Brain organoids, stem-cell-based models of real brain tissue, have moved into petri dishes and test tubes, but they have never quite felt themselves at home. The organoids’ cells don’t divide or diversify very much, and they don’t live very long, limiting their potential to recapitulate neurological diseases for the benefit of medical researchers and drug developers. Organoids may thrive, however, if they settle in more physiological environs—blood vessel–rich regions of mouse brain.

Scientists report a new approach that can develop more sophisticated organoid models by ensuring they receive sufficient oxygen and other nutrients via transplantation into rodents. The work could yield insights into the development of cures for brain disorders, speed up the testing of drugs, and even pave the way for someday transplanting healthy populations of human cells into people's brains to replace damaged or dysfunctional tissue. [Salk Institute]

By transplanting human brain organoids into mouse brains, scientists based at the Salk Institute hope to develop models that better represent the complexity of the brain. And the scientists have already achieved a dramatic first: an organoid that is both infiltrated by blood vessels and is also nourished by the blood flowing through these vessels.

Details of this work appeared April 16 in the journal Nature Biotechnology, in an article entitled “An In Vivo Model of Functional and Vascularized Human Brain Organoids.” This article describes how the “combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.” Such modeling, the article’s authors suggest, could yield insights into the development of cures for brain disorders, expedite the testing of drugs, and even hasten the transplantation of healthy populations of human cells into people's brains to replace damaged or dysfunctional tissue.

The current study goes beyond earlier attempts to develop vascularized organoids. For example, some researchers have attempted to graft vascular tissue onto organoids, but this approach still does not fully mimic the cellular microenvironment of an actual brain.

The Salk scientists, led by Rusty Gage, Ph.D., sought to replicate a more supportive physiological environment by grafting human stem cell–based organoids into a blood vessel–rich area of the mouse brain. The grafted human organoids integrated into the host environment, formed both neurons and neuronal support cells called astrocytes, and were surveyed by immune cells. Significantly, the team saw not only native blood vessels, but vessels with blood flowing through them.

“Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain,” wrote the authors of the Nature Biotechnology article. “In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts.”

As part of the study, the Salk team divided each organoid in half before transplantation, and the scientists maintained one of the halves in culture, so they could directly compare the benefit of both environments. They found that the cultured halves were filled with dying cells after a few months, while the age-matched organoids in the rodents were healthy.

To find out if the transplanted organoids were functional as well as healthy, the team conducted calcium imaging tests, in which neurons produce a dye when they fire. And, indeed, the neurons within the organoids were firing in a synchronized way.

“Finally,” the article’s authors indicated, “in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity.”

Essentially, the Salk team engineered cells to become responsive to light, setting up experiments that confirmed grafted neurons were forming connections with each other and with the host organism. This, too, represents a first in brain organoid development.

“This indicates that the increased blood supply not only helped the organoid to stay healthy longer, but also enabled it to achieve a level of neurological complexity that will help us better understand brain disease,” explained Abed AlFatah Mansour, Ph.D., a Salk research associate and the paper's first author.

Human transplantation in animals has been used for decades in brain and other tissues to enhance survival and test for mature function. “This work builds on a grafting technique I helped develop in 1984,” noted Dr. Gage. “It is gratifying to see that it works so well with brain organoids, which have immense potential to elucidate brain function in neuropsychiatric disease.”

“Brain organoids are powerful tools for investigating human brain development and disorders. But currently they do not fully represent native physiological environments. This work brings us one step closer to a more faithful, functional representation of the human brain and could help us design better therapies for neurological and psychiatric diseases.”

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