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Sci Transl Med. 2017 Dec 13;9(420). pii: eaal3765. doi: 10.1126/scitranslmed.aal3765.

Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis.

Author information

1
Fibrosis Research Center and Center for Immunology and Inflammatory Diseases, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. dlagares@mgh.harvard.edu.
2
Fibrosis Research Center and Center for Immunology and Inflammatory Diseases, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
3
Molecular and Integrative Physiological Sciences Program, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
4
Division of Nephrology and Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan.
5
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
6
Krembil Research Institute, University Health Network and Department of Surgery and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
7
Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
8
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
9
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.

Abstract

Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to-myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells. Mitochondria in activated myofibroblasts, but not quiescent fibroblasts, are primed by death signals such as the proapoptotic BH3-only protein BIM, which creates a requirement for tonic expression of the antiapoptotic protein BCL-XL to sequester BIM and ensure myofibroblast survival. Myofibroblasts become particularly susceptible to apoptosis induced by "BH3 mimetic" drugs inhibiting BCL-XL such as ABT-263. ABT-263 displaces BCL-XL binding to BIM, allowing BIM to activate apoptosis on stiffness-primed myofibroblasts. Therapeutic blockade of BCL-XL with ABT-263 (navitoclax) effectively treats established fibrosis in a mouse model of scleroderma dermal fibrosis by inducing myofibroblast apoptosis. Using a BH3 profiling assay to assess mitochondrial priming in dermal fibroblasts derived from patients with scleroderma, we demonstrate that the extent of apoptosis induced by BH3 mimetic drugs correlates with the extent of their mitochondrial priming, indicating that BH3 profiling could predict apoptotic responses of fibroblasts to BH3 mimetic drugs in patients with scleroderma. Together, our findings elucidate the potential efficacy of targeting myofibroblast antiapoptotic proteins with BH3 mimetic drugs in scleroderma and other fibrotic diseases.

PMID:
29237758
DOI:
10.1126/scitranslmed.aal3765
[Indexed for MEDLINE]

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