Synthetic organoids for studying human hypothalamic development and disease

The hypothalamus is a small area of the brain dedicated to regulating body homeostasis. Dysfunction or diseases of the hypothalamus have multiple and devastating consequences to the whole organism, including to mental health, metabolism and reproduction, creating a high demand for therapeutic options. The experimental inaccessibility of the human hypothalamus has hampered medical innovation in this area. However, the ability of stem cells to self-organise into three dimensional structures, termed organoids, has allowed recapitulation of some of the features of the hypothalamus in vitro, although, in common with organoids of other brain regions, this organisation is somewhat chaotic and unpredictable. Recent studies have provided new evidence for how stem/progenitor cells in the hypothalamus self-organise in vivo, and suggest an important role for neural adhesion molecules. The aim of this project is to test the ability of neural adhesion molecules, shown to have a role in controlling neural stem cell/precursor function, to control the temporal and spatial configuration of hypothalamic organoids, assessing the success of this recapitulation against current knowledge of early events in hypothalamic development in vivo. We will also use state-of-the-art genetic manipulation of human stem cells in vitro to test the roles of specific genes identified in these latter studies. This human-based model will provide an experimental platform for elucidating the mechanisms underpinning hypothalamus development and dysfunction.

Experimental approach will entail genetic engineering of human pluripotent stem cells (e.g. using CRISPR/Cas9), differentiation of stem cells and organoid culture.