M1 and M2 macrophages differentially regulate colonic crypt renewal

AbstractThe colonic epithelium is the most rapidly renewing tissue in the body and is organized into a single cell layer of invaginations called crypts. Crypt renewal occurs through Lgr5+ gut stem cells situated at the crypt base, which divide, produce daughter cells that proliferate, migrate, differentiate into all the cells required for normal gut function (eg. Goblet cells, enterocytes), and are finally shed into the crypt lumen. In health this rapid renewal helps maintain barrier function next to the hostile gut luminal environment that contains microbes and food. In parallel, the peri-cryptal lamina propria hosts the largest monocyte-derived macrophage population in the human body. Different macrophage phenotypes have been associated with intestinal health/intact barrier function, namely M2 compared to M1 macrophages that indicate inflammation/compromised barrier function. However, the direct effect of different macrophage subtypes have on colonic crypt renewal is not well understood. In this study we have utilized a reductionist 3D in vitro co-culture model to determine the regulatory capacity of M1 and M2 macrophages on colonic crypt renewal. We show that colonic crypt proliferation is increased in the presence of M1 or M2 macrophages, while we further demonstrate that a decrease in goblet and tuft cell expression as well as an increase in Lgr5+ stem cell numbers is only achieved through M1-crypt crosstalk in a contact dependent manner.