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

Abstract

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 anti-microbial 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.

Keywords: Cellular Remodeling; Intestinal Crypt; Notch Signaling; Tissue Regeneration; WNT Signaling.

Figure 1

The intestinal stem cell niche. (A) Schematic of an intestinal crypt. Paneth cells produce many niche factors, including Notch ligands (DLL1/DLL4), Wnts, growth factors, metabolites, and mechanical support through anchorage to the basement membrane via β4 integrin. Non-epithelial cells also provide many niche factors. (B) TEM of small intestinal murine crypt, emphasizing the cell-cell contact between ISCs (white outline) and Paneth cells (red outline). (C) Schematic of Paneth-cell specific niche factors requiring cell-cell contact, including Notch ligands DLL1 and DLL4, and β4 integrin. (D) Schematic of a crypt after Paneth cell loss, with ISC clustering and occasional localization of endocrine and tuft cells within the stem cell zone. Although these secretory cells may provide certain niche factors, ISCs may remodel to express niche factors such as Notch ligands to provide support to each other. ∗Created with BioRender.com.

Figure 2

Small intestinal epithelium throughout development. Schematic of the process of Paneth cell emergence as crypts develop around postnatal day 10 (P10) in mice and 29 weeks of gestation in humans. Before that time, ISCs remain clustered together in shallow intervillous regions. Paneth cell emergence and crypt fission gradually increase until the formation of the adult crypt which finishes maturation at P28 in mouse and at full-term gestation in humans. ∗Created with BioRender.com.