Paneth Cells: Dispensable yet Irreplaceable for the Intestinal Stem Cell Niche

Intestinal Paneth cells have been proposed to support intestinal stem cells through the expression of niche factors, including Notch and Wnt ligands. However, the Paneth cell's role as an intestinal stem cell niche cell has been debated as mice lacking Paneth cells retain functional intestinal stem cells that continue to replenish the epithelium. Here, we present a more nuanced view of Paneth cell function to support intestinal stem cells during homeostasis and crypt regeneration after injury. Intestinal stem cells replenish the epithelium throughout life by continuously generating intestinal epithelial cell types, including absorptive enterocytes, and secretory goblet, endocrine, and Paneth cells. This process is orchestrated by a symphony of niche factors required to maintain intestinal stem cells and to direct their proliferation and differentiation. Among the various mature intestinal epithelial cell types, Paneth cells are unique in their location in the stem cell zone, directly adjacent to intestinal stem cells. Although Paneth cells were first described as an epithelial cell component of the innate immune system due to their expression of antimicrobial peptides, they have been proposed to be niche cells due to their close proximity to intestinal stem cells and expression of niche factors. However, function as a niche cell has been debated since mice lacking Paneth cells retain functional stem cells that continue to replenish the intestinal epithelium. In this review, we summarize the intestinal stem cell niche, including the Notch, Wnt, growth factor, mechanical, and metabolic niche, and discuss how Paneth cells might contribute to these various components. We also present a nuanced view of the Paneth cell as a niche cell. Although not required, Paneth cells enhance stem cell function, particularly during intestinal development and regeneration. Furthermore, we suggest that Paneth cell loss induces intestinal stem cell remodeling to adjust their niche demands. (Cell Mol Gastroenterol Hepatol 2025;19:101443; https://doi.org/10.1016/ j.jcmgh.2024.101443)