Rostral Hypothalamic Differentiation With Minimal Exogenous Signals in Human Naive Induced Pluripotent Stem Cells

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs) differentiate into AVP neurons, whereas human ESCs/induced pluripotent stem cells (iPSCs) die. Human ES/iPSCs are generally more similar to mouse epiblast stem cells compared to mouse ESCs, which are termed as primed and naive, respectively. In this study, we converted human FNDI-specific iPSCs from primed to naive cells, and found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.