TY - JOUR
KW - Cell biology
KW - Cellular neuroscience
KW - Scientific community
AU - Laura Castro-Aldrete
AU - Melanie Einsiedler
AU - Carla Cuní-López
AU - Quentin Vanhaelen
AU - Antonia Silvestri
AU - Maria Teresa Ferretti
AU - Martina Elena de Gennaro
AU - Guido Putignano
AU - Maria Guix
AU - Nicola Marino
AU - Liisa A. M. Galea
AU - Kerstin Lenk
AU - Samantha Paoletti
AU - Alex Zhavoronkov
AU - Antonella Santuccione Chadha
AB - Although in vitro models are valuable tools for modelling neurological disorders such as neurodegenerative diseases and neuropsychiatric disorders, it remains unclear whether and how biological sex characteristics should be considered when designing experiments. The historical failure to incorporate sex as a biological variable and acknowledge sex and gender differences in preclinical and clinical research has created a translation gap, which is only now beginning to be addressed. Sex effects are observed across mechanisms in common neuropsychiatric and neurodegenerative disorders. Therefore, it is imperative to incorporate sex differences into both in vitro and in vivo models to develop more precise and sustainable research tools for brain disorders. Such an approach will enable researchers to account for the physiological and pathological characteristics of male and female brains, improving the replicability and translatability of research results. In this Review, we discuss in vitro models of increasing complexity used for exploring pathological mechanisms and pharmacological target development. We address the advantages and challenges of using in vitro models to investigate sex differences in neurological disorders, starting with the types of cells used in in vitro models, including immortalized cell lines, primary cultures, induced pluripotent stem cells, up to 3D organoid and organ-on-a-chip models. Furthermore, we propose a roadmap and discussion of best practices to incorporate sex as a biological variable into in vitro models of neurodegenerative diseases and neuropsychiatric disorders.
BT - Nature Reviews Bioengineering
DA - 2025-10-13
DO - 10.1038/s44222-025-00355-w
LA - en
N2 - Although in vitro models are valuable tools for modelling neurological disorders such as neurodegenerative diseases and neuropsychiatric disorders, it remains unclear whether and how biological sex characteristics should be considered when designing experiments. The historical failure to incorporate sex as a biological variable and acknowledge sex and gender differences in preclinical and clinical research has created a translation gap, which is only now beginning to be addressed. Sex effects are observed across mechanisms in common neuropsychiatric and neurodegenerative disorders. Therefore, it is imperative to incorporate sex differences into both in vitro and in vivo models to develop more precise and sustainable research tools for brain disorders. Such an approach will enable researchers to account for the physiological and pathological characteristics of male and female brains, improving the replicability and translatability of research results. In this Review, we discuss in vitro models of increasing complexity used for exploring pathological mechanisms and pharmacological target development. We address the advantages and challenges of using in vitro models to investigate sex differences in neurological disorders, starting with the types of cells used in in vitro models, including immortalized cell lines, primary cultures, induced pluripotent stem cells, up to 3D organoid and organ-on-a-chip models. Furthermore, we propose a roadmap and discussion of best practices to incorporate sex as a biological variable into in vitro models of neurodegenerative diseases and neuropsychiatric disorders.
PY - 2025
SP - 1
EP - 22
T2 - Nature Reviews Bioengineering
TI - Modelling sex differences of neurological disorders in vitro
UR - https://www.nature.com/articles/s44222-025-00355-w
Y2 - 2025-10-24
SN - 2731-6092
ER -