Biology subjects

Boostanpour, K.

Publications and source records attributed to Boostanpour, K..

3 recordsLinked to original sources

bioRxiv2025

Cellular profiling identifies an early profibrotic alveolar type 2 cell signature in lung fibrosis

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive, age-associated, lung disease characterized by short telomeres in alveolar type 2 (AT2) cells, epithelial remodeling, and fibrosis. ObjectivesThis study investigated how telomere dysfunction in AT2 cells lacking Telomere Repeat Binding Factor 1 (TRF1) drives lung remodeling in SPC-creTRF1flox/flox mice and its relevance to IPF. MethodsMouse model of telomere dysfunction was used to conditionally delete TRF1 in AT2 cells. SPC-creTRF1flox/flox mouse lung epithelial cells were used to perform single cell RNA sequencing. AT2 cells from IPF lungs were analyzed by single cell RNA sequencing in an organoid model. Measurements and Main ResultsSingle cell RNA-sequencing revealed distinct pathological AT2 cells enriched in DNA damage, senescence, oxidative stress, and pro-fibrotic genes, along with fewer "normal" AT2 cells and increased club cells in SPC-creTRF1flox/flox mice. Pathological AT2 cells showed different early and late-stage gene signatures, with a prominent p53 signature at both time-points. Genetic deletion of p53 in SPC-creTRF1flox/flox AT2 cells improved survival and prevented lung fibrosis. p53 deletion or inhibition improved organoid formation, surfactant protein C expression, and reduced pro-fibrotic gene expression in AT2 cells isolated from SPC-creTRF1flox/flox mice or IPF lungs. ConclusionsThese data suggest that the DNA damage response to AT2 cell telomere dysfunction, driven by enhanced p53 activity, mediates early AT2 cell transdifferentiation and senescence, leading to epithelial cell remodeling and fibrosis and that reversing this reprogramming is a potential therapeutic approach for managing IPF.

cell biology↗

bioRxiv2023

Reciprocal inflammatory signals establish profibrotic cross-feeding metabolism

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung remodeling and collagen deposition that leads to respiratory failure. Myeloid cells are abundant in IPF lung and in murine lung fibrosis, but their functional effects are incompletely understood. Using mouse and human lung models, we show that ornithine produced by myeloid cells expressing Arg1 serves as a substrate for proline and collagen synthesis by lung fibroblasts. The predominant Arg1-expressing myeloid cells in mouse lung were macrophages, but in IPF lung, high-dimensional imaging revealed ARG1 to be expressed mainly in neutrophils. Arg1 inhibition suppressed both ornithine levels and collagen expression in cultured, precision-cut IPF lung slices and in murine lung fibrosis. These results were confirmed in macrophage-specific Arg1 KO mice. Furthermore, we find that this pathway is regulated by cell-to-cell crosstalk, starting with purinergic signaling: Fibroblast eATP receptor P2rx4 was necessary for fibroblast IL-6 expression, which in turn was necessary for Arg1 expression by myeloid cells. Taken together, our findings define an immune-mesenchymal circuit that governs profibrotic metabolism in lung fibrosis.

immunology↗

bioRxiv2021

Molecular programs of fibrotic change in aging human lung

Aging is associated with both overt and subclinical lung fibrosis, which increases risk for mortality from viruses and other respiratory pathogens. The molecular programs that induce fibrosis in the aging lung are not well understood. To overcome this knowledge gap, we undertook multimodal profiling of distal lung samples from healthy human donors across the lifespan. Telomere shortening, a cause of cell senescence and fibrosis, was progressive with age in a sample of 86 lungs and was associated with foci of DNA damage. Bulk RNA sequencing confirmed activation of cellular senescence and pro-fibrotic pathways as well as genes necessary for collagen processing with increasing age. These findings were validated in independent datasets for lung and sun-exposed skin, but not other organs including heart, liver and kidney. Cell type deconvolution analysis revealed a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts. Consistent with the observed pro-fibrotic transcriptional profile, second harmonic imaging demonstrated increased density of interstitial collagen in aged human lungs. Furthermore, regions of parenchymal fibrosis were associated with decreased alveolar expansion and surfactant secretion. These findings reveal the transcriptional and structural features of fibrosis and associated physiologic impairments in normal lung aging.

genomics↗