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Aberrant activation of p53/p66Shc-mInsc axis increases asymmetric divisions and attenuates proliferation of aged mammary stem cells

Abstract

Aging is accompanied by the progressive decline in tissue regenerative capacity and functions of resident stem cells (SCs). Underlying mechanisms, however, remain unclear. Here we show that, during chronological aging, self-renewing mitoses of mammary SCs (MaSCs) are preferentially asymmetric and that their progeny divides less frequently, leading to decreased number of MaSCs and reduced regenerative potential. Underlying mechanisms are investigated in the p66Shc−/− mouse, which exhibits several features of delayed aging, including reduced involution of the mammary gland (MG). p66Shc is a mitochondrial redox sensor that activates a specific p53 transcriptional program, in which the aging-associated p44 isoform of p53 plays a pivotal role. We report here that aged p66Shc−/− MaSCs show increased symmetric divisions, increased proliferation and increased regenerative potential, to an extent reminiscent of young wild-type (WT) MaSCs. Mechanistically, we demonstrate that p66Shc, together with p53: (i) accumulates in the aged MG, (ii) sustains expression of the cell polarity determinant mInscuteable and, concomitantly, (iii) down-regulates critical cell cycle genes (e.g.,: Cdk1 and Cyclin A). Accordingly, overexpression of p53/p44 increases asymmetric divisions and decreases proliferation of young WT MaSCs in a p66Shc-dependent manner and overexpression of mInsc restores WT-like levels of asymmetric divisions in aged p66Shc−/− MaSCs. Notably, deletion of p66Shc has negligible effects in young MaSCs and MG development. These results demonstrate that MG aging is due to aberrant activation of p66Shc, which induces p53/p44 signaling, leading to failure of symmetric divisions, decreased proliferation and reduced regenerative potential of MaSCs.

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Fig. 1: Delayed age-related involution of mammary gland (MG) in p66Shc−/− mice.
Fig. 2: Benign ductal hyperplasia and increased epithelial proliferation in aged p66Shc−/− mammary glands (MGs).
Fig. 3: Increased expression of mammary stem cell (MaSC) markers in aged p66Shc−/− mammospheres.
Fig. 4: Increased mammary stem cell (MaSC) frequency and regenerative potential in aged p66Shc−/− mammospheres.
Fig. 5: Increased symmetric divisions and proliferation rate of p66Shc−/− aged mammary stem cells (MaSCs).
Fig. 6: Increased symmetric divisions of aged p66Shc−/− mammary stem cells (MaSCs) are due to impaired expression of mInsc and other cell polarity genes.
Fig. 7: Effects of p44 overexpression on mammary stem cell (MaSC) division.

Data availability

RNA-sequencing data have been deposited at NCBI Gene Expression Omnibus [GSE201253]. The Authors declare that all the data supporting their study are available within the paper or in its Supplemental Material file.

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Acknowledgements

We are grateful to Pier Paolo Di Fiore, Ivan Colaluca, Andrea Basile and Maria Grazia Filippone for sharing protocols and reagents, to Simona Rodighiero for her invaluable assistance with imaging experiments, to Chiara Soriani and Stefano Freddi for advice on image analysis, to Salvatore Pece, Francesca Montani, Micol Tillhon and Giovanna Jodice for assistance with histopathological analyses, to Giorgio Pacecchi for technical help, to Stefania Averaimo for reading the paper and to Cristina Bonvicini for secretarial work. We thank the IEO Genomic Unit and the Cogentech Mouse Genetics and Quantitative PCR facilities.

Funding

European Research Council: 2013-ADG_341131; Fondazione Cariplo: 2016-1031; Associazione Italiana per la Ricerca sul Cancro: AIRC-IG-2014-20162 and AIRC-IG-2017-20162. CP was recipient of a FIRC (Fondazione Italiana per la Ricerca sul Cancro) fellowship and DM of a FUV (Fondazione Umberto Veronesi) fellowship.

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EM and PGP conceptualized and supervised the research project; CP, DM, GDM, and FR performed all the experiments; GBe curated histopathological analysis, GBi contributed to statistical analyses, AP and SR to FACS analyses, LL to bioinformatic analyses, VG, MM, and MG to reagents and interpretation of results. CP, EM, and PGP analyzed the data and wrote the paper.

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Correspondence to Enrica Migliaccio or Pier Giuseppe Pelicci.

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Priami, C., Montariello, D., De Michele, G. et al. Aberrant activation of p53/p66Shc-mInsc axis increases asymmetric divisions and attenuates proliferation of aged mammary stem cells. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01029-5

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