Article

Hypothalamic stem cells control ageing speed partly through exosomal miRNAs

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Abstract

It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.

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Acknowledgements

This study was supported by NIH R01 DK078750, AG031774, HL113180 and DK099136 (D.C.).

Author information

Author notes

    • Yalin Zhang
    • , Min Soo Kim
    • , Baosen Jia
    •  & Jingqi Yan

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, New York 10461, USA

    • Yalin Zhang
    • , Min Soo Kim
    • , Baosen Jia
    • , Jingqi Yan
    • , Juan Pablo Zuniga-Hertz
    • , Cheng Han
    •  & Dongsheng Cai

Authors

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  3. Search for Baosen Jia in:

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  5. Search for Juan Pablo Zuniga-Hertz in:

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Contributions

Y.Z., M.S.K., J.Y. and C.H. performed hypothalamic injections and cell implantation; Y.Z. performed immunostaining, cloning, virus production and CSF sampling; M.S.K. performed behavioural experiments and exosome treatment; B.J. performed cell culture, exosome and miRNA characterization; J.Y. performed lifespan follow-up and initial behavioural and miRNA analysis; J.P.Z.-H. performed cell culture and imaging; D.C. conceived the hypothesis, designed and organized the study and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dongsheng Cai.

Reviewer Information Nature thanks K. Jin, T. Wyss-Coray and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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    Supplementary Figure 1

    This file contains uncropped images of all western blots shown in the manuscript.

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    Supplementary Data 1

    This file contains microarray data of Figure 4d.

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    Supplementary Data 2

    This file contains qPCR data of Figure 4e.