Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling

• Published in: Nature communications Vol. 14; no. 1; pp. 156 - 19
• Main Authors: Yun, Jina, Hansen, Simon, Morris, Otto, Madden, David T., Libeu, Clare Peters, Kumar, Arjun J., Wehrfritz, Cameron, Nile, Aaron H., Zhang, Yingnan, Zhou, Lijuan, Liang, Yuxin, Modrusan, Zora, Chen, Michelle B., Overall, Christopher C., Garfield, David, Campisi, Judith, Schilling, Birgit, Hannoush, Rami N., Jasper, Heinrich
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/106; 14/35; 38/91; 631/136/7; 631/532; 631/532/489; 631/80/509; 64/60; 96/63; Age related diseases; Aging; Animal diseases; Animals; Broken symmetry; Calcium (intracellular); Calcium ions; Calcium signalling; Cell differentiation; Cell Differentiation - genetics; Cellular Senescence - genetics; Deregulation; Differentiation (biology); Fibroblasts; Humanities and Social Sciences; Intestine; Intestines - cytology; Intestines - metabolism; Mice; multidisciplinary; Nuclear transport; Organoids; Phenotypes; Receptor Protein-Tyrosine Kinases - metabolism; Regeneration (physiology); Science; Science (multidisciplinary); Senescence; Signaling; Stem cell transplantation; Stem cells; Stem Cells - metabolism; Tissue engineering; Tissues; Translocation; Wnt protein; Wnt Signaling Pathway; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35487-9

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. We identify the secreted N-terminal domain of Ptk7 as a key component of the SASP that activates non-canonical Wnt / Ca 2+ signaling through FZD7 in intestinal stem cells (ISCs). Changes in cytosolic [Ca 2+ ] elicited by Ptk7 promote nuclear translocation of YAP and induce expression of YAP/TEAD target genes, impairing symmetry breaking and stem cell differentiation. Our study discovers secreted Ptk7 as a factor released by senescent cells and provides insight into the mechanism by which cellular senescence contributes to tissue dysfunction in aging and disease. Cellular senescence and associated secretory phenotype (SASP) are thought to contribute to aging and tissue dysfunction, though it is unclear how SASP impacts regeneration. Here the authors show that SASP factors impair regeneration, and that Ptk7 is a key secreted protein mediating that dysregulation.