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Cell Rep. 2019 Mar 19;26(12):3231-3245.e9. doi: 10.1016/j.celrep.2019.02.083.

In Vivo Generation of Post-infarct Human Cardiac Muscle by Laminin-Promoted Cardiovascular Progenitors.

Author information

1
Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore.
2
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; Cardiovascular Research Institute, National University Heart Centre, Singapore 117599, Singapore.
3
BioLamina AB, Löfströms Allé 5A, Sundbyberg 17266, Sweden.
4
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Cardiovascular Research Institute, National University Heart Centre, Singapore 117599, Singapore.
5
Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore.
6
Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore; National Heart & Lung Institute, Imperial College London, Cale Street, London SW3 6LY, UK.
7
Division of Obstetrics and Gynecology, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute and Karolinska University Hospital, Huddinge, Stockholm 141 86, Sweden.
8
Cardiovascular Research Institute, National University Heart Centre, Singapore 117599, Singapore; University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
9
Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore; Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden. Electronic address: karl.tryggvason@duke-nus.edu.sg.

Abstract

Regeneration of injured human heart muscle is limited and an unmet clinical need. There are no methods for the reproducible generation of clinical-quality stem cell-derived cardiovascular progenitors (CVPs). We identified laminin-221 (LN-221) as the most likely expressed cardiac laminin. We produced it as human recombinant protein and showed that LN-221 promotes differentiation of pluripotent human embryonic stem cells (hESCs) toward cardiomyocyte lineage and downregulates pluripotency and teratoma-associated genes. We developed a chemically defined, xeno-free laminin-based differentiation protocol to generate CVPs. We show high reproducibility of the differentiation protocol using time-course bulk RNA sequencing developed from different hESC lines. Single-cell RNA sequencing of CVPs derived from hESC lines supported reproducibility and identified three main progenitor subpopulations. These CVPs were transplanted into myocardial infarction mice, where heart function was measured by echocardiogram and human heart muscle bundle formation was identified histologically. This method may provide clinical-quality cells for use in regenerative cardiology.

KEYWORDS:

cardiovascular progenitors; hESC-based cardiac muscle regeneration; laminin; regenerative cardiology

PMID:
30893597
DOI:
10.1016/j.celrep.2019.02.083
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