Human ISL1 + Ventricular Progenitors Self-Assemble into an In Vivo Functional Heart Patch and Preserve Cardiac Function Post Infarction

Mol Ther. 2018 Jul 5;26(7):1644-1659. doi: 10.1016/j.ymthe.2018.02.012. Epub 2018 Feb 17.

Abstract

The generation of human pluripotent stem cell (hPSC)-derived ventricular progenitors and their assembly into a 3-dimensional in vivo functional ventricular heart patch has remained an elusive goal. Herein, we report the generation of an enriched pool of hPSC-derived ventricular progenitors (HVPs), which can expand, differentiate, self-assemble, and mature into a functional ventricular patch in vivo without the aid of any gel or matrix. We documented a specific temporal window, in which the HVPs will engraft in vivo. On day 6 of differentiation, HVPs were enriched by depleting cells positive for pluripotency marker TRA-1-60 with magnetic-activated cell sorting (MACS), and 3 million sorted cells were sub-capsularly transplanted onto kidneys of NSG mice where, after 2 months, they formed a 7 mm × 3 mm × 4 mm myocardial patch resembling the ventricular wall. The graft acquired several features of maturation: expression of ventricular marker (MLC2v), desmosomes, appearance of T-tubule-like structures, and electrophysiological action potential signature consistent with maturation, all this in a non-cardiac environment. We further demonstrated that HVPs transplanted into un-injured hearts of NSG mice remain viable for up to 8 months. Moreover, transplantation of 2 million HVPs largely preserved myocardial contractile function following myocardial infarction. Taken together, our study reaffirms the promising idea of using progenitor cells for regenerative therapy.

Keywords: cardiac regeneration; differentiation; human; myocardial infarction; stem cell; ventricular progenitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Separation / methods
  • Cells, Cultured
  • Heart Ventricles / metabolism*
  • Heart Ventricles / physiopathology*
  • Humans
  • LIM-Homeodomain Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / physiopathology*
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • Pluripotent Stem Cells / metabolism
  • Pluripotent Stem Cells / physiology
  • Transcription Factors / metabolism*

Substances

  • LIM-Homeodomain Proteins
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1