Researchers use arcuate organoids to study development and disease of the hypothalamus

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Organoids of the human brain are remarkable platforms for modeling features of development and diseases of the human brain. Building on methods of creating organoids to model different brain regions such as the cortex and midbrain, researchers at the Perelman School of Medicine at the University of Pennsylvania created the first arcuate core organoids (ARC), an essential structure in the hypothalamus that sends signals of hunger and satiety . This part of the hypothalamus has an enormous cell diversity and is far more complex than previously modeled parts of the brain.

In an article published today in Cell Stem Cell, Penn researchers report that they create arched organoids (ARCOs) that model the ARC of the hypothalamus. Previous studies have generated 2D hypothalamic-like neurons and 3D hypothalamic organoids from human-induced pluripotent stem cells (iPSCs). To date, however, there have been no protocols for generating hypothalamic nucleus-specific organoids.

Researchers took a machine learning approach and used published mouse data to predict ARC populations in the human hypothalamus at the single cell level. The researchers then compared individual cell clusters from the ARCO dataset with the predicted human ARC cells in the neonatal human hypothalamus. Using this approach, they found that the ARCOs have very similar cell type diversity and molecular signatures to human ARCs.

“This model offers the opportunity to study the previously inaccessible fetal development of the hypothalamic arcuate nucleus in humans,” says lead author Dr. med. Guo-li Ming, professor of neuroscience at Penn University. “For the first time, we have an atlas of cell types in the human hypothalamus that will be a blueprint for better understanding the development of brain disorders such as certain causes of obesity and autism.”

Knowing that a dysfunction in the hypothalamus can lead to disorders such as Prader-Willi Syndrome (PWS) – a genetic disorder caused by the loss of function of certain genes on chromosome 15 that causes patients to become constantly hungry and often obese and other diseases cause complications – researchers generated iPSCs from two patients with known genetic mutations that cause PWS and used these to derive ARCOs. They showed that ARCOs from patients with PWS retain disease- and patient-specific gene signatures. For example, one of the cell types within the ARC is responsible for regulating the leptin response, which regulates food intake, and this pathway is known to not work in patients with PWS. The researchers found that there is indeed a dysfunction in the leptin response and signaling pathways in the PWS-ARCO, suggesting that the ARCOs can not only recapitulate individual nuclei in terms of cell type diversity and molecular signatures, but also recapitulate the patient-derived ARCOs can have certain disease signatures.

“Our study provides a scalable, efficient, and robust protocol for generating ARC-specific organoids that can be used to model early hypothalamic developmental processes and related brain diseases,” says Ming. “I look forward to future studies with a larger cohort of Prader-Willi syndrome donors to better model PWS in ARCOs and better understand the possible pathology of the disorder at the cellular and molecular level.”

Scientists reveal the origin of neural diversity in the hypothalamus

More information:
Wei-Kai Huang et al., Generation of Hypothalamic Arcuate Organoids from Human-Induced Pluripotent Stem Cells, Cell Stem Cell (2021). DOI: 10.1016 / j.stem.2021.04.006 Provided by the Perelman School of Medicine at the University of Pennsylvania

Quote: Researchers Use Arch-Shaped Organoids to Study Hypothalamus Development and Disease (2021 May 10), released on May 11, 2021 from hypothalamus.html

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