Laminin-221 Enhances Therapeutic Effects of Human-Induced Pluripotent Stem Cell-Derived 3-Dimensional Engineered Cardiac Tissue Transplantation in a Rat Ischemic Cardiomyopathy Model

J Am Heart Assoc. 2020 Aug 18;9(16):e015841. doi: 10.1161/JAHA.119.015841. Epub 2020 Aug 12.


Background Extracellular matrix, especially laminin-221, may play crucial roles in viability and survival of human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) after in vivo transplant. Then, we hypothesized laminin-221 may have an adjuvant effect on therapeutic efficacy by enhancing cell viability and survival after transplantation of 3-dimensional engineered cardiac tissue (ECT) to a rat model of myocardial infarction. Methods and Results In vitro study indicates the impacts of laminin-221 on hiPS-CMs were analyzed on the basis of mechanical function, mitochondrial function, and tolerance to hypoxia. We constructed 3-dimensional ECT containing hiPS-CMs and fibrin gel conjugated with laminin-221. Heart function and in vivo behavior were assessed after engraftment of 3-dimensional ECT (laminin-conjugated ECT, n=10; ECT, n=10; control, n=10) in a rat model of myocardial infarction. In vitro assessment indicated that laminin-221 improves systolic velocity, diastolic velocity, and maximum capacity of oxidative metabolism of hiPS-CMs. Cell viability and lactate dehydrogenase production revealed that laminin-221 improved tolerance to hypoxia. Furthermore, analysis of mRNA expression revealed that antiapoptotic genes were upregulated in the laminin group under hypoxic conditions. Left ventricular ejection fraction of the laminin-conjugated ECT group was significantly better than that of other groups 4 weeks after transplantation. Laminin-conjugated ECT transplantation was associated with significant improvements in expression levels of rat vascular endothelial growth factor. In early assessments, cell survival was also improved in laminin-conjugated ECTs compared with ECT transplantation without laminin-221. Conclusions In vitro laminin-221 enhanced mechanical and metabolic function of hiPS-CMs and improved the therapeutic impact of 3-dimensional ECT in a rat ischemic cardiomyopathy model. These findings suggest that adjuvant laminin-221 may provide a clinical benefit to hiPS-CM constructs.

Keywords: 3‐dimensional engineered cardiac tissue; heart failure; human‐induced pluripotent stem cells; laminin‐221; regenerative therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Hypoxia / drug effects
  • Cell Survival*
  • Disease Models, Animal
  • Gene Expression Regulation
  • Heart Transplantation
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / physiology
  • L-Lactate Dehydrogenase / biosynthesis
  • Laminin / pharmacology*
  • Male
  • Myocardial Contraction / physiology
  • Myocardial Infarction / therapy*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / physiology
  • Myocytes, Cardiac / transplantation
  • Neovascularization, Physiologic
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Nude
  • Recombinant Proteins / pharmacology
  • Stroke Volume
  • Tissue Engineering* / methods
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism
  • Ventricular Remodeling


  • Laminin
  • RNA, Messenger
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • L-Lactate Dehydrogenase