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Hypothalamus-specific NSCs derived from human brain organoids ameliorate age-associated dysfunction upon transplantation into aged mouse hypothalamus [human]

ABSTRACT: The hypothalamus is the brain region that regulates systemic body metabolism and multiple functions in other brain regions. In adult mice, the hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with the dysregulation of body metabolism and physiology that occurs during aging, the NSC population in the hypothalamus declines with age. Here, we introduce a novel protocol that yields scalable and storable hypothalamus-specific NSCs (htNSCs) from hypothalamus-like organoids derived from human pluripotent stem cells (hPSCs). Implanting htNSCs into the medio-basal hypothalami of aged mice conspicuously ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function and produced corresponding histologic changes in various body tissues. Single transcriptome and immunohistochemical analyses of the grafted hypothalamic tissues showed that the anti-aging effects were attained by correcting glial NF-κB, TNFα, and NLRP3 inflammasome pathways. Collectively, our findings support the potential of anti- or healthy aging therapies that target htNSCs and hypothalamic inflammation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215173 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:The hypothalamus is an anatomically small, but functionally crucial region of the human brain. Normal hypothalamus functioning is central to the regulation of neuroendocrine and neurovegetative systems as well as modulation of chronobiology and behavioral aspects of the human body. Till date the human hypothalamus proteome profile is lacking from literature. In this study, we attempt to delineate the human hypothalamus proteome using high-resolution mass spectrometry approach. We identified a total of 5,349 proteins in the proteomics study. The unassigned spectra from the proteomics study were further used for identifying multiple post translational modification sites as well as for proteogenomics analysis. This resulted in the identification of 616 additional proteins. We observed a higher representation of mitochondrial and synaptic proteins in the proteomics data, as well as enrichment of pathways supporting the hypothalamic involvement in autophagy and adult neurogenesis. Interestingly, the phospholipase D signaling pathway emerged as a junction to the various aspects of hypothalamic functions, and relation to neurodegenerative disorders. Additionally, the investigation for multiple post translational modifications led to the identification of several known and novel post translational modification sites. A total of 13,544 peptides corresponding to 2,542 proteins with modifications of R/K-methylation, S/T/Y-phosphorylation, N/Q-deamidation, R-citrullination, and K-acetylation have been reported in this study. Proteogenomic analysis of hypothalamus resulted in the identification of 291 GSSPs which were further categorised into probable gene correction events. Among these, we confirmed 28 peptides to confer evidence for 10 predicted pseudogenes with coding potential, 4 novel protein-coding (3 novel isoforms, and 1 novel SEP), and 3 protein correction (1 novel exon, 1 alternate frame of translation and 1 N-terminal protein extension) events. We believe that hypothalamic proteome would aid as a platform to decipher the molecular basis for the diverse range of functions performed by this region and provide a baseline for exploring the role of these proteins in neurological health and disorders.

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Hypothalamus-specific NSCs derived from human brain organoids ameliorate age-associated dysfunction upon transplantation into aged mouse hypothalamus [human]

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