Dataset Information

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

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): Mus musculus

PROVIDER: GSE214896 | GEO | 2023/12/31

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

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.

Project description:The crucial role of nutrition for cerebral health and the impact of dietary habits on brain structure and function have been long far recognized. To date a major health concern is associated with the increased consumption of fructose as added sugar in many types of drinks and processed foods, especially among young people. High-fructose intake has been pointed out as the possible culprit for the raised incidence of chronic diseases, such as obesity, cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabete. Further, it has been reported that high-fructose intake is associated with the over-activation of its cerebral metabolism, which was proposed to negatively impact on whole brain physiology and cognitive function. Notably, we previously reported that short-term fructose-rich diet induces mitochondrial dysfunction, oxidative stress, and neuroinflammation in hippocampus of young rats, as well as the imbalance of redox homeostasis, autophagic mechanisms and representation of synaptic markers in frontal cortex of both adult and young rats. Animal studies have also revealed the damaging effect of high-fructose diets on hippocampal functions during periods of neurocognitive development, such as childhood and adolescence. Hypothalamus plays a crucial role in maintaining whole body homeostasis. Long-term fructose overfeeding was reported to alter hypothalamic-pituitary-adrenal axis, leading to elevations in glucocorticoids in peri-adolescent rats [22]. Further, fructose overconsumption was associated with impairment of hypothalamic insulin signalling, oxidative stress and inflammation , and it was proposed that fructose-driven perturbations of hypothalamic function may compromise the potential for satiety, thereby increasing the prospect of developing obesity. Data currently available on hypothalamic dysfunctions related to a high-fructose diet essentially refer to the effects of long-term sugar feeding, while information on corresponding alterations associated with a short-term dietary treatment, particularly in the critical period of adolescence, is still lacking. Due to complexity and multiplicity of hypothalamic functions, there is also the need for a holistic characterization aimed at unveiling the general picture of hypothalamic dysfunctions associated with a high-fructose diet. To fill this gap, we investigated adolescent rats fed a fructose-rich or control diet, for 3 weeks. To verify whether the fructose-driven changes are rescued after the switch to a control diet, half of the rats from both animal groups were then fed a control diet for additional 3 weeks until young adulthood phase. Quantitative proteomics on hypothalamic extracts of all animal groups was used to identify molecular alterations triggered by fructose-rich diet and to obtain insights into the relationship between sugar feeding and possible dysfunctions of hypothalamus.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure