Biology subjects

Salton, F.

Publications and source records attributed to Salton, F..

3 recordsLinked to original sources

bioRxiv2026

Targeting hypoxia-responsive miR-155-5p and miR-210-3p restores alveolar regeneration and reverses pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an age-associated degenerative disease largely driven by failure of alveolar epithelial regeneration, yet current therapies slow fibrosis progression without restoring epithelial repair. Building on our previous unbiased microRNA screen in primary murine alveolar type II (ATII) cells, we identified miR-155-5p and miR-210-3p as previously unrecognized mediators of alveolar epithelial regenerative failure. Both microRNAs were markedly upregulated in ATII cells from patients with IPF and enriched within KRT17+/KRT5- aberrant transitional epithelial cells. Their expression also increased spontaneously with ageing in ATII cells from uninjured mice, linking these microRNAs to the age-dependent loss of ATII to ATI transdifferentiation capacity. Furthermore, we found that hypoxia-induced HIF signalling drives the expression of these microRNAs in ATII cells, locking them in a dysfunctional transitional state characterized by a profibrotic secretome that promotes paracrine myofibroblasts activation. Antisense oligonucleotide (ASO) inhibition of selected miRNAs restored ATII-to-ATI differentiation, eliminated aberrant transitional states, normalized epithelial-mesenchymal communication, promoted de novo alveolar regeneration and reversed fibrosis, including in both young and aged mice. Together, these findings identify the hypoxia-responsive miRNAs miR-155-5p and miR-210-3p as therapeutically actionable regulators of alveolar regenerative failure and establish their inhibition as a strategy to restore endogenous lung repair while disrupting pathological epithelial-mesenchymal crosstalk in pulmonary fibrosis.

cell biology↗

bioRxiv2026

AAV-miR-124 enhances endogenous alveolar epithelial regenerative plasticity and reverses bleomycin-induced pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by irreversible destruction of the alveolar epithelium and impaired regeneration. Although current therapies slow disease progression, they do not restore functional alveoli, highlighting the need for regenerative approaches that promote endogenous lung repair. Here, we performed the first unbiased functional screen of 2,042 human microRNA mimics in primary mouse alveolar type II (ATII) cells to identify regulators of ATII-to-alveolar type I (ATI) cell transdifferentiation. The screen identified miR-124-3p as the most effective promoter of ATI differentiation. In vitro, miR-124-3p promoted ATII-to-ATI transdifferentiation in healthy and bleomycin-injured ATII cells while also increasing the ATII cell pool, consistent with activity on epithelial progenitors. Using the engineered AAV6.2FF capsid, we generated a vector encoding miR-124-3p, which efficiently transduced ATII cells, MHC-II club distal progenitor cells, and injury-induced KRT8 epithelial intermediates. Therapeutic administration after fibrosis establishment reduced lung fibrosis, restored alveolar architecture, and showed greater efficacy than nintedanib in the bleomycin mouse model. Mechanistically, we propose a context-dependent model whereby miR-124-3p regulates epithelial cell states through the EZH2-C/EBP axis while attenuating epithelial transcriptional programs associated with IPF. Together, these findings support AAV-mediated delivery of miR-124 to promote alveolar repair in pulmonary fibrosis.

cell biology↗

bioRxiv2024

Vapor-based Fixation of Pulmonary Tissue in its Physiological State: A Novel Approach to Histological Validation of Ultra High Resolution Phase Contrast CT in Human Sized Lungs

Lung diseases continue to present a major burden on public health. Therefore, improving the process of diagnosis by the development of novel imaging techniques is of great importance. In this perspective, phase sensitive CT imaging techniques such as propagation based imaging (PBI) might play an important role as they allow increasing the spatial resolution at very low x-ray dose levels that are comparable to clinical CT. However, the development of such methods is not only hindered by technological problems but also by the lack of precise validation strategies. We adapted formaldehyde (FA) vapor fixation to demonstrate that fresh porcine lungs that have been investigated by PBI can be fixed in their physiological shape and studied by multi-scale microCT imaging as well as classical histology. In addition, we show that FA vapor fixed pig lungs can be scanned by PBI without visible deterioration of image quality compared to fresh tissue. This opens the possibility of fixing and storing, for instance, human lung tissue before performing a PBI experiment, which in turn allows to study pathological changes in human lungs without questioning the translate-ability of findings in pig lung. The setup can be used by any interested researchers.

pathology↗