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

Jina Yun, Simon Hansen, Otto Morris, David T. Madden, Clare Peters Libeu, Arjun J. Kumar, Cameron Wehrfritz, Aaron H. Nile, Yingnan Zhang, Lijuan Zhou, Yuxin Liang, Zora Modrusan, Michelle B. Chen, Christopher C. Overall, David Garfield, Judith Campisi, Birgit Schilling, Rami N. Hannoush () and Heinrich Jasper ()
Additional contact information
Jina Yun: Genentech, Inc.
Simon Hansen: NBE Therapeutics
Otto Morris: The Schrödinger Building Oxford Science Park
David T. Madden: Buck Institute for Research on Aging
Clare Peters Libeu: Buck Institute for Research on Aging
Arjun J. Kumar: Fred Hutch/University of Washington
Cameron Wehrfritz: Buck Institute for Research on Aging
Aaron H. Nile: Calico Labs LLC.
Yingnan Zhang: Genentech, Inc.
Lijuan Zhou: Genentech, Inc.
Yuxin Liang: Genentech, Inc.
Zora Modrusan: Genentech, Inc.
Michelle B. Chen: Genentech, Inc.
Christopher C. Overall: Genentech, Inc.
David Garfield: Genentech, Inc.
Judith Campisi: Buck Institute for Research on Aging
Birgit Schilling: Buck Institute for Research on Aging
Rami N. Hannoush: Genentech, Inc.
Heinrich Jasper: Genentech, Inc.

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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 / Ca2+ signaling through FZD7 in intestinal stem cells (ISCs). Changes in cytosolic [Ca2+] 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.

Date: 2023
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DOI: 10.1038/s41467-022-35487-9

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