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Long-term contractile activity and thyroid hormone supplementation produce engineered rat myocardium with adult-like structure and function.

Publication ,  Journal Article
Jackman, C; Li, H; Bursac, N
Published in: Acta biomaterialia
September 2018

The field of cardiac tissue engineering has developed rapidly, but structural and functional immaturity of engineered heart tissues hinder their widespread use. Here, we show that a combination of low-rate (0.2 Hz) contractile activity and thyroid hormone (T3) supplementation significantly promote structural and functional maturation of engineered rat cardiac tissues ("cardiobundles"). The progressive maturation of cardiobundles during first 2 weeks of culture resulted in cell cycle exit and loss of spontaneous activity, which in longer culture yielded decreased contractile function. Maintaining a low level of contractile activity by 0.2 Hz pacing between culture weeks 3 and 5, combined with T3 treatment, yielded significant growth of cardiobundle and myocyte cross-sectional areas (by 68% and 32%, respectively), increased nuclei numbers (by 22%), improved twitch force (by 39%), shortened action potential duration (by 32%), polarized N-cadherin distribution, and switch from immature (slow skeletal) to mature (fast) cardiac troponin I isoform expression. Along with advanced functional output (conduction velocity 53.7 ± 0.8 cm/s, specific force 70.1 ± 5.8 mN/mm2), quantitative ultrastructural analyses revealed similar metrics and abundance of sarcomeres, T-tubules, M-bands, and intercalated disks compared to native age-matched (5-week) and adult (3-month) ventricular myocytes. Unlike 0.2 Hz regime, chronic 1 Hz pacing resulted in significant cardiomyocyte loss and formation of necrotic core despite the use of dynamic culture. Overall, our results demonstrate remarkable ultrastructural and functional maturation of neonatal rat cardiomyocytes in 3D culture and reveal importance of combined biophysical and hormonal inputs for in vitro engineering of adult-like myocardium.Compared to human stem cell-derived cardiomyocytes, neonatal rat ventricular myocytes show advanced maturation state which makes them suitable for in vitro studies of postnatal cardiac development. Still, maturation process from a neonatal to an adult cardiomyocyte has not been recapitulated in rodent cell cultures. Here, we show that low-frequency pacing and thyroid hormone supplementation of 3D engineered neonatal rat cardiac tissues synergistically yield significant increase in cell and tissue volume, robust formation of T-tubules and M-lines, improved sarcomere organization, and faster and more forceful contractions. To the best of our knowledge, 5-week old engineered cardiac tissues described in this study are the first that exhibit both ultrastructural and functional characteristics approaching or matching those of adult ventricular myocardium.

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Published In

Acta biomaterialia

DOI

EISSN

1878-7568

ISSN

1742-7061

Publication Date

September 2018

Volume

78

Start / End Page

98 / 110

Related Subject Headings

  • Tissue Engineering
  • Time Factors
  • Thyroid Hormones
  • Rats, Sprague-Dawley
  • Myocytes, Cardiac
  • Myocardium
  • Myocardial Contraction
  • Electric Stimulation
  • Cells, Cultured
  • Cell Differentiation
 

Citation

APA
Chicago
ICMJE
MLA
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Jackman, C., Li, H., & Bursac, N. (2018). Long-term contractile activity and thyroid hormone supplementation produce engineered rat myocardium with adult-like structure and function. Acta Biomaterialia, 78, 98–110. https://doi.org/10.1016/j.actbio.2018.08.003
Jackman, Christopher, Hanjun Li, and Nenad Bursac. “Long-term contractile activity and thyroid hormone supplementation produce engineered rat myocardium with adult-like structure and function.Acta Biomaterialia 78 (September 2018): 98–110. https://doi.org/10.1016/j.actbio.2018.08.003.
Jackman, Christopher, et al. “Long-term contractile activity and thyroid hormone supplementation produce engineered rat myocardium with adult-like structure and function.Acta Biomaterialia, vol. 78, Sept. 2018, pp. 98–110. Epmc, doi:10.1016/j.actbio.2018.08.003.
Journal cover image

Published In

Acta biomaterialia

DOI

EISSN

1878-7568

ISSN

1742-7061

Publication Date

September 2018

Volume

78

Start / End Page

98 / 110

Related Subject Headings

  • Tissue Engineering
  • Time Factors
  • Thyroid Hormones
  • Rats, Sprague-Dawley
  • Myocytes, Cardiac
  • Myocardium
  • Myocardial Contraction
  • Electric Stimulation
  • Cells, Cultured
  • Cell Differentiation