2. Academic Validation
  3. mTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis

mTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis

  • EMBO Rep. 2024 Oct;25(10):4570-4593. doi: 10.1038/s44319-024-00251-1.
Angus T Stock 1,  Sarah Parsons 2 3,  Jacinta A Hansen 4,  Damian B D'Silva 4,  Graham Starkey 5 6,  Aly Fayed 7,  Xin Yi Lim 8,  Rohit D'Costa 9 10,  Claire L Gordon 8 11 12,  Ian P Wicks 13 14 15
Affiliations

Affiliations

  • 1 WEHI, Melbourne, VIC, 3052, Australia. stock.a@wehi.edu.au.
  • 2 Department of Forensic Medicine, Monash University, Melbourne, VIC, 3006, Australia.
  • 3 Victorian Institute of Forensic Medicine, Melbourne, VIC, 3006, Australia.
  • 4 WEHI, Melbourne, VIC, 3052, Australia.
  • 5 Liver & Intestinal Transplant Unit, Austin Health, Melbourne, VIC, 3084, Australia.
  • 6 Department of Surgery, The University of Melbourne, Austin Health, Melbourne, VIC, 3084, Australia.
  • 7 Department of Surgery, Austin Health, Melbourne, VIC, 3084, Australia.
  • 8 Department of Infectious Diseases, Austin Health, Melbourne, VIC, 3084, Australia.
  • 9 DonateLife Victoria, Carlton, VIC, 3053, Australia.
  • 10 Department of Intensive Care Medicine, Melbourne Health, Melbourne, VIC, 3084, Australia.
  • 11 Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3052, Australia.
  • 12 North Eastern Public Health Unit, Austin Health, Melbourne, VIC, 3084, Australia.
  • 13 WEHI, Melbourne, VIC, 3052, Australia. wicks@wehi.edu.au.
  • 14 Rheumatology Unit, The Royal Melbourne Hospital, Parkville, VIC, 3050, Australia. wicks@wehi.edu.au.
  • 15 University of Melbourne, Department of Medical Biology, Melbourne, VIC, 3052, Australia. wicks@wehi.edu.au.
PMID: 39271773 DOI: 10.1038/s44319-024-00251-1
Abstract

The accumulation of myofibroblasts within the intimal layer of inflamed blood vessels is a potentially catastrophic complication of vasculitis, which can lead to arterial stenosis and ischaemia. In this study, we have investigated how these luminal myofibroblasts develop during Kawasaki disease (KD), a paediatric vasculitis typically involving the coronary arteries. By performing lineage tracing studies in a murine model of KD, we reveal that luminal myofibroblasts develop independently of adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs). Notably, the emergence of SMC-derived luminal myofibroblasts-in both mice and patients with KD, Takayasu's arteritis and Giant Cell arteritis-coincided with activation of the mechanistic target of rapamycin (mTOR) signalling pathway. Moreover, SMC-specific deletion of mTOR signalling, or pharmacological inhibition, abrogated the emergence of luminal myofibroblasts. Thus, mTOR is an intrinsic and essential regulator of luminal myofibroblast formation that is activated in vasculitis patients and therapeutically tractable. These findings provide molecular insight into the pathogenesis of coronary artery stenosis and identify mTOR as a therapeutic target in vasculitis.

Keywords

Kawasaki Disease; Myofibroblasts; Stenosis; Vasculitis; mTOR.

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