Encouraging advancements for human brain organoids

A Broad Institute-Harvard team demonstrates that long-term culturing of human brain organoids results in significant cell maturation

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CAMBRIDGE, Mass.—Organoids, miniature, 3D versions of organs grown in vitro from embryonic or induced pluripotent stem cells, are a promising resource for a variety of types of lab work, from watching disease progression to testing toxicity on a small scale in miniaturized livers or kidneys. As technology—and techniques—have progressed, scientists have moved from 2D to 3D models, experimenting with culture components and bioscaffolds to allow cells to grow more organically. Given the complexity of the brain and the variety of cells within the central nervous system, generating accurate brain organoid models has been more difficult, and only the last decade has shown significant progress, with successful development of grey and white brain tissue in 3D models happening only as recently as 2014 (check out “Tufts sees a touchdown with 3D tissue” for more information).
And in advancing things even further, a joint team from Harvard University and the Broad Institute of MIT and Harvard working with human brain organoids has found that a longer culture time can offer more accurate and mature organoids, ones that present with multiple different cell types found in human brains. Their work was published in the paper “Cell diversity and network dynamics in photosensitive human brain organoids,” which appeared in Nature.
In general, most brain organoids are cultured over the course of days or weeks. The Harvard-Broad team adjusted their culture conditions in order to produce organoids that would mature over a matter of months—up to nine months or longer. They were also able to offer in their paper the largest molecular map to date of the different kinds of cells produced in brain organoids and their reproducibility.

“In the past, researchers have used a cocktail of factors to develop pluripotent stem cells into different types of cells from the nervous system—neurons, astrocytes, sometimes even specific classes of neurons,” said senior author Paola Arlotta, an institute member in the Stanley Center for Psychiatric Research at the Broad Institute, co-director of the nervous system disease program at the Harvard Stem Cell Institute, and professor of stem cell and regenerative biology at Harvard University. “But the brain contains an incredible diversity of cell types that interact and form connections. We took on the challenge of investigating to what extent such complexity and diversity of cell types can be produced in the dish, and how closely the organoid cell types mirror those in the endogenous tissue.”
As noted on Arlotta's faculty page, her work is focused on studying the mammalian cerebral cortex, neuronal diversity in that system and how that diversity affects the function of certain cells. She cites the lab's work with organoids as well, noting that they have “been building in-vitro models that resemble the cellular complexity, tissue architecture and local connectivity of the developing human cerebral cortex, which can become a platform for understanding higher-order circuit function and dysfunction that is affected in neurodevelopmental and neuropsychiatric cortical disease.”
Giorgia Quadrato, first author on the paper and a postdoctoral fellow in Arlotta's lab, and his fellow researchers adjusted lab protocols in order to allow for organoids that would develop over a longer period of time from induced pluripotent stem cell lines. Single-cell RNA sequencing (also known as “Drop-seq”) was utilized to analyze gene expression in more than 80,000 individual cells isolated from 31 organoids in order to categorize the different cell types these mini organs create. Their results showed that the more time the organoids had to develop, the more cell types they formed.
The cell types generated included subtypes of neurons and progenitors of the cerebral cortex, as well as many cell types comprising the visual system—upon further analysis, the team found a nearly complete collection of cell types seen in the human retina, including photoreceptor-like cells that caused a response when stimulated with light. Based on their findings, the researchers believe these models “may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli,” as noted in the paper's abstract.

“The cellular diversity that the organoids generated stunned all of us,” said paper co-author Steve McCarroll, an institute member at Broad, director of genetics for the Stanley Center for Psychiatric Research, and associate professor of genetics at Harvard Medical School. “The ability of stem cells within organoids to generate so many of the brain’s cell types—using their own genetic and molecular instruction book—evokes how development works inside the body.”
Roughly eight months into culturing, the neurons in the organoids developed dendritic spines, which protrude from the dendrites where synapses form and are a feature of mature neurons; thus far, it's been difficult to replicate them in culture.

According to McCarroll, “The presence of dendritic spines in these organoids is an important step for studying development and disease. Genetic studies indicate that disorders such as schizophrenia involve dysfunction at synapses and perhaps in the regulation or pruning of dendritic spines. An experimental model that develops spines can open the door to understanding how genes, and perhaps new pharmacological therapies, shape synaptic biology.”
Moving forward, the team plans further investigate options for maturing organoids more rapidly and guiding their anatomical organization as they mature, as well as hopefully reducing variability between organoids to better study neuronal maturation and networks.
As for Arlotta's lab, her faculty page also notes that “In the long term, our work aims at developing approaches to aid neuronal regeneration in neurodegenerative diseases of the cortical output circuitry, and at understanding and modulating neuronal function in neuropsychiatric diseases affecting the cerebral cortex.”

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