In vitro cellular reprogramming to model gonad development and its disorders

During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of a...

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Published in:Science advances 2023-01, Vol.9 (1), p.eabn9793-eabn9793
Main Authors: Gonen, Nitzan, Eozenou, Caroline, Mitter, Richard, Elzaiat, Maëva, Stévant, Isabelle, Aviram, Rona, Bernardo, Andreia Sofia, Chervova, Almira, Wankanit, Somboon, Frachon, Emmanuel, Commère, Pierre-Henri, Brailly-Tabard, Sylvie, Valon, Léo, Barrio Cano, Laura, Levayer, Romain, Mazen, Inas, Gobaa, Samy, Smith, James C, McElreavey, Kenneth, Lovell-Badge, Robin, Bashamboo, Anu
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Cellular Reprogramming
Cellular Reprogramming - genetics
Developmental Biology
Diseases and Disorders
Female
Gonadal Dysgenesis, 46,XY
Gonadal Dysgenesis, 46,XY - genetics
Gonads
Humans
Induced Pluripotent Stem Cells
Life Sciences
Male
Mice
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Summary:During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro-derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9-mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abn9793