title: Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration.
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.
authors.affiliation: 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.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fiore
authors.affiliation: 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.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Judson
authors.affiliation: 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.
authors.forename: Marcela
authors.initials: M
authors.lastname: Low
authors.affiliation: The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: leesunny.96@gmail.com.
authors.forename: Sunny
authors.initials: S
authors.lastname: Lee
authors.affiliation: The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: zxy_ez_lz@hotmail.com.
authors.forename: Erica
authors.initials: E
authors.lastname: Zhang
authors.affiliation: The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: claudia.i.hopkins@gmail.com.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hopkins
authors.affiliation: The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: z.xu@alumni.ubc.ca.
authors.forename: Peter
authors.initials: P
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lenzi
authors.affiliation: 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.
authors.forename: Fabio M V
authors.initials: FM
authors.lastname: Rossi
authors.affiliation: 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.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Lemos
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D051379:Mice; D008856:Microscopy, Fluorescence; D024510:Muscle Development / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D011743:Pyrimidines; C498826:nilotinib
keywords: Fibro/adipogenic progenitors; Fibrosis; Myogenesis; Protein-tyrosine kinase inhibitors; Regeneration; Satellite cells