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July 21, 2020

Human brain organoids extended axons into mice and monkeys

The Jun Takahashi lab reports that cerebral organoids made of human ES cells engraft into mice and monkeys.

Brain damage due to injury or stroke can leave patients with a severe loss of several neurological functions. Drugs and rehabilitation can ameliorate the loss, but there is no cure for a full recovery. The Jun Takahashi lab has been investigating the use of organoid transplantation. In their newest study, they identify the conditions for which human cerebral organoids best engraft into the brains of mice and monkeys. The study serves to show the conditions in which the organoids exert their most therapeutic benefit.

In stem cell therapies, the stem cells are differentiated into specific types of cells that are transplanted into a patient. This is the strategy Prof. Takahashi has used in his lab's work to treat Parkinson's disease (iPS cell-based Parkinson's disease therapy administered to first patient ), which at the cellular level is attributed mostly to the loss of one cell type.

For other neurological diseases or disorders, however, the cellular loss can be more complex, and replacing each and every type of damaged cell by cell transplantation is not feasible. In these cases, organoids are preferred.

"Organoids are made of pluripotent stem cells, but they mimic development, so they include many cell types rather than just one cell type," explains Takahashi.

With its Parkinson's disease work having progressed to the clinical stage, the lab has now shifted its attention to stroke and has been developing methods to produce cerebral organoids.

Interestingly, previous work from other groups have shown that human brain organoids can have a therapeutic effect in animals like rats, indicating animal studies could be used to optimize the transplantation procedure for humans.

"No one knows the best conditions for the organoid transplantation. We want to see if different organoid stages have different effects," says Neurosurgeon Takahiro Kitahara, who first-authored the study.

Kitahara and colleagues prepared two types of organoids from human embryonic stem cells. One was grown for six weeks and the other for ten weeks. These two times reflect differences in the type of neurons in the organoids.

"Organoids mimic normal development. Our six-week organoids express more subcerebral projection neurons, which extend axons to the brainstem and spinal cord, and our 10-week organoids express more callosal projection neurons, which extend neurons to other areas of the cerebral cortex," he explained.

When transplanted into mice, both organoids showed good engraftment and an ability to extend axons to the host 12 weeks after the transplantation. They also showed vascularization, which is key to keeping the transplant alive. However, the six-week grafts tended to show overgrowth, which could cause serious complications. One property of stem cells is their proliferation, thus excessive growth is a concern in any stem cell-based transplantation.

The 10-week organoids did not show overgrowth, suggesting they contained less proliferative cell types.

"The 6-week organoids showed more fibers along the corticospinal tract, but the overgrowth meant the 10-week organoids are safer," says Kitahara.

The study also examined the best time to transplant the organoid. Treatment immediately after an injury does not necessarily lead to the best recovery, as additional experiments would show. Waiting a week between the brain injury and transplantation resulted in better engraftment results, as the organoids had higher survival and volume than had they been transplanted immediately after the injury, and they extended more axons to the host brain.

"The one-week delay suggests the brain environment is also important for the transplantation. It has to be in a condition that is optimal for receiving the transplant," says Kitahara.

He adds that the immunological milieu and presence of angiogenesis factors changes with time following an injury.

The research team also wanted to examine if the same benefits could extend to monkeys, since among animals, the neurological systems of monkeys most closely resemble that of humans. Indeed, like in mice, transplanted cerebral organoids showed positive effects in terms of engraftment, vascularization and axon extension.

"Monkey experiments are a necessary pre-clinical test, but they are extremely costly. This study gives us a basis for understanding the best conditions to conduct our monkey experiments in the future," says Takahashi.

Paper Details
  • Journal: Stem Cell Reports
  • Title: Axonal extensions along corticospinal tracts from transplanted human cerebral organoids
  • Authors: Takahiro Kitahara1,2, Hideya Sakaguchi1,3, Asuka Morizane1, Tetsuhiro Kikuchi1, Susumo Miyamoto2 and Jun Takahashi1,2
  • Author Affiliations:
    1. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    2. Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    3. RIKEN BDR-Otsuka Pharmaceutical Collaboration Center, Kobe, Japan** Authors in correspondence
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