Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging.

American journal of respiratory cell and molecular biology 2020 May

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Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease with no cure. Although IPF is widely regarded as a disease of aging, the cellular mechanisms that contribute to this age-associated predilection remain elusive. In this study, we sought to evaluate the consequences of senescence on myofibroblast cell fate and fibrotic responses to lung injury in the context of aging. We demonstrated that nonsenescent lung myofibroblasts maintained the capacity for dedifferentiation, whereas senescent/IPF myofibroblasts exhibited an impaired capacity for dedifferentiation. We previously demonstrated that the transcription factor MyoD acts as a critical switch in the differentiation and dedifferentiation of myofibroblasts. Here, we demonstrate that decreased levels of MyoD preceded myofibroblast dedifferentiation and apoptosis susceptibility in nonsenescent cells, whereas MyoD expression remained elevated in senescent/IPF myofibroblasts, which failed to undergo dedifferentiation and demonstrated resistance to apoptosis. Genetic strategies to silence MyoD restored the susceptibility of IPF myofibroblasts to undergo apoptosis and led to a partial reversal of age-associated persistent fibrosis in vivo. The capacity for myofibroblast dedifferentiation and subsequent apoptosis may be critical for normal physiologic responses to tissue injury, whereas restricted dedifferentiation and apoptosis resistance in senescent cells may underlie the progressive nature of age-associated human fibrotic disorders. These studies support the concept that senescence may promote profibrotic effects via impaired myofibroblast dedifferentiation and apoptosis resistance, which contributes to myofibroblast accumulation and ultimately persistent fibrosis in aging.

Citation

Kosuke Kato, Naomi J Logsdon, Yoon-Joo Shin, Sunny Palumbo, Adam Knox, Joseph D Irish, Skye P Rounseville, Sydney R Rummel, Mohamed Mohamed, Kareem Ahmad, Johnny M Trinh, Deepali Kurundkar, Kenneth S Knox, Victor J Thannickal, Louise Hecker. Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging. American journal of respiratory cell and molecular biology. 2020 May;62(5):633-644