Senescent Cells Degrade Intestinal Stem Cell Function

Senescent cells are constantly created and destroyed in all tissues of the body throughout life, but the number present at any given time increases with age, in large part because the immune system ceases to clear senescent cells as efficiently as it should. Senescent cells secrete pro-growth, pro-inflammatory factors that are useful in the short term, such as during wound healing, or to draw attention to potentially cancerous cells. When kept up for the long term, however, the signaling of senescent cells is highly disruptive to tissue structure and function. The example given here, of disrupted intestinal stem cell function resulting from specific molecules generated by senescent cells, is but one of many.

Cellular senescence and the senescence-associated secretory phenotype (SASP) are implicated in aging and age-related disease, and SASP-related inflammation is thought to contribute to tissue dysfunction in aging and diseased animals. However, whether and how SASP factors influence the regenerative capacity of tissues remains unclear. Here, using intestinal organoids as a model of tissue regeneration, we show that SASP factors released by senescent fibroblasts deregulate stem cell activity and differentiation and ultimately impair crypt formation.

The SASP (including factors like Ptk7, which are not technically secreted but are shed as a consequence of senescent cell surface remodeling) is believed to be a critical part of the contribution of senescent cells to age-related disease, primarily by influencing the tissue microenvironment and spreading senescence through a "bystander effect". Accordingly, selective elimination of senescent cells improves many aging symptoms and disease phenotypes. Our study identifies sPtk7 as a critical SASP factor that has a direct and reversible impact on intestinal stem cell proliferation and differentiation.

Our data show that Ptk7 is also expressed in fibroblasts and epithelial cells of the mouse small intestine, and that shedding of the N-terminal domain of Ptk7 is increased in the gut of old mice. Our co-culture experiments of intestinal organoids with senescent intestinal fibroblasts further show that fibroblast-derived Ptk7 impairs differentiation of intestinal stem cells. How this effect on intestinal stem cells influences epithelial homeostasis and regeneration remains to be established.

Link: https://doi.org/10.1038/s41467-022-35487-9