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Cell Stem Cell. 2020 Feb 6;26(2):205-220.e8. doi: 10.1016/j.stem.2019.12.008. Epub 2020 Jan 23.

Pathogenic Potential of Hic1-Expressing Cardiac Stromal Progenitors.

Author information

1
Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada; Faculty of Pharmaceutical Sciences, Minia University, Minia, Egypt.
2
Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
3
Harvard Medical School, Boston, MA 02115, USA.
4
Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza, University of Rome, Viale Regina Elana 324, 00161 Rome, Italy.
5
Department of Biology, School of Science, University of Padova, Via 8 Febbraio 2, 35122 Padova, Italy.
6
Department of Cell and Developmental Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague 4, Czech Republic.
7
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC 27710, USA.
8
Molecular and Cellular Pharmacology Research Group, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
9
Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Electronic address: fabio@brc.ubc.ca.

Abstract

The cardiac stroma contains multipotent mesenchymal progenitors. However, lineage relationships within cardiac stromal cells are poorly defined. Here, we identified heart-resident PDGFRa+ SCA-1+ cells as cardiac fibro/adipogenic progenitors (cFAPs) and show that they respond to ischemic damage by generating fibrogenic cells. Pharmacological blockade of this differentiation step with an anti-fibrotic tyrosine kinase inhibitor decreases post-myocardial infarction (post-MI) remodeling and leads to improvement in cardiac function. In the undamaged heart, activation of cFAPs through lineage-specific deletion of the gene encoding the quiescence-associated factor HIC1 reveals additional pathogenic potential, causing fibrofatty infiltration within the myocardium and driving major pathological features pathognomonic in arrhythmogenic cardiomyopathy (AC). In this regard, cFAPs contribute to multiple pathogenic cell types within cardiac tissue and therapeutic strategies aimed at modifying their activity are expected to have tremendous benefit for the treatment of diverse cardiac diseases.

KEYWORDS:

Hic1; PDGFRa; arrhythmogenic cardiomyopathy; cFAP; cardiac fibrosis; fibroadipogenic progenitor; fibrofatty infiltration; mesenchymal progenitor; myocardial infarction; nilotinib

PMID:
31978365
DOI:
10.1016/j.stem.2019.12.008

Conflict of interest statement

Declaration of Interests The authors have no competing interests.

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