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Distinct roles of tip progenitor subpopulation in shaping the murine lung

ABSTRACT: A gradient SOX9+ distal progenitor cell differentiation impacts the patterning of the lung during branching morphogenesis. Although the heterogeneity of this population has been suggested, the specific roles of these subgroups still largely obscure. Here, we explore at least two distinct functional subgroups: the tip progenitors residing at the tips are critical for bud extension and cell allocation, while the transition progenitors sitting immediately to them are indispensable for cell transition. It’s suggested Hippo pathway could regulate the gradient cell differentiation during lung branching. We observed the Cre recombinase driving by Sftpc promoter couldn’t delete Lats1/2 floxed alleles in majority of the tip of SOX9+ distal region, even though the Cre was activated in all the conducting airway. Genetic evidence implied the distal tip progenitors alone is sufficient to help construct the comparable lung structures, while cells at transition stage contributed to the conducting airways. At the expense of themselves, the distal tip progenitors would quickly switch to the transition state when activate YAP via LATS1/2 perturbation. The increasing of cells at transition state results in aggregation of AT1 cells and missing of AT2 cells. Lacking Lats1/2 in SOX9+ distal progenitors in 3D culture could also promote the cell differentiation toward the transition state. Thus, a lower YAP activity is benefit for tip progenitor cell reservation.

ORGANISM(S): Mus musculus

PROVIDER: GSE269537 | GEO | 2026/02/13

REPOSITORIES: GEO

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Project description:Underdeveloped lungs are the primary cause of death in premature infants, however, little is known about stem and progenitor cell maintenance during human lung development. In this study, we have identified that FGF7, Retinoic Acid and CHIR-99021, a small molecule that inhibits GSK3 to activate Wnt signaling, support in vitro maintenance of primary human fetal lung bud tip progenitor cells in a progenitor state. Furthermore, these factors are sufficient to derive a population of human bud tip-like progenitor cells in 3D organoid structures from human pluripotent stem cells (hPSC). Functional studies showed that hPSC-derived bud tip progenitor organoids do not contain any mesenchymal cell types, maintain multilineage potential in vitro and are able to engraft into the airways of injured mice and respond to systemic factors. We performed RNA-sequencing to assess the degree of similarity in global gene expression profiles between the full human fetal lung (59-127 days gestation), isolated human fetal bud tip progenitors, organoids grown from primary fetal bud tip progenitors, and hPSC-derived bud tip organoids. Results showed that hPSC-derived organoids have molecular profiles similar to organoids generated from primary human fetal lung tissue. Gene expression differences between hPSC-derived bud tip organoids and fetal progenitor organoids may be related to the presence of contaminating mesenchymal cells in primary cultures. hPSC-derived bud tip organoids are generated from a well-defined human cell sources, offering a distinct advantage over rare primary tissue as a means to study human specific lung development, homeostasis and disease. Sample Nomenclature - Description ------------------------------------------------------------------------- Peripheral fetal lung the distal/peripheral portion of the fetal lung (i.e., distal 0.5 cm) was excised from the rest of the lung using a scalpel. This includes all components of the lung (e.g., epithelial, mesenchymal, vascular). Isolated fetal bud tip the bud peripheral portion of the fetal lung was excised with a scalpel and subjected to enzymatic digestion and microdissection. The epithelium was dissected and separated from the mesenchyme, but a small amount of associated mesenchyme likely remained. Fetal progenitor organoid 3D organoid structures that arose from culturing isolated fetal epithelial bud tips. Foregut spheroid 3D foregut endoderm structure as described in Dye et al. (2015). Gives rise to patterned lung organoid (PLO) when grown in 3F medium. Patterned lung organoid (PLO) lung organoids that were generated by differentiating hPSCs, as described throughout the manuscript. Bud tip organoid organoids derived from PLOs, enriched for SOX2/SOX9 co-expressing cells, and grown/passaged in 3F medium.

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Distinct roles of tip progenitor subpopulation in shaping the murine lung

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