Abstract
Mammary morphogenesis is an orchestrated process involving differentiation, proliferation and organization of cells to form a bi-layered epithelial network of ducts and lobules embedded in stromal tissue. We have engineered a 3D biomimetic human breast that makes it possible to study how stem cell fate decisions translate to tissue-level structure and function. Using this advancement, we describe the mechanism by which breast epithelial cells build a complex three-dimensional, multi-lineage tissue by signaling through a collagen receptor. Discoidin domain receptor tyrosine kinase 1 induces stem cells to differentiate into basal cells, which in turn stimulate luminal progenitor cells via Notch signaling to differentiate and form lobules. These findings demonstrate how human breast tissue regeneration is triggered by transmission of signals from the extracellular matrix through an epithelial bilayer to coordinate structural changes that lead to formation of a complex ductal-lobular network.
Highlights
The presence of GSI led to a failure of TDLU formation, phenocopying the defect due to inhibition of DDR1 (Supplementary Fig. 3d). These findings indicate that breast tissue regeneration in 3D culture involves collagen stimulation of DDR1 in basal cells, leading to activation of Notch[1] signaling in adjacent luminal cells, driving luminal differentiation and TDLU formation
We examined the expression of the Notch[1] ligands JAG1, JAG2, DLL1, DLL3 and DLL4 in basal cells following DDR1 inhibition and release and found that JAG1 expression is downregulated following DDR1 inhibition and upregulated following release (Fig. 5a)
Tissue regeneration in a 3D context is facilitated by spatially regulated cell fate decisions
Summary
Recognizing that DDR1 activity promoted differentiation in more than one mammary lineage, we aimed to identify how DDR1 exerts its effect on different cell types
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