Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging.
Publication/Presentation Date
5-1-2020
Abstract
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
Volume
62
Issue
5
First Page
633
Last Page
644
ISSN
1535-4989
Published In/Presented At
Kato, K., Logsdon, N. J., Shin, Y. J., Palumbo, S., Knox, A., Irish, J. D., Rounseville, S. P., Rummel, S. R., Mohamed, M., Ahmad, K., Trinh, J. M., Kurundkar, D., Knox, K. S., Thannickal, V. J., & Hecker, L. (2020). Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging. American journal of respiratory cell and molecular biology, 62(5), 633–644. https://doi.org/10.1165/rcmb.2019-0092OC
Disciplines
Medicine and Health Sciences
PubMedID
31962055
Department(s)
Department of Medicine
Document Type
Article