Research ArticleFibrosis

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

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Science Translational Medicine  13 Dec 2017:
Vol. 9, Issue 420, eaal3765
DOI: 10.1126/scitranslmed.aal3765

Reversing fibrosis through apoptosis

Myofibroblasts are integral in a feedback loop that perpetuates fibrosis through stiffening of the extracellular matrix. Lagares et al. determined that proapoptotic proteins are increased in these stiffness-activated myofibroblasts, and these cells become dependent on antiapoptotic protein expression to prevent their death. A drug that mimics a proapoptotic protein to block the antiapoptotic protein BCL-XL induced apoptosis in fibroblasts from patients with scleroderma, a fibrotic connective tissue disorder. The drug, ABT-263, was also effective in reversing established fibrosis in a mouse model of scleroderma. This study suggests that targeting antiapoptotic proteins to induce myofibroblast apoptosis could be an effective strategy to treat fibrosis.


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.

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