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

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

Author information

1
Department of Medicine, Karolinska Institutet, Huddinge, Sweden.
2
Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.
3
Stem Cell and Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Dr. Li Dak-Sum Research Centre, University of Hong Kong-Karolinska Institutet Collaborations in Regenerative Medicine, The University of Hong Kong, Hong Kong, China.
4
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
5
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
6
Stem Cell and Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
7
Stem Cell and Regenerative Medicine Consortium, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Dr. Li Dak-Sum Research Centre, University of Hong Kong-Karolinska Institutet Collaborations in Regenerative Medicine, The University of Hong Kong, Hong Kong, China; Ming Wai Lau Centre for Reparative Medicine-Karolinska Institutet, Hong Kong, China.
8
Department of Medicine, Karolinska Institutet, Huddinge, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden. Electronic address: kenneth.chien@ki.se.

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

PMID:
29606507
PMCID:
PMC6035340
DOI:
10.1016/j.ymthe.2018.02.012
[Indexed for MEDLINE]
Free PMC Article

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