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1.
PLoS One ; 17(11): e0276694, 2022.
Article in English | MEDLINE | ID: mdl-36356043

ABSTRACT

The hypothalamus is comprised of heterogenous cell populations and includes highly complex neural circuits that regulate the autonomic nerve system. Its dysfunction therefore results in severe endocrine disorders. Although recent experiments have been conducted for in vitro organogenesis of hypothalamic neurons from embryonic stem (ES) or induced pluripotent stem (iPS) cells, whether these stem cell-derived hypothalamic neurons can be useful for regenerative medicine remains unclear. We therefore performed orthotopic transplantation of mouse ES cell (mESC)-derived hypothalamic neurons into adult mouse brains. We generated electrophysiologically functional hypothalamic neurons from mESCs and transplanted them into the supraoptic nucleus of mice. Grafts extended their axons along hypothalamic nerve bundles in host brain, and some of them even projected into the posterior pituitary (PPit), which consists of distal axons of the magnocellular neurons located in hypothalamic supraoptic and paraventricular nuclei. The axonal projections to the PPit were not observed when the mESC-derived hypothalamic neurons were ectopically transplanted into the substantia nigra reticular part. These findings suggest that our stem cell-based orthotopic transplantation approach might contribute to the establishment of regenerative medicine for hypothalamic and pituitary disorders.


Subject(s)
Hypothalamus , Mouse Embryonic Stem Cells , Animals , Mice , Hypothalamus/physiology , Axons/physiology , Neurons/physiology , Supraoptic Nucleus , Paraventricular Hypothalamic Nucleus
2.
eNeuro ; 9(2)2022.
Article in English | MEDLINE | ID: mdl-35437265

ABSTRACT

Hypothalamic melanin-concentrating hormone (MCH) neurons are important regulators of multiple physiological processes, such as sleep, feeding, and memory. Despite the increasing interest in their neuronal functions, the molecular mechanism underlying MCH neuron development remains poorly understood. We report that a three-dimensional culture of mouse embryonic stem cells (mESCs) can generate hypothalamic-like tissues containing MCH-positive neurons, which reproduce morphologic maturation, neuronal connectivity, and neuropeptide/neurotransmitter phenotype of native MCH neurons. Using this in vitro system, we demonstrate that Hedgehog (Hh) signaling serves to produce major neurochemical subtypes of MCH neurons characterized by the presence or absence of cocaine- and amphetamine-regulated transcript (CART). Without exogenous Hh signals, mESCs initially differentiated into dorsal hypothalamic/prethalamic progenitors and finally into MCH+CART+ neurons through a specific intermediate progenitor state. Conversely, activation of the Hh pathway specified ventral hypothalamic progenitors that generate both MCH+CART- and MCH+CART+ neurons. These results suggest that in vivo MCH neurons may originate from multiple cell lineages that arise through early dorsoventral patterning of the hypothalamus. Additionally, we found that Hh signaling supports the differentiation of mESCs into orexin/hypocretin neurons, a well-defined cell group intermingled with MCH neurons in the lateral hypothalamic area (LHA). The present study highlights and improves the utility of mESC culture in the analysis of the developmental programs of specific hypothalamic cell types.


Subject(s)
Hypothalamic Hormones , Mouse Embryonic Stem Cells , Animals , Hedgehog Proteins/metabolism , Hypothalamic Hormones/metabolism , Hypothalamus/metabolism , Melanins/metabolism , Mice , Mouse Embryonic Stem Cells/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/physiology , Orexins/metabolism , Pituitary Hormones/metabolism
3.
Cell Rep ; 30(1): 18-24.e5, 2020 01 07.
Article in English | MEDLINE | ID: mdl-31914385

ABSTRACT

The pituitary is a major hormone center that secretes systemic hormones responding to hypothalamus-derived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs). Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a life-threatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues.


Subject(s)
Hypothalamus/physiology , Induced Pluripotent Stem Cells/cytology , Pituitary Gland/physiology , Adrenocorticotropic Hormone/metabolism , Aging/physiology , Animals , Cell Differentiation , Cells, Cultured , Corticotrophs/cytology , Corticotrophs/ultrastructure , Humans , Induced Pluripotent Stem Cells/ultrastructure , Mice , Neurons/cytology , Organoids/cytology
4.
Sci Rep ; 8(1): 3615, 2018 02 26.
Article in English | MEDLINE | ID: mdl-29483626

ABSTRACT

Arginine-vasopressin (AVP) neurons exist in the hypothalamus, a major region of the diencephalon, and play an essential role in water balance. Here, we established the differentiation method for AVP-secreting neurons from human embryonic stem cells (hESCs) by recapitulating in vitro the in vivo embryonic developmental processes of AVP neurons. At first, the differentiation efficiency was improved. That was achieved through the optimization of the culture condition for obtaining dorsal hypothalamic progenitors. Secondly, the induced AVP neurons were identified by immunohistochemistry and these neurons secreted AVP after potassium chloride stimulation. Additionally, other hypothalamic neuropeptides were also detected, such as oxytocin, corticotropin-releasing hormone, thyrotropin-releasing hormone, pro-opiomelanocortin, agouti-related peptide, orexin, and melanin-concentrating hormone. This is the first report describing the generation of secretory AVP neurons derived from hESCs. This method will be applicable to research using disease models and, potentially, for regenerative medicine of the hypothalamus.


Subject(s)
Arginine Vasopressin/metabolism , Human Embryonic Stem Cells/cytology , Human Embryonic Stem Cells/metabolism , Neurons/cytology , Neurons/metabolism , Agouti-Related Protein/metabolism , Corticotropin-Releasing Hormone/metabolism , Humans , Hypothalamic Hormones/metabolism , Hypothalamus/cytology , Hypothalamus/metabolism , Immunohistochemistry , Melanins/metabolism , Neurophysins/metabolism , Orexins/metabolism , Oxytocin/metabolism , Pituitary Hormones/metabolism , Protein Precursors/metabolism , Stem Cells/cytology , Stem Cells/metabolism , Vasopressins/metabolism
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