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Stem Cell Res. 2016 Jul;17(1):161-9. doi: 10.1016/j.scr.2016.06.007. Epub 2016 Jun 26.

Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration.

Author information

1
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Viale Regina Elena, 324, Rome 00161, Italy. Electronic address: daniela.fiore@uniroma1.it.
2
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Faculty of Medicine, The University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: robert.judson@stemcell.com.
3
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Faculty of Medicine, The University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: mlow@brc.ubc.ca.
4
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: leesunny.96@gmail.com.
5
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: zxy_ez_lz@hotmail.com.
6
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: claudia.i.hopkins@gmail.com.
7
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: z.xu@alumni.ubc.ca.
8
Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Viale Regina Elena, 324, Rome 00161, Italy. Electronic address: andrea.lenzi@uniroma1.it.
9
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Faculty of Medicine, The University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: fabio@brc.ubc.ca.
10
The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada; Faculty of Medicine, The University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: dario@brc.ubc.ca.

Abstract

Acute skeletal muscle injury triggers an expansion of fibro/adipogenic progenitors (FAPs) and a transient stage of fibrogenesis characterized by extracellular matrix deposition. While the perpetuation of such phase can lead to permanent tissue scarring, the consequences of its suppression remain to be studied. Using a model of acute muscle damage we were able to determine that pharmacological inhibition of FAP expansion by Nilotinib, a tyrosine kinase inhibitor with potent antifibrotic activity, exerts a detrimental effect on myogenesis during regeneration. We found that Nilotinib inhibits the damage-induced expansion of satellite cells in vivo, but it does not affect in vitro proliferation, suggesting a non cell-autonomous effect. Nilotinib impairs regenerative fibrogenesis by preventing the injury-triggered expansion and differentiation of resident CD45(-):CD31(-):α7integrin(-):Sca1(+) mesenchymal FAPs. Our data support the notion that the expansion of FAPs and transient fibrogenesis observed during regeneration play an important trophic role toward tissue-specific stem cells.

KEYWORDS:

Fibro/adipogenic progenitors; Fibrosis; Myogenesis; Protein-tyrosine kinase inhibitors; Regeneration; Satellite cells

PMID:
27376715
DOI:
10.1016/j.scr.2016.06.007
[Indexed for MEDLINE]
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