BioTechniques News
Tristan Free
In a new milestone for stem cell research, neuroscientists have kept human brain organoids alive for more than 5 years, demonstrating that they can mature and record the passage of time over extended periods.
The longest-lived human brain organoids to date have been created by researchers from Harvard University and the Broad Institute (both MA, USA). Having been sustained in the lab for over 5 years, the so-called ‘mini brains’ have trounced the previous record of 694 days, providing a wealth of data on previously inscrutable stages of the human brain’s postnatal development.
Human brain maturation occurs over an incredibly lengthy timescale, spanning nearly two decades. The process is governed by spatially and temporally regulated waves of gene expression; however, the exact molecular mechanisms behind this crucial period of development are difficult to study in vivo and so remain largely unclear.
Organoids offer a promising in vitro model for studying these elusive processes of human brain maturation; however, so far they have typically only been able to mimic early stages of development. Extending the longevity of human brain organoids, as the researchers of the current study have done, presents scientists with a unique opportunity to explore this uncharted chunk of our developmental timeline.
To do so, the team cultured human organoids of the cerebral cortex, optimizing growth conditions to extend excitatory neuron viability beyond previous limits. They then used single-cell RNA sequencing to characterize the composition and molecular features of cell types in 34 organoids at eight time points between 6 months and 5 years. Combined with previously published data, they analyzed a total of 110 organoids and just under 425,000 individual cells.
They then compared transcriptional changes in organoids with those occurring in the human brain using label transfer from reference datasets of endogenous human cortex, which allowed them to estimate the transcriptional ‘age’ of organoid cells. Doing so highlighted similarities with in vivo developmental trajectories, with postnatal-like signatures emerging in organoids after 12 months.
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Meanwhile, whole-genome methylation profiling of organoids at nine time points from 3 months to 5 years revealed that the predicted epigenomic age of organoids correlates with time spent in vitro and resembles epigenomic aging seen in endogenous tissues.
Together, these findings demonstrate that human brain organoids are capable of recapitulating transcriptional and epigenetic signatures associated with aging in vivo, making them an ideal model system for studying the biology of both the prenatal and postnatal human brain.
The scientists also conducted experiments in chimeric organoids, created by mixing neural progenitors of different ages. This revealed that older cells skipped the production of earlier neuronal progeny, rapidly producing later-stage neurons. In other words, the researchers write, the mini brains “[record] the passage of time and retain a memory of the developmental steps already performed.”
“We were a little bit shocked by the results,” senior author Paola Arlotta exclaimed. “I like to call this a ‘time warp’ of development.”
The findings show that human brain organoids can not only survive but also develop and mature over unprecedented time frames, underscoring their potential for advancing the study of brain development and disease, as well as drug discovery.
“We can unlock a whole spectrum of human brain biology that we didn’t see before,” Arlotta added.
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