Male sex hormones increase excitatory neuron production in developing human neocortex

Abstract

The presence of male-female brain differences has long been a controversial topic. Yet simply negating the existence of biological differences has detrimental consequences for all sexes and genders, particularly for the development of accurate diagnostic tools, effective drugs and understanding of disease. The most well-established morphological difference is size, with males having on average a larger brain than females; yet a mechanistic understanding of how this difference arises remains to be elucidated. Here, we use brain organoids to test the roles of sex chromosomes and sex steroids during development. While we show no observable differences between XX and XY brain organoids, sex steroids, namely androgens, increase proliferation of cortical neural progenitors. Transcriptomic analysis reveals effects on chromatin remodelling and HDAC activity, both of which are also implicated in the male-biased conditions autism spectrum disorder and schizophrenia. Finally, we show that higher numbers of progenitors result specifically in increased upper-layer excitatory neurons. These findings uncover a hitherto unknown role for male sex hormones in regulating excitatory neuron number within the human neocortex and represent a first step towards understanding the origin of human sex-related brain differences.

Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes

“…We experimentally confirmed this prediction, demonstrating accuracy of the GRN for predicting gene regulatory processes in human β-cells. Interestingly, a similar pro-proliferative effect of androgens has been reported during neurogenesis in human brain organoids (Kelava et al, 2022), suggesting a shared mechanism between pancreatic and neuronal cells. Our findings predict a role for sex hormones in postnatal β-cell expansion.…”

Complexity of Sex Differences and Their Impact on Alzheimer’s Disease

“…For instance, no significant differences were observed between cerebral organoids generated from both male and female ESCs, suggesting that sex chromosomes alone are not driving the developmental differences observed in the human brain. However, after treatment with sex steroids, there was a significant increase in cortical neural progenitor cell numbers in the male-derived cerebral organoids, which resulted in a thicker upper layer of excitatory neurons, and therefore morphological differences in male-compared to female-derived organoids [220]. This is most likely more representative of the differential developmental pathways occurring in female and male human brain development, during which the importance of sex hormones has been established.…”

Modeling brain macrophage biology and neurodegenerative diseases using human iPSC-derived neuroimmune organoids

“…Harnessing the human iPSC-based neuroimmune organoid technology will be especially beneficial for studying polygenic and sporadic diseases, such as AD, that cannot be easily recapitulated in animal models. In addition to the neuroimmune organoids discussed in this Opinion, further advances to the BO technology may enable modeling of meningeal structures and their resident dural and leptomeningeal macrophages (Kierdorf et al, 2019;Mildenberger et al, 2022), defining the roles of peripheral immune cells (Pasciuto et al, 2020;Zhang et al, 2022;Chen et al, 2023) and noncellular factors (Chen et al, 2021;Liu et al, 2022) in microglia development and disease, and clarifying the transcriptomic and functional sexual dimorphism of microglia (Hanamsagar et al, 2017;Thion et al, 2018;Kelava et al, 2022). Finally, the same principles of using specialized neuroimmune organoids to establish a distinct iMG environment could also be applied to brain tumor organoids to better define the diversity and function of microglia and macrophages in the context of brain cancer (Hambardzumyan et al, 2016;Keane et al, 2021).…”