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TGFbeta determines epithelial tissue spacing by regulating mesenchymal condensation

ABSTRACT: The branched structure of the vertebrate lung provides a high surface area-to-volume ratio, which increases the efficiency of diffusion-driven gas exchange. Generating this structure requires that the epithelial branches avoid contacting each other as they elongate during development. Previous studies have suggested that the spacing between neighboring branches is intrinsic to growth of the epithelium, but the underlying physical mechanisms remain elusive. Here, we used the embryonic chicken lung as a model system and found that branch spacing is regulated primarily by signaling to the mesenchyme through transforming growth factor-beta (TGFbeta). Although proliferation decreases in epithelial cells that are located in close proximity to an adjacent branch, these patterns surprisingly emerge after regular branch spacing has been established. Instead, we find that TGFbeta promotes the directed migration of mesenchymal cells, which form a condensation that physically displaces the adjacent epithelium and tunes branch spacing. Continuous disruption of TGFbeta signaling prevents mesenchymal condensation and eventually results in contact between adjacent branches. These data suggest that the spacing between epithelial branches results from mesenchymal cell dynamics rather than from epithelial-intrinsic self-avoidance.

ORGANISM(S): Gallus gallus

PROVIDER: GSE333735 | GEO | 2026/06/20

REPOSITORIES: GEO

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Project description:Transforming growth factor beta-1 (TGFbeta) is a tumor suppressor during the initial stage of tumorigenesis, but it can switch to a tumor promoter during neoplastic progression. Ionizing radiation (IR), both a carcinogen and a therapeutic agent, induces TGFbeta activation in vivo. We now show that IR sensitizes human mammary epithelial cells (HMEC) to undergo TGFbeta-mediated epithelial to mesenchymal transition (EMT). Non-malignant HMEC (MCF10A, HMT3522 S1 and 184v) were irradiated with 2 Gy shortly after attachment in monolayer culture, or treated with a low concentration of TGFbeta (0.4 ng/ml), or double-treated. All double-treated (IR+TGFbeta) HMEC underwent a morphological shift from cuboidal to spindle-shaped. This phenotype was accompanied by decreased expression of epithelial markers E-cadherin, beta-catenin and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin and vimentin. Furthermore, double-treatment increased cell motility, promoted invasion and disrupted acinar morphogenesis of cells subsequently plated in Matrigel. Neither radiation nor TGFbeta alone elicited EMT, even though IR increased chronic TGFbeta signaling and activity. Gene expression profiling revealed that double treated cells exhibit a specific 10-gene signature associated with Erk/MAPK signaling. We hypothesized that IR-induced MAPK activation primes non-malignant HMEC to undergo TGFbeta-mediated EMT. Consistent with this, Erk phosphorylation were transiently induced by irradiation, persisted in irradiated cells treated with TGFbeta, and treatment with U0126, a Mek inhibitor, blocked the EMT phenotype. Together, these data demonstrate that the interactions between radiation-induced signaling pathways elicit heritable phenotypes that could contribute to neoplastic progression. Keywords: response to ionizing radiation, response to transforming growth factor-beta, nonmalignant human mammary epithelial MCF10A cells, epithelial to mesenchymal transition

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TGFbeta determines epithelial tissue spacing by regulating mesenchymal condensation

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