Biology subjects

Auyeung, V. C.

Publications and source records attributed to Auyeung, V. C..

4 recordsLinked to original sources

bioRxiv2025

Alveolar Type II Cell-derived MMP1high basal cells promote destructive microcysts in idiopathic pulmonary fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease characterized by progressive epithelial metaplasia and widespread fibrosis. Alveolar microcysts develop near terminal airways in IPF and are linked to poor outcome. Using HTII-280 as a short-term lineage marker of AT2-derived AT0 (SFTPC+/SCGB3A2+) and basaloid (KRT17) cells, together with organoids and spatial transcriptomics (Xenium), we highlight epithelial similarities between respiratory bronchioles (RBs) and alveolar microcysts both having AT0, SCGB3A2+, and basaloid/basal cells (BCs), albeit with expanded BCs in IPF microcysts. The AT0- and AT2-derived BCs strongly express the collagenase, matrix metalloproteinase protein-1, MMP1 in organoids -- mirroring in situ BCs lining IPF microcysts, but distinct from MMP1low BCs in large airways or normal lungs. Expression of MMP1 correlates with basal cell hypoxia pathway activity. MMP1high AT2-derived BCs and IPF BCs promoted type 1 collagen degradation ex vivo and in vivo after xenotransplantation, forming microcystic structures that were abrogated by concurrent MMP inhibitor treatment. Notably, a Frizzled 5 WNT agonist antibody reversed the MMP1high state of AT2-derived BCs, raising a possible therapeutic approach. These findings suggest AT2 transdifferentiation to basaloid/basal cells is uncommon in normal lungs but can expand as a potential source of alveolar destruction, likely contributing to the pernicious course of IPF.

cell biology↗

bioRxiv2023

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification

Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGF{beta}) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGF{beta} signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGF{beta} signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFb signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.

physiology↗

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↗

bioRxiv2018

Small molecule inhibition of IRE1α kinase/RNase has anti-fibrotic effects in the lung

Endoplasmic reticulum stress (ER stress) has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease of progressive fibrosis and respiratory failure. ER stress activates a signaling pathway called the unfolded protein response (UPR) that either restores homeostasis or promotes apoptosis. The bifunctional kinase/RNase IRE1 is a UPR sensor that promotes apoptosis if ER stress remains high (i.e., a \"terminal\" UPR). Using multiple small molecule inhibitors against IRE1, we show that ER stress-induced apoptosis of murine alveolar epithelial cells can be mitigated in vitro. In vivo, we show that bleomycin exposure to murine lungs causes early ER stress to activate IRE1 and the terminal UPR prior to development of pulmonary fibrosis. Small-molecule IRE1 kinase-inhibiting RNase attenuators (KIRAs) that we developed were used to evaluate the importance of IRE1 activation in bleomycin-induced pulmonary fibrosis. One such KIRA--KIRA7--provided systemically to mice at the time of bleomycin exposure decreases terminal UPR signaling and prevents lung fibrosis. Administration of KIRA7 14 days after bleomycin exposure even promoted the reversal of established fibrosis. Finally, we show that KIRA8, a nanomolar-potent, monoselective KIRA compound derived from a completely different scaffold than KIRA7, likewise promoted reversal of established fibrosis. These results demonstrate that IRE1 may be a promising target in pulmonary fibrosis and that kinase inhibitors of IRE1 may eventually be developed into efficacious anti-fibrotic drugs.

molecular biology↗