Biology subjects

Elitz, A.

Publications and source records attributed to Elitz, A..

4 recordsLinked to original sources

bioRxiv2026

Alveolar-Basal Intermediates Drive Pulmonary Fibrosis via Coordination of a Pro-Fibrotic Signaling Niche in Silicosis

Pulmonary fibrosis is a progressive, terminal disease with high morbidity. Existing therapeutics slow disease progression but do not reverse fibrotic lung remodeling, accentuating the importance of identifying cellular mechanisms that underlie lung fibrosis. Recent literature suggests that alveolar type 2 (AT2) progenitors undergo transition to stressed Krt8high cells following lung injury. Accumulation of stressed Krt8high cells is a hallmark of acute and chronic lung diseases, particularly pulmonary fibrosis. Whether Krt8high cells actively participate in the fibrotic process or are simply an epiphenomenon of lung injury remains unclear. We previously described a genetic model in which deletion of the lung transcription factor Nkx2-1 in the AT2 progenitor lineage induces AT2 progenitors to transition to the Krt8high cell state. Here, we use this tractable genetic model to directly test the pathogenic influence of Krt8high cells. We show that Nkx2-1-/- Krt8high cells accumulate in a Krt7high/Krt19high/Krt17neg alveolar-basal intermediate cell state (ABI). Following induction of fibrotic lung injury with inhaled silica, ABI enter a unique inflammatory state (iABI) that drives fibrotic remodeling via coordination of a fibrotic signaling niche containing inflammatory alveolar fibroblasts (iAF) and pulmonary osteoclast-like cells (POLC). Computational analysis predicts that iABI elaborate pro-inflammatory signals which increase matrix deposition by iAF and induce differentiation of interstitial macrophages to a profibrotic POLC variant. Niche mapping demonstrates that iABI, iAF, and POLCs interact within newly formed fibrotic niches in the lung alveolus in mice with pre-existing accumulation of ABI. These data provide direct evidence that ABI accumulation in fibrotic lung disease is pathogenic.

systems biology↗

bioRxiv2026

The chromatin remodeling complex PRC2 safeguards cell fate in alveolar epithelial type 2 cells

Maintenance of the gas exchange surface throughout life and regeneration of the lung after injury requires tight regulation of epithelial cell fate and function. Alveolar epithelial type 2 (AT2) cells serve as the progenitors of the distal epithelium, differentiating into alveolar epithelial type 1 (AT1) cells or proliferating to maintain the quorum of AT2 cells. Here we describe the role of the chromatin regulator polycomb repressive complex 2 (PRC2) in the maintenance of AT2 cell fate in the adult alveolus. Cross-species single-cell transcriptomic analyses identified PRC2 activation in proliferative AT2 populations. PRC2 loss of function in human iPSC-derived AT2 (iAT2) cells and primary murine AT2 cells in vitro resulted in loss of AT2 cell state and emergence of programs reminiscent of alveolar-basal intermediate (ABI) cell states, while overexpression of the PRC2 enzymatic component EZH2 in human iAT2 cells augmented the AT2 cell program. Genetic loss of PRC2 function in the AT2 lineage in adult mice in vivo led to emphysematous remodeling of the lung and induced a time-dependent series of transitions of AT2 cells through an alveolar-basal intermediate (ABI) state into Krt5+ basal-like cells. Comparison of murine ABI cells to human disease-associated ABI cells demonstrates de-repression of canonical PRC2 targets during transition to ABI and basal-like states in human fibrosis, implicating PRC2 is a conserved regulator of AT2 cell fate. Together, these findings define PRC2 complex function during AT2 cell self-renewal as a critical guardrail for maintaining epithelial cell fate in the adult lung.

genetics↗

bioRxiv2025

Early cell autonomous and niche-mediated alveolar epithelial response to influenza infection in primary lung organoids

Influenza A virus (IAV) infection is a significant cause of morbidity and mortality for patients worldwide. Alveolar type 2 (AT2) cells are the preferential target of IAV as part of the pathogenesis of viral pneumonia and acute respiratory distress syndrome (ARDS). Early IAV infection of alveolar cells has been challenging to model both in vitro and in vivo. To address this challenge, we used a combination of murine and human primary alveolar organoids to define methods for robust IAV infection and evaluated cell-autonomous consequences of IAV using a temporal series of multiome paired single nuclei RNA/ATAC sequencing. Infected AT2 cells undergo conserved changes defined by early loss of surfactant secretion, decreased lipid biogenesis, a rapid burst of antiviral response, and late viral-mediated suppression. Surprisingly, uninfected AT2 cells undergo substantial transcriptional and epigenomic changes in IAV-treated cultures, leading to transition to damage-associated cell states within hours via a process driven by the inflammatory milieu of murine organoids. Together, these data provide new methods for high-fidelity modeling of IAV infection in alveolar cells and define a conserved AT2 cell response signature to IAV with implications for ARDS pathogenesis.

systems biology↗

bioRxiv2025

Cell fate specification during respiratory development requires ARID1A-containing canonical BAF complex activity

Development of the mammalian lung requires formation of a definitive lung bud from the foregut endoderm, branching morphogenesis, specification of a proximal to distal axis, and differentiation of extensive specialized airway and alveolar epithelial lineages. These steps require coordinated temporal and regional gene expression to define the lung epithelium in preparation for the first breath at birth. While the transcriptional and signaling regulators required for lung development are increasingly well known, the key epigenetic complexes that interact with lineage transcription factors for cell-specific control of gene expression remain to be defined. Here, we identify a key role for the canonical BAF complex, an ATP-dependent chromatin remodeling complex, during lung epithelial development. Loss of canonical BAF activity throughout the foregut endoderm leads to complete failure of lung formation, and selective deletion of a single key subunit, ARID1A, leads to failure of proximal-distal axis specification, with dilated airway-like structures lined by ectopic basal cells found throughout the distal lung, and failure of specification of alveolar type 1 (AT1) cells in the distal saccular epithelium. In place of AT1 cells, we identified a highly proliferative epithelial cell state defined by joint activation of YAP and WNT signaling and loss of BMP signaling response, leading to increased proliferation and failure of appropriate epithelial differentiation. These changes resulted in secondary failure of mesenchymal and endothelial specification, leading to broad loss of patterning of the distal lung further disrupting peripheral lung morphogenesis. Using embryonic lung organoids, we demonstrate that exogenous BMP4 signaling is sufficient to rescue AT1 and AT2 cell differentiation in ARID1A-null epithelium, while WNT and YAP signaling require functional BAF complex. Together, these data demonstrate a requirement for the BAF complex for lung formation, proximal-distal patterning, and cell fate acquisition, and reveal surprising differential specificity between signaling pathways during lung development. One-Sentence SummaryFunctional BAF complex containing ARID1A is required for lung development.

developmental biology↗