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Cited by 878Congenital heart defects researchTissue Engineering and Regenerative MedicineMesenchymal stem cell research

Cardiomyocyte Grafting for Cardiac Repair: Graft Cell Death and Anti-Death Strategies

Zhang, Ming, Methot, Danielle, Poppa, Veronica, Fujio, Yasushi, Walsh, Kenneth, Murry, Charles E.·2001·Journal of Molecular and Cellular Cardiology
DOI 10.1006/jmcc.2001.1367
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Abstract

M. Zhang, D. Methot, V. Poppa, Y. Fujio, K. Walsh and C. E. Murry. Cardiomyocyte Grafting for Cardiac Repair: Graft Cell Death and Anti-Death Strategies. Journal of Molecular and Cellular Cardiology (2001) 33, 907-921. Recent studies indicate that cardiomyocyte grafting forms new myocardium in injured hearts. It is unknown, however, whether physiologically significant amounts of new myocardium can be generated. Pilot experiments showed that death of grafted rat neonatal cardiomyocytes limited formation of new myocardium after acute cryoinjury. Time-course studies showed that, at 30 min after grafting, only 1.8(+/-0.4)% of graft cells were TUNEL-positive. At 1 day, however, TUNEL indices increased to 32.1(+/-3.5)% and remained high at 4 days, averaging 9.8(+/-3.8)%. By 7 days, TUNEL decreased to 1.0(+/-0.2)%. Electron microscopy revealed that dead cells had features of both irreversible ischemic injury and apoptosis. To test whether ischemia contributed to poor graft survival, grafts were placed into vascularized 2-week-old cardiac granulation tissue or normal myocardium. TUNEL indices were reduced by 53% and 86%, respectively. Adenoviral infection of graft cells with the cytoprotective kinase Akt, or constitutively active Akt, reduced TUNEL indices by 31% and 40%, respectively, compared to beta -gal-transfected controls. Neither treatment reached statistical significance compared to untreated controls, however. Heat shock reduced cardiomyocyte death in vitro in response to serum deprivation, glucose depletion, and viral activation of the Fas death pathway. When cardiomyocytes were heat shocked prior to grafting, graft cell death in vivo was reduced by 54% at day 1. Therefore, high levels of cardiomyocyte death occur for at least 4 days after grafting into injured hearts, in large part due to ischemia. Death can be limited by activating the Akt pathway and even more effectively by heat shock prior to transplantation.

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  • Studies show that 50-90% of injected cells are lost by extrusion and that ∼90% of remaining cells die within 1 wk of implantation.

    “Studies show that 50–90% of injected cells are lost by extrusion (1) and that ∼90% of remaining cells die within 1 wk of implantation (2).”

    From Proangiogenic scaffolds as functional templates for cardiac tissue engineering (2010) · cites this paper as [2]

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Authors
Zhang, M., Methot, D., Poppa, V., Fujio, Y., Walsh, K., & Murry, C. E.
Affiliations
University of Washington (US)
ORCID
Venue
Journal of Molecular and Cellular Cardiology
Publisher
Elsevier BV
Published
2001-05
Volume
33
Issue
5
Pages
907-921
ISSN
0022-2828 (ISSN-L)
DOI
10.1006/jmcc.2001.1367
OpenAlex
W2094457676
Cited by
878
References
39
Citations by year
2026: 4 · 2025: 10 · 2024: 8 · 2023: 17 · 2022: 17 · 2021: 28 · 2020: 29 · 2019: 28 · 2018: 43 · 2017: 36 · 2016: 37 · 2015: 41 · 2014: 46 · 2013: 52 · 2012: 61
FWCI
9.45
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Molecular and Cellular Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • World Health Organization
  • National Institutes of Health (5k08hl003094-04)
  • National Heart, Lung, and Blood Institute (R01HL61553, P01-HL03174, R01HL061553, K08-HL03094, P01HL003174)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
cardiomyocyte transplantation, cardiac repair, apoptosis, ischemic injury, Akt kinase, heat shock, neonatal cardiomyocytes, cryoinjury, adenoviral gene transfer, TUNEL
MeSH terms
Adenoviridae, Animals, Cell Survival, Cells, Cultured, Hot Temperature, Ischemia, Male, Microscopy, Electron, Myocardium, Necrosis, Proto-Oncogene Proteins, Rats, Inbred F344, Time Factors, Blotting, Western, Tissue Transplantation, Culture Media, Serum-Free, Cell Death, Protein Serine-Threonine Kinases, In Situ Nick-End Labeling, Proto-Oncogene Proteins c-akt, Rats

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