Hypothalamus-specific NSCs derived from hPSCs ameliorate age-associated dysfunction upon transplantation into aged mouse hypothalamus

Sulistio, Y. A.; Pieknell, K.; Hong, S.; Lee, Y.; Kim, M. S.; Park, W.-Y.; Han, K. Y.; Hong, T.; Park, K.-S.; Yoon, S. G.; Kim, I. Y.; Seong, J. K.; Lee, T. Y.; Lee, S.-H.

doi:10.1101/2024.05.23.595504

bioRxiv · 10.1101/2024.05.23.595504

Hypothalamus-specific NSCs derived from hPSCs ameliorate age-associated dysfunction upon transplantation into aged mouse hypothalamus

Sulistio, Y. A.·Pieknell, K.·Hong, S.·Lee, Y.·Kim, M. S.·Park, W.-Y.·Han, K. Y.·Hong, T.·Park, K.-S.·Yoon, S. G.·Kim, I. Y.·Seong, J. K.·Lee, T. Y.·Lee, S.-H.

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Abstract

The hypothalamus is the brain region that regulates systemic body metabolism and multiple brain functions. The adult hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with age-related body changes, the hypothalamic NSC (htNSC) population declines, indicating the potential of htNSC replacement as an anti-aging strategy. Here, we developed protocol to generate htNSCs from human pluripotent stem cells (hPSCs). Implanting the hPSC-derived htNSCs into the hypothalamus of aged mice ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function. Mechanistically, these anti-aging effects were mediated by inter-tissue communication: enhanced neuronal activity in the htNSC-transplanted hypothalamus stimulated adipose tissues to produce and release the anti-aging molecule eNAMPT into systemic circulation via the sympathetic nervous system. Concurrently, the aged inflammatory environment in the hypothalamus was alleviated by peripheral anti-aging signals. Collectively, our findings support the potential of anti- or healthy aging therapies by targeting hypothalamus.

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Sulistio, Y. A., Pieknell, K., Hong, S., Lee, Y., Kim, M. S., Park, W.-Y., Han, K. Y., Hong, T., Park, K.-S., Yoon, S. G., Kim, I. Y., Seong, J. K., Lee, T. Y., Lee, S.-H.. 2024-05-24. Hypothalamus-specific NSCs derived from hPSCs ameliorate age-associated dysfunction upon transplantation into aged mouse hypothalamus. https://doi.org/10.1101/2024.05.23.595504

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