Biology subjects

Kathiriya, J. J.

Publications and source records attributed to Kathiriya, J. J..

5 recordsLinked to original sources

bioRxiv2026

Epigenetic de-repression of basal cell metaplasia in aging AT2 cells is a risk factor for idiopathic pulmonary fibrosis (IPF).

Idiopathic pulmonary fibrosis (IPF) is a fatal, age-associated lung disease in which alveolar type II (AT2) cells lose regenerative capacity and can adopt aberrant basal-like fates that promote fibrosis. Using 3D organoid co-cultures with primary human fibroblasts, we find that healthy human AT2 cell trans-differentiation into KRT5+/KRT17+ basal cells increases progressively with age, while differentiation into RAGE+ AT1-like cells decreases. We identify a shared gene signature in AT2 cells at downstream targets of p63 characterized both by acquisition of bivalent, poised chromatin marks with age and increased accessibility in IPF, indicating epigenetic "priming" towards a basal cell lineage. In vitro treatment of young AT2 cells with IL-1{beta} recapitulates this priming toward basal differentiation via a NF-kB-regulated histone demethylase, JMJD3. Conversion of primed AT2 cells to a basal fate requires recruitment of a shared transcription factor, KLF5, from AT1-specific to basal-specific promoters by HIF-1. AT2 cells instead convert to KRT5-/KRT17+ basaloid cells via a non-age-dependent pathway that requires KLF5-SMAD2/3 complexing through TGF{beta}1 signaling. These findings define an inflammation-driven epigenetic de-repressive mechanism that links aging, inflammatory stress, hypoxia, and dysfunctional epithelial metaplasia, and accounts for the likely origin of aberrant epithelial cell populations in fibrotic lung disease.

cell biology↗

bioRxiv2026

Chronic TGFβ1 Signaling Drives Aberrant Alveolar-Basaloid Metaplasia through a KRT17-Stratifin migratory complex

Chronic fibrotic disorders like idiopathic pulmonary fibrosis (IPF) are characterized by aberrant alveolar regeneration and severely limited treatment options. Identification of the mechanisms driving aberrant epithelial repair can lead to new viable therapeutic targets. Using integrated single nucleus ATAC- and RNA-sequencing on human lungs and an in vitro model of dysplastic repair, we identify two distinct regenerative trajectories for alveolar type 2 (AT2) cells: a resolvable euplastic repair trajectory and a persistent, non-resolving dysplastic repair trajectory. The latter is governed by a spatially restricted ITGB6/TGF {beta} 1/SMAD3 signaling axis in fibrotic regions of IPF lungs and in murine lungs characterized by chronic epithelial remodeling. Mechanistically, SMAD3 directly regulates dysplastic transitional cell (DTC) markers, including KRT17 and Stratifin. We show that TGF {beta} 1-induced physical interaction between KRT17 and Stratifin at the leading edge of migrating DTCs is essential for their migration. These findings collectively define the molecular regulation of AT2-driven dysplastic regeneration and identify TGF {beta} 1-induced KRT17-Stratifin axis as a central driver of AT2 remodeling and their migration in chronic fibrosis, highlighting a therapeutically targetable signaling axis.

cell biology↗

bioRxiv2025

CFTR function in alveolar type 1 cells drives lung liquid secretion and host defense

Loss of the liquid layer that lines the lungs air-facing surface underpins mechanisms of major lung diseases, but the development of therapies that restore liquid secretion is hampered by an incomplete understanding of the cell types that drive it. Here, we show CFTR function in alveolar type 1 (AT1) cells - a cell type that comprises 95% of the lung surface but is presumed to be unimportant in CFTR-related diseases - is critical to lung liquid secretion and the secretion-mediated clearance of particles and S. aureus from lung alveoli. Our findings reveal essential roles for AT1 cells in lung homeostasis and defense, and they call for a reevaluation of the role of AT1 cells in CFTR-related diseases. We suggest AT1 cells be considered key targets of secretion-restoring therapies.

cell biology↗

bioRxiv2021

IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive interstitial fibrosis, which leads to severe debilitation, respiratory failure, and death. In IPF, environmental exposures interact with genetic risk factors to engender critical patho-etiological events in lung epithelial cells, including endoplasmic reticulum (ER) stress and TGF{beta} signaling, but the interactions between these disparate pathways are not well understood. We previously showed that kinase inhibitors of the IRE1 bifunctional kinase/RNase--a central mediator of the unfolded protein response (UPR) to ER stress--protected mice from bleomycin-induced pulmonary fibrosis. Here we show that a nanomolar-potent, mono-selective kinase inhibitor of IRE1 (KIRA8) decreases ER-stress induced TGF{beta} signaling and the senescence-associated secretory phenotype (SASP) in the lung epithelium after bleomycin exposure. A recently-described subset of "damage-associated transient progenitors" (DATPs) display IRE1-regulated pathological gene signatures that are quelled by KIRA8, in vivo. After injury, these cells uniquely express integrin v{beta}6, a key activator of TGF{beta} in pulmonary fibrosis. KIRA8 inhibition of IRE1 decreases both DATP number and Itgb6 expression in remaining cells, with a decrease in local collagen accumulation. Single-cell RNA sequencing from IPF lungs revealed an analogous Itgb6+ cell population that may also be regulated by IRE1. These findings suggest that lung epithelial progenitor cells sit at the center of the fibrotic niche, and IRE1 signaling locks them into a dysfunctional state that establishes and perpetuates pathological fibrosis.

cell biology↗

bioRxiv2020

Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

Understanding differential lineage potential of orthologous stem cells across species can shed light on human disease. Here, utilizing 3D organoids, single cell RNAseq, and xenotransplants, we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, are multipotent and able to transdifferentiate into KRT5+ basal cells when co-cultured with primary fibroblasts in 3D organoids. Trajectory analyses and immunophenotyping of epithelial progenitors in idiopathic pulmonary fibrosis (IPF) indicate that hAEC2s transdifferentiate into metaplastic basal cells through alveolar-basal intermediate (ABI) cells that we also identify in hAEC2-derived organoids. Modulating hAEC2-intrinsic and niche factors dysregulated in IPF can attenuate metaplastic basal cell transdifferentiation and preserve hAEC2 identity. Finally, hAEC2s transplanted into fibrotic immune-deficient murine lungs engraft as either hAEC2s or differentiated KRT5+ basal cells. Our study indicates that hAEC2s-loss and expansion of alveolar metaplastic basal cells in IPF are causally connected, which would not have been revealed utilizing murine AEC2s as a model. HighlightsO_LIHuman AEC2s transdifferentiate into KRT5+ basal cells when accompanied by primary adult human lung mesenchyme in 3D organoid culture. C_LIO_LIAlterations of hAEC2-intrinsic and niche factors dysregulated in IPF can modify metaplastic hAEC2 transdifferentiation. C_LIO_LIhAEC2s engraft into fibrotic lungs of immune-deficient mice and transdifferentiate into metaplastic basal cells. C_LIO_LITranscriptional trajectory analysis suggests that hAEC2s in IPF gives rise to metaplastic basal cells via alveolar-basal intermediate cells. C_LI

cell biology↗