Fibrosis, marked by excess extracellular matrix (ECM) deposition, is the end stage of many diseases. Single-cell studies have highlighted the emergence of disease-specific fibroblast populations, including a high collagen–synthesizing CTHRC1+ subpopulation. The profibrotic cytokine TGF-β1 promotes fibrogenesis via cooperation between Smad and mTORC1/4E-BP1 signaling axes. Using CRISPR-Cas9 gene editing, we report that more than one-third of TGF-β1–regulated matrisome genes are under mTORC1 control. Mapping the transcriptome of TGF-β1–stimulated fibroblasts revealed similarity to CTHRC1+ fibroblasts identified in idiopathic pulmonary fibrosis (IPF). This overlap is lost when mTORC1 is disabled. Using the selective mTORC1 inhibitor RMC-5552, we confirm a causal role for mTORC1 in promoting the acquisition of the collagen-high, CTHRC1+ phenotype in response to TGF-β1 stimulation in fibroblasts derived from patients with either IPF or lung adenocarcinoma. We conclude that mTORC1 plays a key role in shaping the transcriptional identity of these fibroblasts, with implications for therapeutic inhibition of mTORC1 in fibrosis and cancer.
Jo-Anne Am Wilson, Rachel Walters, Greg Contento et al.· Science Advances· 0 citations
Over the past two decades, progress in stem cell biology, bioengineering, and systems biology has improved our understanding of lung regeneration and repair. Building on work presented at the 20th Anniversary Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, this review examines the evolving trajectory of the field and outlines remaining challenges and opportunities for future research. We focus on three main areas: improving ex vivo lung models to better capture cellular heterogeneity and biomechanics; using single-cell, spatial, and computational approaches to support translation into clinical practice; and innovative therapeutic strategies, including gene therapies, epithelial cell therapies, immune cell engineering, extracellular matrix reconditioning, senescence targeting, and whole-organ bioengineering and xenotransplantation. Together, these approaches are shifting lung regeneration from descriptive studies toward precision, mechanism-driven therapies. Future progress in lung regenerative medicine will require integration of omics-driven insights with functional validation and biomaterial innovation to achieve meaningful clinical impact.
Lei Wang, Sarah Y Shin, J. Hook et al.· American Journal of Respirat...· 0 citations
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