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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 Modrušan, Michelle B. Chen, Christopher C. Overall, David Garfield

Nature Communications · 2023 · ▲ 61 citations

Cellular senescence Stem-cell exhaustion Altered intercellular communication Chronic inflammation Cell culture / in vitro

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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 / 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.

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Provenance

Source: OpenAlex
DOI: 10.1038/s41467-022-35487-9
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Fetched: 2026-06-07 MST

Cite this

APA

Yun, J., Hansen, S., Morris, O., Madden, D.T., Libeu, C.P., Kumar, A.J., Wehrfritz, C., Nile, A.H., Zhang, Y., Zhou, L., Liang, Y., Modrušan, Z., Chen, M.B., Overall, C.C., Garfield, D., Campisi, J., Schilling, B., Hannoush, R.N., & Jasper, H. (2023). Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling. <em>Nature Communications</em>. https://doi.org/10.1038/s41467-022-35487-9

Vancouver

Yun J, Hansen S, Morris O, Madden DT, Libeu CP, Kumar AJ, et al. Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling. Nature Communications. 2023. doi:10.1038/s41467-022-35487-9.

BibTeX

@article{jina2023Senesc, title = {Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling}, author = {Jina Yun and Simon Hansen and Otto Morris and David T. Madden and Clare Peters Libeu and Arjun J. Kumar and Cameron Wehrfritz and Aaron H. Nile and Yingnan Zhang and Lijuan Zhou and Yuxin Liang and Zora Modrušan and Michelle B. Chen and Christopher C. Overall and David Garfield and Judith Campisi and Birgit Schilling and Rami N. Hannoush and Heinrich Jasper}, journal = {Nature Communications}, year = {2023}, doi = {10.1038/s41467-022-35487-9}, }