CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation

Abstract

Intestinal stem cells (ISCs) at the crypt base contribute to intestinal homeostasis through a balance between self-renewal and differentiation. However, the molecular mechanisms regulating this homeostatic balance remain elusive. Here we show that the matricellular protein CCN1/CYR61 coordinately regulates ISC proliferation and differentiation through distinct pathways emanating from CCN1 interaction with integrins αvβ3/αvβ5. Mice that delete Ccn1 in Lgr5 + ISCs or express mutant CCN1 unable to bind integrins αvβ3/αvβ5 exhibited exuberant ISC expansion and enhanced differentiation into secretory cells at the expense of absorptive enterocytes in the small intestine, leading to nutrient malabsorption. Analysis of crypt organoids revealed that through integrins αvβ3/αvβ5, CCN1 induces NF-κB-dependent Jag1 expression to regulate Notch activation for differentiation and promotes Src-mediated YAP activation and Dkk1 expression to control Wnt signaling for proliferation. Moreover, CCN1 and YAP amplify the activities of each other in a regulatory loop. These findings establish CCN1 as a niche factor in the intestinal crypts, providing insights into how matrix signaling exerts overarching control of ISC homeostasis.

FUT2-dependent fucosylation of HYOU1 protects intestinal stem cells against inflammatory injury by regulating unfolded protein response

“…ISCs remodel intestinal composition in response to epithelial defects by dividing symmetrically, either forming two daughter stem cells or two daughter non-stem progenitor cells which differentiate into the diverse types of epithelial cells [ 34 , 42 ]. A recent study has also revealed that ISC proliferation and differentiation are coordinately regulated to maintain homeostasis by regulating distinct pathways [ 43 ], which keeps in line with our results that FUT2-dependent fucosylation motivates the regenerative capacity of ISCs upon inflammatory injury.…”

Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis

“…Several reports suggest that liver inflammation alters hepatic glucose and lipid homeostasis because of direct effects of inflammatory MΦs, like those activated by CYR61 (52)(53)(54). Alternatively, there may be direct effects on hepatocyte metabolism that CYR61 exerts in the context of injury, as has been shown for other cell types (24,55,56). Although deletion of CYR61 has beneficial effects on fibrosis, inflammation, and metabolic signaling, its known roles in ductular reaction (22), angiogenesis (57,58), and cellular senescence (59,60) suggest that there may be deleterious long-term aspects of repair and regeneration that should be considered.…”

Single‐cell transcriptomics implicates the FEZ1–DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence

“…Proliferation and differentiation are fundamental for adult stem cells to help maintaining tissue homeostasis and promote wound healing 3,4 . Upon differentiation, switches in the levels of specific keratins are observed in most epithelial tissues.…”

“…2 Proliferation and differentiation are fundamental for adult stem cells to help maintaining tissue homeostasis and promote wound healing. 3,4 Upon differentiation, switches in the levels of specific keratins are observed in most epithelial tissues. For example, in the cornea, keratin 19 (KRT19)-and KRT15-positive cells are mainly located in the limbus, whereas the central corneal epithelium is defined by markers of a mature corneal epithelium (KRT3 and KRT12).…”