Generate hypothalamic neurons from hESCs and human iPSCs


Monogenic obesity is reported to be caused by mutations of genes encoding hypothalamic leptin-melanocortin signaling. Due to the inaccessiblility of human hypothalamic, a better understanding of these important pathways requires cultured hypothalamic neurons, which has not been well studied. Wang et al. reported a protocol of differeiciating human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into hypothalamic cells. The article was published in The Journal of Clinical Investigation.


The early activation of sonic hedgehog (SHH) signaling and inhibition of SMAD, followed by Notch signaling inhibition, efficiently converted hESCs into NKX2.1+FOXG1- progenitors, which enable to develop hypothalamic neurons. Researchers further inhibited Notch signaling to develop hypothalamic neurons. The protocol can also be used on human iPSC lines derived from healthy and monogenetic obesity subjects. They measured hypothalamic neuron markers and found signature markers, such as proopimelanocortin (POMC), neuropeptide Y (NPY), agouti-related peptide (AGRP), somatostatin, and dopamine, etc, were expressed in hypothalamic-like neurons. In addition, they didn't express pituitary markers. Moreover, the cells performed characteristics like hypothalamic neurons, such as secretion of neuropeptides and response to insulin and leptin.  The study provides a efficient protocol on generating hypothalamic neuron, leads to a effective strategy of investigation of the neurophysiology.


J Clin Invest. 2015 Jan 2. pii: 79220. 

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