Niche-adjacent Type IV collagen promotes GLP-1/Notch receptor activation in the C. elegans germline

Abstract Basement membranes are thin and dense proteinaceous layers of specialized extracellular matrix that surround tissues to maintain their structure and function¹. With age, chronic inflammation typically stiffens this basement membrane in a phenomenon called fibrosis, the progression of which is reflected by increasing levels of the basement membrane’s main component, type IV collagen (COL IV)²,³. Tissue fibrosis and elevated Notch signaling are two co-occurring hallmarks of many inflammation-linked diseases, including cancer³⁻⁶. Many reasoned that fibrosis may be a consequence of elevated Notch signaling, a belief that has led to Notch targeting antifibrotic therapy attempts⁷,⁸,⁹. Yet, the in vivo relationship between Notch activity and fibrosis has not been clearly defined. Here, we show that EMB-9/COL IV accumulation adjacent to the C. elegans germline stem cell niche promotes GLP-1/Notch receptor activation in germline stem cells. Increased Notch activity is therefore a consequence of high basement membrane COL IV contents. Moreover, we find that reducing GLP-1/Notch activity in vivo leads to a generalized dramatic increase in EMB-9/COL IV levels, and thereby promotes fibrosis. The generalized fibrosis that comes along with inflammaging may therefore act as a root cause for cancer by promoting Notch signaling, and perhaps more widely, many other ligand-receptor interactions.