to regenerate the lost myocardium with robust de novo force-producing tissue.
Authors:
Scott D Lundy; Wei-Zhong Zhu; Michael Regnier; Michael A Laflamme
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-05
Journal Detail:
Title:  Stem cells and development     Volume:  22     ISSN:  1557-8534     ISO Abbreviation:  Stem Cells Dev.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-02     Completed Date:  2014-01-21     Revised Date:  2014-08-03    
Medline Journal Info:
Nlm Unique ID:  101197107     Medline TA:  Stem Cells Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1991-2002     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Action Potentials / physiology*
Biological Markers / metabolism
Calcium / metabolism
Cell Differentiation
Cells, Cultured
Connexin 43 / genetics,  metabolism
Embryonic Stem Cells / cytology,  physiology*
Gene Expression
Humans
Induced Pluripotent Stem Cells / cytology,  physiology*
Myocytes, Cardiac / cytology,  physiology*
Myofibrils / physiology*,  ultrastructure
Patch-Clamp Techniques
Time Factors
Ventricular Myosins / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
K08 HL080431/HL/NHLBI NIH HHS; K08-HL80431/HL/NHLBI NIH HHS; P01 HL094374/HL/NHLBI NIH HHS; P01-HL094374/HL/NHLBI NIH HHS; R01 HL064387/HL/NHLBI NIH HHS; R01 HL111197/HL/NHLBI NIH HHS; R01-HL064387/HL/NHLBI NIH HHS; R01-HL111197/HL/NHLBI NIH HHS; R21 HL091368/HL/NHLBI NIH HHS; R21-HL091368/HL/NHLBI NIH HHS; T32 GM007266/GM/NIGMS NIH HHS; T32 HL007828/HL/NHLBI NIH HHS; T32-GM 7266-37/GM/NIGMS NIH HHS; U01-HL09997/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Connexin 43; EC 3.6.1.-/Ventricular Myosins; SY7Q814VUP/Calcium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  [Dilution volume of intravenous drugs in patients under fluid restriction therapy].
Next Document:  Vibrationally Hot Bands of the SiCN Ã 2? - X 2? System.