Human induced pluripotent stem cells differentiate into hypothalamic vasopressin neurons with minimal exogenous signals and partial transformation into a naïve state or treatable central diabetes insipidus

The hypothalamus plays an important role in maintaining physiological balance, one of which is the production and secretion of arginine vasopressin (AVP), which controls water balance
.
Familial neuropituitary diabetes insipidus (FNDI) is characterized by the degeneration of neurons in the hypothalamus leading to a gradual decrease
in AVP secretion.
Mutations in the AVP gene locus in FINDI patients have been identified, mostly in the region encoding the AVP vector protein, known as neuroprotein II (NPII).

Therefore, the team used transgenic technology to obtain FNDI mice with the Cys98stop (formerly known as Cys67stop) mutation, which occurred in FNDI patients, for pathological analysis
.

In previous studies, the team used the Cys98stop-knock-in FNDI mouse model to find that endoplasmic reticulum (ER) stress caused by the accumulation of mutant proteins in ER may be related to
FNDI pathology.
However, further research is needed, including the use of human patient models, to investigate the overall pathological mechanism of
FNDI.
Research on FNDI in humans is technically limited because hypothalamic biopsies cannot be performed on living people, and loss of AVP neurons in human FNDI patients has only been
reported in autopsy studies.
Therefore, AVP neurons extracted from human FNDI-specific induced pluripotent stem cells (iPSCs) are a promising human model that can be used in pathological analysis and drug development
.

Research Objectives:

The team induced differentiation from human FNDI disease-specific iPSCs to AVP neurons with minimal exogenous signals, as described previously described for miPSCs
.
To apply minimal exogenous signals to human iPSCs, the team focused on the differences
in initial state between human iPSCs and mouse iPSCs.

In vivo model studies in mice have shown that the accumulation of mutant AVP prehormones is associated
with FNDI pathology.
However, studying human FNDI pathology in vivo is technically challenging
.
Therefore, in vitro mannequins
need to be developed.
When exogenous signals are minimized in the early stages of in vitro differentiation, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons while human ESCs/iPSCs die
.

Human ESC/iPSCs generally resemble mouse ectodermal stem cells (mEpiSC)
compared to mouse ESCs.
In this study, the team converted human FNDI-specific iPSCs
via a naive conversion kit.
While the conversion was partial, the study found improved
cell survival with minimal exogenous signals and differentiation into hypothalamic beak organoids.
Overall, this method provides a simple and direct direction of differentiation that can improve the efficiency of
hypothalamic differentiation.

References:

Ozaki H, Suga H, Sakakibara M, Soen M, Miyake N, Miwata T, Taga S, Nagai T, Kano M, Mitsumoto K, Miyata T, Kobayashi T, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Iwama S, Banno R, Iguchi G, Takahashi Y, Muguruma K, Inoue H, Arima H.
Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state.
Sci Rep.
2022 Oct 17; 12(1):17381.
doi: 10.
1038/s41598-022-22405-8.
PMID: 36253431; PMCID: PMC9576732.