Biology subjects

Kaserman, J.

Publications and source records attributed to Kaserman, J..

3 recordsLinked to original sources

bioRxiv2026

AT2-intrinsic Z-AAT expression drives conserved inflammatory and proteotoxic stress responses and predisposes to emphysema

Individuals homozygous for the SERPINA1 "Z" mutation with alpha-1 antitrypsin deficiency (AATD) are highly susceptible to emphysema. This predisposition has classically been attributed to a relative deficiency of circulating alpha-1 antitrypsin (AAT) reaching the lungs and associated protease-antiprotease imbalance. Accumulating evidence suggests that the presence of misfolded Z-AAT protein either in the circulation, the lung interstitium, or within resident lung cells could contribute to emphysema pathogenesis. We have shown that type 2 alveolar epithelial cells (AT2s), progenitor cells of the lung alveolus, heterogeneously retain Z-AAT and exhibit a transcriptional disease signature in AATD patient samples. However, a lack of model systems that faithfully recapitulate AT2 biology and associated Z-AAT expression has limited our ability to study this phenomenon. Here, we apply syngeneic induced pluripotent stem cell-derived AT2s (iAT2s) and a novel mouse model featuring AT2-specific inducible human SERPINA1 expression to interrogate the cell-instrinsic consequences of Z-AAT expression, validating findings in an independent dataset of human COPD lung tissue comparing ZZ to MM SERPINA1 genotypes. We find further evidence of Z-AAT retention within AT2s and identify shared AT2 transcriptomic disease signatures conserved across model systems, characterized by innate immune and inflammatory signaling, NF-{kappa}B activation, and endoplasmic reticulum stress. Mice with AT2-specific Z-AAT expression additionally demonstrate increased susceptibility to elastase-induced emphysema, providing functional evidence for AT2-intrinsic contributions to AATD-associated lung disease. Within iAT2s, a subpopulation of Z-AAT expressing cells exhibits activation of the PERK-eIF2 signaling axis and markers of an alveolar basal intermediate (ABI) state, emerging cell-autonomously in the absence of mesenchymal co-culture.Together, these data provide evidence that Z-AAT expression in AT2s induces heterogenous cell-intrinsic stress responses including proteotoxic stress, inflammatory signaling, and aberrant cell fate adoption, and is sufficient to result in predisposition to injury, supporting a potential contribution of AT2-intrinsic Z-AAT toxicity to human AATD-associated emphysema pathogenesis.

cell biology↗

bioRxiv2024

The proteomic landscape of proteotoxic stress in a fibrogenic liver disease

Protein misfolding diseases, including alpha-1 antitrypsin deficiency (AATD), pose significant health challenges, with their cellular progression still poorly understood1-3. We utilize spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis4,5, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudo-time across fibrosis stages. We achieve unprecedented proteome depth of up to 3,800 proteins from a third of a single cell in formalin-fixed, paraffin-embedded (FFPE) tissue. This dataset revealed a potentially clinically actionable peroxisomal upregulation that precedes the canonical unfolded protein response. Our single-cell proteomics data show alpha-1 antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomic data with AI-guided image-based phenotyping across multiple disease stages, revealing a terminal hepatocyte state characterized by globular protein aggregates and distinct proteomic signatures, notably including elevated TNFSF10/TRAIL expression. This phenotype may represent a critical disease progression stage. Our study offers novel insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue.

cell biology↗

bioRxiv2022

Modeling of Alpha-1 Antitrypsin Deficiency with Syngeneic Human iPSC-Hepatocytes Reveals Metabolic Dysregulation and Cellular Heterogeneity in PiMZ and PiZZ Hepatocytes

Individuals homozygous for the pathogenic "Z" mutation in alpha-1 antitrypsin deficiency (AATD) are known to be at increased risk for chronic liver disease. That some degree of risk is similarly conferred by the heterozygous state, estimated to affect 2% of the US population, has also become clear. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of expressing a single ZAAT allele on hepatocyte biology. Here, through the application of CRISPR-Cas9 editing, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-derived hepatocytes (iHeps) relative to homozygous mutant (ZZ) or corrected (MM) cells. We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations in hepatic metabolic function including ER and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in subpopulations of cells. Our cellular model of MZ heterozygosity thus provides evidence that expression of a single Z allele is sufficient to disrupt hepatocyte homeostatic function and suggest a mechanism underlying the increased risk of liver disease observed among MZ individuals.

cell biology↗