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Passive Stretch Induces Structural and Functional Maturation of Engineered Heart Muscle as Predicted by Computational

Oscar J Abilez1,2,3,4, Evangeline Tzatzalos1,2, Huaxiao Yang1,2

  • 1Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA.

Stem Cells (Dayton, Ohio)
|November 1, 2017
PubMed
Summary

Passive stretch enhances the maturation of engineered heart muscle derived from human pluripotent stem cells. This study optimized cell alignment and calcium dynamics for cardiovascular tissue engineering applications.

Keywords:
BioengineeringCalcium handlingCardiacCardiomyocyteComputational modelingEngineered heart muscleHeartPluripotent stem cellsTissue engineeringTissue regeneration

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Area of Science:

  • Cardiovascular Research
  • Stem Cell Biology
  • Biomaterials Engineering

Background:

  • Human pluripotent stem cells (hPSCs) can differentiate into cardiomyocytes (CMs), offering potential for cardiac repair and disease modeling.
  • Current hPSC-derived CMs (hPSC-CMs) exhibit immature characteristics, limiting their therapeutic and research applications.
  • Optimizing maturation of hPSC-CMs in engineered heart muscle (EHM) is crucial for advancing cardiovascular tissue engineering.

Purpose of the Study:

  • To investigate the impact of varying passive stretch on the structural and functional maturation of EHMs.
  • To utilize computational modeling to predict stress distribution and guide EHM design.
  • To enhance the development of mature and functional hPSC-derived cardiac tissues.

Main Methods:

  • Differentiated hPSCs into hPSC-CMs using a small molecule protocol.
  • Constructed EHMs by combining hPSC-CMs and fibroblasts within type-I collagen and applying varying passive stretch (5, 7, or 9 mm).
  • Employed computational modeling to predict stress distribution and analyzed EHM structure, function, and gene expression.

Main Results:

  • EHMs with 7 mm passive stretch demonstrated the most consistent formation.
  • Computational modeling accurately predicted cell alignment and coordinated calcium wave propagation.
  • hPSC-derived EHMs exhibited mature cardiomyocyte gene expression, including ion channels and receptors, and functional characteristics comparable to neonatal rat EHMs.

Conclusions:

  • Passive stretch is a critical factor in promoting the structural and functional maturation of hPSC-derived EHMs.
  • Computational modeling provides a framework for optimizing EHM design for improved cell alignment and calcium dynamics.
  • These findings support the rational design of EHMs for future clinical applications in cardiovascular tissue engineering.