Biology subjects

Begthel, H.

Publications and source records attributed to Begthel, H..

4 recordsLinked to original sources

bioRxiv2025

A human organoid model of alveolar regeneration reveals distinct epithelial responses to interferon-gamma

Chronic obstructive pulmonary disease is characterized by inflammation and emphysema, leading to progressive alveolar destruction. Currently, no therapies effectively regenerate the alveolar epithelium. Here, we describe a feeder- and serum-free primary adult human organoid model to investigate how inflammation influences alveolar regeneration. We achieve long-term expansion of multipotent progenitor-like cells, while an alveolar type 2 (AT2) maturation protocol enhances surfactant production and supports tubular myelin formation. Introducing a LATS inhibitor to the expansion condition induces alveolar type 1 (AT1) differentiation while maintaining AT2 cells. Using this platform, we find that interferon-gamma exerts cytotoxic effects on AT1 cells while promoting the growth of regenerating AT2 cells, illustrating how a single inflammatory stimulus can have divergent effects on alveolar epithelial cell types. These findings underscore the nuanced influence of pro-inflammatory cytokines on alveolar regeneration. Our organoid model provides a reductionist platform for mechanistic studies, aimed to identify strategies to enhance alveolar regeneration.

cell biology↗

bioRxiv2024

Tuft cells act as regenerative stem cells in the human intestine

In mice, intestinal tuft cells have been described as a long-lived, post-mitotic cell type of which two distinct subsets have been identified, named tuft-1 and tuft-21. By combining analysis of primary human intestinal resection material and intestinal organoids, we identify four distinct human tuft cell states, two of which overlap with their murine counterparts. We show that tuft cell development depends on the presence of Wnt ligands, and that tuft cell numbers rapidly increase upon interleukin (IL)-4 and IL-13 exposure, as reported previously in mouse2-4. This occurs through proliferation of pre-existing tuft cells, rather than through increased de novo generation from stem cells. Indeed, proliferative tuft cells occur in vivo both in fetal and in adult human intestine. Single mature proliferating tuft cells can form organoids that contain all intestinal epithelial cell types. Unlike stem- and progenitor cells, human tuft cells survive irradiation damage and retain the ability to generate all other epithelial cell types. Accordingly, organoids engineered to lack tuft cells fail to recover from radiation-induced damage. Thus, tuft cells represent a damage-induced reserve intestinal stem cell pool in humans.

cell biology↗

bioRxiv2022

Druggable Growth Dependencies and Tumor Evolution Analysis in Patient-Derived Organoids of Neuroendocrine Cancer

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors and poorly-differentiated carcinomas. Treatment options for patients with NENs are limited, in part due to lack of accurate models. To address this need we established the first patient-derived tumor organoids (PDTOs) from pulmonary neuroendocrine tumors and derived PDTOs from an understudied NEN subtype, large cell neuroendocrine carcinoma (LCNEC). PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through drug sensitivity analyses, we uncover therapeutic sensitivities to an inhibitor of NAD salvage biosynthesis and to an inhibitor of BCL-2. Finally, we identify a dependency on EGF in pulmonary neuroendocrine tumor PDTOs. Consistent with these findings, analysis of an independent cohort showed that approximately 50% of pulmonary neuroendocrine tumors expressed EGFR. This study identifies a potentially actionable vulnerability for a subset of NENs, and further highlights the utility of these novel PDTO models for the study of NENs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/514549v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@14bed0borg.highwire.dtl.DTLVardef@1b7791forg.highwire.dtl.DTLVardef@7120a6org.highwire.dtl.DTLVardef@116b21d_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPDTOs of pulmonary NETs and LCNEC were established C_LIO_LIPDTOs recapitulate intra-tumoral heterogeneity and evolution of parental tumors C_LIO_LIDrug assays reveal therapeutic vulnerabilities and biomarkers C_LIO_LIPulmonary NET PDTOs are dependent on EGF C_LI

cancer biology↗

bioRxiv2018

Long-term expanding human airway organoids for disease modelling.

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar biopsies or lavage material. The pseudostratified airway organoid epithelium consists of basal cells, functional multi-ciliated cells, mucus-producing goblet cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoid culture conditions also allow gene editing as well as the derivation of various types of lung cancer organoids. Respiratory syncytial virus (RSV) infection recapitulated central disease features and dramatically increases organoid cell motility, found to be driven by the non-structural viral NS2 protein. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

cell biology↗