Derivation of Diverse Hormone-Releasing Pituitary Cells from Human Pluripotent Stem Cells.
Human pluripotent stem cells (hPSCs) provide an unlimited cell source for regenerative medicine. Hormone-producing cells are particularly suitable for cell therapy, and hypopituitarism, a defect in pituitary gland function, represents a promising therapeutic target. Previous studies have derived pituitary lineages from mouse and human ESCs using 3D organoid cultures that mimic the complex events underlying pituitary gland development in vivo. Instead of relying on unknown cellular signals, we present a simple and efficient strategy to derive human pituitary lineages from hPSCs using monolayer culture conditions suitable for cell manufacturing. We demonstrate that purified placode cells can be directed into pituitary fates using defined signals. hPSC-derived pituitary cells show basal and stimulus-induced hormone release in vitro and engraftment and hormone release in vivo after transplantation into a murine model of hypopituitarism. This work lays the foundation for future cell therapy applications in patients with hypopituitarism.
The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA.
Bastian
B
Zimmer
The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Jinghua
J
Piao
The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; SKI Stem Cell Research Facility, 1275 York Avenue, New York, NY 10065, USA.
Kiran
K
Ramnarine
The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; SKI Stem Cell Research Facility, 1275 York Avenue, New York, NY 10065, USA.
Mark J
MJ
Tomishima
The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Viviane
V
Tabar
The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address: studerl@mskcc.org.
Lorenz
L
Studer
D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy; D052680:Corticotrophs / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000096:biosynthesis / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D013006:Growth Hormone / Q000096:biosynthesis / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007018:Hypopituitarism / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D052684:Thyrotrophs / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C525809:BMP4 protein, human; D001549:Benzamides; D015415:Biomarkers; D055415:Bone Morphogenetic Protein 4; D004149:Dioxoles; C088334:Distal-less homeobox proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C099236:SIX1 protein, human; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; D000324:Adrenocorticotropic Hormone; D005640:Follicle Stimulating Hormone; D013006:Growth Hormone; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases