TY - JOUR
KW - Cellular neuroscience
KW - Neuronal development
AU - Irene Faravelli
AU - Noelia Antón-Bolaños
AU - Anqi Wei
AU - Tyler Faits
AU - Abhishek Sampath Kumar
AU - Sophia Andreadis
AU - Rahel Kastli
AU - Marta Montero Crespo
AU - Mara Steiger
AU - Daniel Leible
AU - Elizabeth Zhang
AU - Bobae An
AU - Yaron Meirovitch
AU - Sayara Silwal
AU - Sung Min Yang
AU - Alexander Kovacsovics
AU - Xian Adiconis
AU - Helene Kretzmer
AU - Joshua Z. Levin
AU - Edward S. Boyden
AU - Jeff Lichtman
AU - Aviv Regev
AU - Alexander Meissner
AU - Paola Arlotta
AB - The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models1. While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development. Here we develop human brain organoids for 5 years in culture, optimizing growth conditions to extend excitatory neuron viability beyond previous limits. Using maturation-associated modules derived from endogenous human brain, we show that brain organoids transcriptionally age with cell type specificity over years in culture. Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids correlates precisely with time spent in vitro, and parallels epigenomic ageing in vivo. Notably, we show that in chimeric organoids generated by mixing neural progenitors of different ages, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny, therefore showing that progenitors that age in organoids retain a memory of the time spent in vitro. The data indicate that human brain organoids can continue to mature and record the passage of time over many years in culture.
BT - Nature
DA - 2026-08-19
DO - 10.1038/s41586-026-10877-x
LA - en
N2 - The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models1. While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development. Here we develop human brain organoids for 5 years in culture, optimizing growth conditions to extend excitatory neuron viability beyond previous limits. Using maturation-associated modules derived from endogenous human brain, we show that brain organoids transcriptionally age with cell type specificity over years in culture. Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids correlates precisely with time spent in vitro, and parallels epigenomic ageing in vivo. Notably, we show that in chimeric organoids generated by mixing neural progenitors of different ages, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny, therefore showing that progenitors that age in organoids retain a memory of the time spent in vitro. The data indicate that human brain organoids can continue to mature and record the passage of time over many years in culture.
PY - 2026
SP - 1
EP - 11
T2 - Nature
TI - Human brain organoids record the passage of time over multiple years
UR - https://www.nature.com/articles/s41586-026-10877-x
Y2 - 2026-08-26
SN - 1476-4687
ER -