Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling.
Jina YunSimon HansenOtto MorrisDavid T MaddenClare Peters LibeuArjun J KumarCameron WehrfritzAaron H NileYingnan ZhangLijuan ZhouYuxin LiangZora ModrusanMichelle B ChenChristopher C OverallDavid GarfieldPierre-Yves DesprezBirgit SchillingRami N HannoushHeinrich JasperPublished in: Nature communications (2023)
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.
Keyphrases
- stem cells
- induced apoptosis
- oxidative stress
- dna damage
- endothelial cells
- cell cycle arrest
- cell therapy
- stress induced
- poor prognosis
- gene expression
- diabetic rats
- cell proliferation
- signaling pathway
- endoplasmic reticulum stress
- mesenchymal stem cells
- genome wide
- cell death
- dna methylation
- protein kinase
- long non coding rna