Novel human pluripotent stem cell-derived hypothalamus organoids demonstrate cellular diversity

Lily Sarrafha; Drew R. Neavin; Gustavo M. Parfitt; Ilya A. Kruglikov; Kristen Whitney; Ricardo Reyes; Elena Coccia; Tatyana Kareva; Camille Goldman; Regine Tipon; Gist Croft; John F. Crary; Joseph E. Powell; Joel Blanchard; Tim Ahfeldt

iScience (Sep 2023)

Novel human pluripotent stem cell-derived hypothalamus organoids demonstrate cellular diversity

Lily Sarrafha,
Drew R. Neavin,
Gustavo M. Parfitt,
Ilya A. Kruglikov,
Kristen Whitney,
Ricardo Reyes,
Elena Coccia,
Tatyana Kareva,
Camille Goldman,
Regine Tipon,
Gist Croft,
John F. Crary,
Joseph E. Powell,
Joel Blanchard,
Tim Ahfeldt

Affiliations

Lily Sarrafha: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Department of Neurology, Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Mount Sinai, New York, NY 10029, USA
Drew R. Neavin: Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
Gustavo M. Parfitt: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Mount Sinai, New York, NY 10029, USA
Ilya A. Kruglikov: New York Stem Cell Foundation, New York, NY 10019, USA
Kristen Whitney: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular, and Cell-Based Medicine, Mount Sinai, New York, NY 10029, USA
Ricardo Reyes: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Department of Neurology, Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Mount Sinai, New York, NY 10029, USA
Elena Coccia: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Department of Neurology, Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Mount Sinai, New York, NY 10029, USA
Tatyana Kareva: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Department of Neurology, Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Mount Sinai, New York, NY 10029, USA
Camille Goldman: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Department of Neurology, Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Mount Sinai, New York, NY 10029, USA
Regine Tipon: New York Stem Cell Foundation, New York, NY 10019, USA
Gist Croft: New York Stem Cell Foundation, New York, NY 10019, USA
John F. Crary: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular, and Cell-Based Medicine, Mount Sinai, New York, NY 10029, USA; Windreich Department of Artificial Intelligence and Human Health, Mount Sinai, New York, NY 10029, USA
Joseph E. Powell: Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; UNSW Cellular Genomics Futures Institute, University of New South Wales, Kensington, Sydney, NSW 2052, Australia
Joel Blanchard: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Mount Sinai, New York, NY 10029, USA; Corresponding author
Tim Ahfeldt: Nash Family Department of Neuroscience, Mount Sinai, New York, NY 10029, USA; Department of Neurology, Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Mount Sinai, New York, NY 10029, USA; Ronald M. Loeb Center for Alzheimer’s Disease, Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Mount Sinai, New York, NY 10029, USA; Corresponding author

Journal volume & issue: Vol. 26, no. 9
p. 107525

Abstract

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Summary: The hypothalamus is a region of the brain that plays an important role in regulating body functions and behaviors. There is a growing interest in human pluripotent stem cells (hPSCs) for modeling diseases that affect the hypothalamus. Here, we established an hPSC-derived hypothalamus organoid differentiation protocol to model the cellular diversity of this brain region. Using an hPSC line with a tyrosine hydroxylase (TH)-TdTomato reporter for dopaminergic neurons (DNs) and other TH-expressing cells, we interrogated DN-specific pathways and functions in electrophysiologically active hypothalamus organoids. Single-cell RNA sequencing (scRNA-seq) revealed diverse neuronal and non-neuronal cell types in mature hypothalamus organoids. We identified several molecularly distinct hypothalamic DN subtypes that demonstrated different developmental maturities. Our in vitro 3D hypothalamus differentiation protocol can be used to study the development of this critical brain structure and can be applied to disease modeling to generate novel therapeutic approaches for disorders centered around the hypothalamus.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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