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Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes.

Publication ,  Journal Article
Zhang, D; Shadrin, IY; Lam, J; Xian, H-Q; Snodgrass, HR; Bursac, N
Published in: Biomaterials
July 2013

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) provide a promising source for cell therapy and drug screening. Several high-yield protocols exist for hESC-CM production; however, methods to significantly advance hESC-CM maturation are still lacking. Building on our previous experience with mouse ESC-CMs, we investigated the effects of 3-dimensional (3D) tissue-engineered culture environment and cardiomyocyte purity on structural and functional maturation of hESC-CMs. 2D monolayer and 3D fibrin-based cardiac patch cultures were generated using dissociated cells from differentiated Hes2 embryoid bodies containing varying percentage (48-90%) of CD172a (SIRPA)-positive cardiomyocytes. hESC-CMs within the patch were aligned uniformly by locally controlling the direction of passive tension. Compared to hESC-CMs in age (2 weeks) and purity (48-65%) matched 2D monolayers, hESC-CMs in 3D patches exhibited significantly higher conduction velocities (CVs), longer sarcomeres (2.09 ± 0.02 vs. 1.77 ± 0.01 μm), and enhanced expression of genes involved in cardiac contractile function, including cTnT, αMHC, CASQ2 and SERCA2. The CVs in cardiac patches increased with cardiomyocyte purity, reaching 25.1 cm/s in patches constructed with 90% hESC-CMs. Maximum contractile force amplitudes and active stresses of cardiac patches averaged to 3.0 ± 1.1 mN and 11.8 ± 4.5 mN/mm(2), respectively. Moreover, contractile force per input cardiomyocyte averaged to 5.7 ± 1.1 nN/cell and showed a negative correlation with hESC-CM purity. Finally, patches exhibited significant positive inotropy with isoproterenol administration (1.7 ± 0.3-fold force increase, EC50 = 95.1 nm). These results demonstrate highly advanced levels of hESC-CM maturation after 2 weeks of 3D cardiac patch culture and carry important implications for future drug development and cell therapy studies.

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Published In

Biomaterials

DOI

EISSN

1878-5905

ISSN

0142-9612

Publication Date

July 2013

Volume

34

Issue

23

Start / End Page

5813 / 5820

Related Subject Headings

  • Tissue Scaffolds
  • Tissue Engineering
  • Time Factors
  • Receptors, Adrenergic, beta
  • Phenotype
  • Myocytes, Cardiac
  • Myocardial Contraction
  • Mice
  • Humans
  • Gene Expression Regulation
 

Citation

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Zhang, D., Shadrin, I. Y., Lam, J., Xian, H.-Q., Snodgrass, H. R., & Bursac, N. (2013). Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes. Biomaterials, 34(23), 5813–5820. https://doi.org/10.1016/j.biomaterials.2013.04.026
Zhang, Donghui, Ilya Y. Shadrin, Jason Lam, Hai-Qian Xian, H Ralph Snodgrass, and Nenad Bursac. “Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes.Biomaterials 34, no. 23 (July 2013): 5813–20. https://doi.org/10.1016/j.biomaterials.2013.04.026.
Zhang D, Shadrin IY, Lam J, Xian H-Q, Snodgrass HR, Bursac N. Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes. Biomaterials. 2013 Jul;34(23):5813–20.
Zhang, Donghui, et al. “Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes.Biomaterials, vol. 34, no. 23, July 2013, pp. 5813–20. Epmc, doi:10.1016/j.biomaterials.2013.04.026.
Zhang D, Shadrin IY, Lam J, Xian H-Q, Snodgrass HR, Bursac N. Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes. Biomaterials. 2013 Jul;34(23):5813–5820.
Journal cover image

Published In

Biomaterials

DOI

EISSN

1878-5905

ISSN

0142-9612

Publication Date

July 2013

Volume

34

Issue

23

Start / End Page

5813 / 5820

Related Subject Headings

  • Tissue Scaffolds
  • Tissue Engineering
  • Time Factors
  • Receptors, Adrenergic, beta
  • Phenotype
  • Myocytes, Cardiac
  • Myocardial Contraction
  • Mice
  • Humans
  • Gene Expression Regulation