Modeling sex differences in humans using isogenic induced pluripotent stem cells


Biological sex is a fundamental trait influencing development, reproduction, pathogenesis, and medical treatment outcomes. Modeling sex differences is challenging because of the masking effect of genetic variability and the hurdle of differentiating chromosomal versus hormonal effects. In this work we developed a cellular model to study sex differences in humans. Somatic cells from a mosaic Klinefelter syndrome patient were reprogrammed to generate isogenic induced pluripotent stem cell (iPSC) lines with different sex chromosome complements: 47,XXY/46,XX/46,XY/45,X0. Transcriptional analysis of the hiPSCs revealed novel and known genes and pathways that are sexually dimorphic in the pluripotent state and during early neural development. Female hiPSCs more closely resembled the naive pluripotent state than their male counterparts. Moreover, the system enabled differentiation between the contributions of X versus Y chromosome to these differences. Taken together, isogenic hiPSCs present a novel platform for studying sex differences in humans and bear potential to promote gender-specific medicine in the future. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Authors Waldhorn I, Turetsky T, Steiner D, Gil Y, Benyamini H, Gropp M, Reubinoff BE
Journal Stem cell reports
Publication Date 2022 Dec 13;17(12):2732-2744
PubMed 36427492
PubMed Central PMC9768579
DOI 10.1016/j.stemcr.2022.10.017

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