Biomaterial Database

Subcutaneous transplantation of human embryonic stem cells-derived pituitary organoids. 2023

Hiroo Sasaki, and Hidetaka Suga, and Kazuhito Takeuchi, and Yuichi Nagata, and Hideyuki Harada, and Tatsuma Kondo, and Eiji Ito, and Sachi Maeda, and Mayu Sakakibara, and Mika Soen, and Tsutomu Miwata, and Tomoyoshi Asano, and Hajime Ozaki, and Shiori Taga, and Atsushi Kuwahara, and Tokushige Nakano, and Hiroshi Arima, and Ryuta Saito

Department of Neurosurgery, Graduate School of Medicine, Nagoya University, Nagoya, Japan.

The pituitary gland, regulating various hormones, is central in the endocrine system. As spontaneous recovery from hypopituitarism is rare, and exogenous-hormone substitution is clumsy, pituitary replacement via regenerative medicine, using pluripotent stem cells, is desirable. We have developed a differentiation method that in mice yields pituitary organoids (POs) derived from human embryonic stem cells (hESC). Efficacy of these POs, transplanted subcutaneously into hypopituitary mice, in reversing hypopituitarism was studied. hESC-derived POs were transplanted into inguinal subcutaneous white adipose tissue (ISWAT) and beneath dorsal skin, a relatively avascular region (AR), of hypophysectomized severe combined immunodeficient (SCID) mice. Pituitary function was evaluated thereafter for ¾ 6mo, assaying basal plasma ACTH and ACTH response to corticotropin-releasing hormone (CRH) stimulation. Histopathologic examination of organoids 150d after transplantation assessed engraftment. Some mice received an inhibitor of vascular endothelial growth factor (VEGF) to permit assessment of how angiogenesis contributed to subcutaneous engraftment. During follow-up, both basal and CRH-stimulated plasma ACTH levels were significantly higher in the ISWAT group (p < 0.001 - 0.05 and 0.001 - 0.005, respectively) than in a sham-operated group. ACTH secretion also was higher in the ISWAT group than in the AR group. Histopathologic study found ACTH-producing human pituitary-cell clusters in both groups of allografts, which had acquired a microvasculature. POs qPCR showed expression of angiogenetic factors. Plasma ACTH levels decreased with VEGF-inhibitor administration. Subcutaneous transplantation of hESC-derived POs into hypopituitary SCID mice efficaciously renders recipients ACTH-sufficient.

UI	MeSH Term	Description	Entries
D007018	Hypopituitarism	Diminution or cessation of secretion of one or more hormones from the anterior pituitary gland (including LH; FOLLICLE STIMULATING HORMONE; SOMATOTROPIN; and CORTICOTROPIN). This may result from surgical or radiation ablation, non-secretory PITUITARY NEOPLASMS, metastatic tumors, infarction, PITUITARY APOPLEXY, infiltrative or granulomatous processes, and other conditions.	Adenohypophyseal Hyposecretion,Anterior Pituitary Hyposecretion Syndrome,Sheehan Syndrome,Simmonds Disease,Hyposecretion Syndrome, Anterior Pituitary,Hyposecretion, Adenohypophyseal,Pituitary Insufficiency,Postpartum Hypopituitarism,Postpartum Panhypopituitarism,Postpartum Pituitary Insufficiency,Sheehan's Syndrome,Simmonds' Disease,Disease, Simmonds,Hypopituitarism, Postpartum,Insufficiency, Pituitary,Panhypopituitarism, Postpartum,Pituitary Insufficiency, Postpartum,Sheehans Syndrome,Simmond's Disease,Syndrome, Sheehan,Syndrome, Sheehan's
D010900	Pituitary Diseases	Disorders involving either the ADENOHYPOPHYSIS or the NEUROHYPOPHYSIS. These diseases usually manifest as hypersecretion or hyposecretion of PITUITARY HORMONES. Neoplastic pituitary masses can also cause compression of the OPTIC CHIASM and other adjacent structures.	Adenohypophyseal Diseases,Hypophyseal Disorders,Neurohypophyseal Diseases,Anterior Pituitary Diseases,Pituitary Disorders,Pituitary Gland Diseases,Posterior Pituitary Diseases,Adenohypophyseal Disease,Anterior Pituitary Disease,Disease, Adenohypophyseal,Disease, Anterior Pituitary,Disease, Neurohypophyseal,Disease, Pituitary,Disease, Pituitary Gland,Disease, Posterior Pituitary,Diseases, Adenohypophyseal,Diseases, Anterior Pituitary,Diseases, Neurohypophyseal,Diseases, Pituitary,Diseases, Pituitary Gland,Diseases, Posterior Pituitary,Disorder, Hypophyseal,Disorder, Pituitary,Disorders, Hypophyseal,Disorders, Pituitary,Hypophyseal Disorder,Neurohypophyseal Disease,Pituitary Disease,Pituitary Disease, Anterior,Pituitary Disease, Posterior,Pituitary Diseases, Anterior,Pituitary Diseases, Posterior,Pituitary Disorder,Pituitary Gland Disease,Posterior Pituitary Disease
D010902	Pituitary Gland	A small, unpaired gland situated in the SELLA TURCICA. It is connected to the HYPOTHALAMUS by a short stalk which is called the INFUNDIBULUM.	Hypophysis,Hypothalamus, Infundibular,Infundibular Stalk,Infundibular Stem,Infundibulum (Hypophysis),Infundibulum, Hypophyseal,Pituitary Stalk,Hypophyseal Infundibulum,Hypophyseal Stalk,Hypophysis Cerebri,Infundibulum,Cerebri, Hypophysis,Cerebrus, Hypophysis,Gland, Pituitary,Glands, Pituitary,Hypophyseal Stalks,Hypophyses,Hypophysis Cerebrus,Infundibular Hypothalamus,Infundibular Stalks,Infundibulums,Pituitary Glands,Pituitary Stalks,Stalk, Hypophyseal,Stalk, Infundibular,Stalks, Hypophyseal,Stalks, Infundibular
D003346	Corticotropin-Releasing Hormone	A peptide of about 41 amino acids that stimulates the release of ADRENOCORTICOTROPIC HORMONE. CRH is synthesized by neurons in the PARAVENTRICULAR NUCLEUS of the HYPOTHALAMUS. After being released into the pituitary portal circulation, CRH stimulates the release of ACTH from the PITUITARY GLAND. CRH can also be synthesized in other tissues, such as PLACENTA; ADRENAL MEDULLA; and TESTIS.	ACTH-Releasing Hormone,CRF-41,Corticotropin-Releasing Factor,Corticotropin-Releasing Hormone-41,ACTH-Releasing Factor,CRF (ACTH),Corticoliberin,Corticotropin-Releasing Factor-41,ACTH Releasing Factor,ACTH Releasing Hormone,Corticotropin Releasing Factor,Corticotropin Releasing Factor 41,Corticotropin Releasing Hormone,Corticotropin Releasing Hormone 41
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000066449	Human Embryonic Stem Cells	A type of PLURIPOTENT STEM CELLS derived from early stage human embryos, up to and including the BLASTOCYST stage.	hESC,Cells, Human Embryonic Stem,Human Embryonic Stem Cell,Stem Cells, Human Embryonic,hESCs
D000324	Adrenocorticotropic Hormone	An anterior pituitary hormone that stimulates the ADRENAL CORTEX and its production of CORTICOSTEROIDS. ACTH is a 39-amino acid polypeptide of which the N-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotrophic activity. Upon further tissue-specific processing, ACTH can yield ALPHA-MSH and corticotrophin-like intermediate lobe peptide (CLIP).	ACTH,Adrenocorticotropin,Corticotropin,1-39 ACTH,ACTH (1-39),Adrenocorticotrophic Hormone,Corticotrophin,Corticotrophin (1-39),Corticotropin (1-39),Hormone, Adrenocorticotrophic,Hormone, Adrenocorticotropic
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D016513	Mice, SCID	Mice homozygous for the mutant autosomal recessive gene "scid" which is located on the centromeric end of chromosome 16. These mice lack mature, functional lymphocytes and are thus highly susceptible to lethal opportunistic infections if not chronically treated with antibiotics. The lack of B- and T-cell immunity resembles severe combined immunodeficiency (SCID) syndrome in human infants. SCID mice are useful as animal models since they are receptive to implantation of a human immune system producing SCID-human (SCID-hu) hematochimeric mice.	SCID Mice,SCID-hu Mice,Severe Combined Immunodeficient Mice,Immunodeficient Mice, Severe Combined,Mouse, SCID,Mouse, SCID-hu,Mice, SCID-hu,Mouse, SCID hu,SCID Mouse,SCID hu Mice,SCID-hu Mouse
D042461	Vascular Endothelial Growth Factor A	The original member of the family of endothelial cell growth factors referred to as VASCULAR ENDOTHELIAL GROWTH FACTORS. Vascular endothelial growth factor-A was originally isolated from tumor cells and referred to as "tumor angiogenesis factor" and "vascular permeability factor". Although expressed at high levels in certain tumor-derived cells it is produced by a wide variety of cell types. In addition to stimulating vascular growth and vascular permeability it may play a role in stimulating VASODILATION via NITRIC OXIDE-dependent pathways. Alternative splicing of the mRNA for vascular endothelial growth factor A results in several isoforms of the protein being produced.	Vascular Endothelial Growth Factor,Vascular Endothelial Growth Factor-A,GD-VEGF,Glioma-Derived Vascular Endothelial Cell Growth Factor,VEGF,VEGF-A,Vascular Permeability Factor,Vasculotropin,Glioma Derived Vascular Endothelial Cell Growth Factor,Permeability Factor, Vascular