Hypothalamic stem cells control aging speed partly through exosomal miRNAs

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SUMMARY

Hypothalamic control of aging was recently proposed, but the responsible mechanisms still remain unclear. Here, following the observation that aging of mice started with a substantial loss of hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1, we developed several mouse models with ablation of these hypothalamic cells, each of them consistently displaying an acceleration in aging-like physiological changes or shortening in lifespan. Conversely, aging retardation and lifespan extension were achieved in mid-aged mice when locally implanted with healthy hypothalamic stem/progenitor cells that were genetically engineered to survive from aging-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells greatly contributed to exosomal miRNAs in the cerebrospinal fluid which declined over aging, while central treatment with healthy hypothalamic stem/progenitor cells-secreted exosomes led to slowdown of aging. In conclusion, aging speed is controlled significantly by hypothalamic stem cells partially through release of exosomal miRNAs.

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Most cited references 30

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Object recognition test in mice.

Marianne Leger, Anne Quiedeville, Valentine Bouet … (2013)

The object recognition test is now among the most commonly used behavioral tests for mice. A mouse is presented with two similar objects during the first session, and then one of the two objects is replaced by a new object during a second session. The amount of time taken to explore the new object provides an index of recognition memory. As more groups have used the protocol, the variability of the procedures used in the object recognition test has increased steadily. This protocol provides a necessary standardization of the procedure. This protocol reduces inter-individual variability with the use of a selection criterion based on a minimal time of exploration for both objects during each session. In this protocol, we describe the three most commonly used variants, containing long (3 d), short (1 d) or no habituation phases. Thus, with a short intersession interval (e.g., 6 h), this procedure can be performed in 4, 2 or 1 d, respectively, according to the duration of the habituation phase. This protocol should allow for the comparison of results from different studies, while permitting adaption of the protocol to the constraints of the experimenter.

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A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration.

Thorsten Buch, Frank Heppner, Christine Tertilt … (2005)

A new system for lineage ablation is based on transgenic expression of a diphtheria toxin receptor (DTR) in mouse cells and application of diphtheria toxin (DT). To streamline this approach, we generated Cre-inducible DTR transgenic mice (iDTR) in which Cre-mediated excision of a STOP cassette renders cells sensitive to DT. We tested the iDTR strain by crossing to the T cell- and B cell-specific CD4-Cre and CD19-Cre strains, respectively, and observed efficient ablation of T and B cells after exposure to DT. In MOGi-Cre/iDTR double transgenic mice expressing Cre recombinase in oligodendrocytes, we observed myelin loss after intraperitoneal DT injections. Thus, DT crosses the blood-brain barrier and promotes cell ablation in the central nervous system. Notably, we show that the developing DT-specific antibody response is weak and not neutralizing, and thus does not impede the efficacy of DT. Our results validate the use of iDTR mice as a tool for cell ablation in vivo.

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Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation.

Anna V. Molofsky, Ricardo Pardal, Toshihide Iwashita … (2003)

Stem cells persist throughout life by self-renewing in numerous tissues including the central and peripheral nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4a deficiency partially reverses the self-renewal defect in Bmi-1-/- neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16Ink4a expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 15 July 2017

Publication date (Electronic): 26 July 2017

Publication date (Print): 03 August 2017

Publication date PMC-release: 13 June 2018

Volume: 548

Issue: 7665

Pages: 52-57

Affiliations

[1 ]Department of Molecular Pharmacology, Diabetes Research Center, Institute of Aging, Albert Einstein College of Medicine, Bronx, NY 10461

Author notes

Correspondence should be addressed to D.C. ( dongsheng.cai@ 123456einstein.yu.edu ), Phone: 718-430-2426, Fax: 718-430-8922, dongsheng.cai@ 123456einstein.yu.edu

[2]

These authors equally contributed to this work.

Article

Manuscript ID: NIHMS884456

DOI: 10.1038/nature23282

PMC ID: 5999038

PubMed ID: 28746310

SO-VID: 8bdea0a1-997a-40f2-8b7b-25e18c1e89e9

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Hypothalamic stem cells control aging speed partly through exosomal miRNAs

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SUMMARY

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Aging Pathobiology and Therapeutics

Most cited references 30

Object recognition test in mice.

A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration.

Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation.

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