Good Neighbors: The Niche that Fine Tunes Mammalian Intestinal Regeneration

The intestinal epithelium undergoes continuous cellular turnover, making it an attractive model to study tissue renewal and regeneration. Intestinal stem cells (ISCs) can both self-renew and differentiate along all epithelial cell lineages. Decisions about which fate to pursue are controlled by a balance between high Wnt signaling at the crypt bottom, where Lgr5+ ISCs reside, and increasing bone morphogenetic protein (BMP) levels toward the villus, where differentiated cells are located. Under stress conditions, epithelial cells in the intestine are quite plastic, with dedifferentiation, the reversal of cell fate from a differentiated cell to a more stem-like cell, allowing for most mature epithelial cell types to acquire stem cell-like properties. The ISC niche, mainly made up of mesenchymal, immune, enteric neuronal, and endothelial cells, plays a central role in maintaining the physiological function of the intestine. Additionally, the immune system and the microbiome play an essential role in regulating intestinal renewal. The development of various mouse models, organoid co-cultures and single-cell technologies has led to advances in understanding signals emanating from the mesenchymal niche. Here, we review how intestinal regeneration is driven by stem cell self-renewal and differentiation, with an emphasis on the niche that fine tunes these processes in both homeostasis and injury conditions.