Brain-like organ technology in regenerative medicine

Brain-like organs cultured in vitro provide simplified and easily accessible cellular models that mimic the three-dimensional structure, cell types, and neural network functions of the human brain.

In the field of regenerative medicine, brain organoid technology shows great potential to be used as a platform for disease modeling and drug testing, as well as providing new approaches and ideas for cell transplantation therapies and brain injury research.

brain injury modeling

Neurons in the human brain are usually difficult to self-repair after injury due to the lack of growth and regenerative capacity after development is complete. Effective human-derived brain injury modeling is the key to study brain repair.

Brain-like organs can be used to simulate brain injury and regeneration processes, to explore regeneration mechanisms and regulatory factors, and to screen drugs or small molecule compounds that promote regeneration.

Brain-like organs provide a human-derived platform to mimic organic brain lesions caused by neurological disorders and delve into their underlying mechanisms. Due to its ability to mimic the organizational structure and developmental trajectory of the brain, brain-like organs are uniquely suited to study diseases associated with brain developmental disorders.

Brain-like organs can also mimic human brain damage caused by pathogen infestation. For example, studies since 2016 have shown that Zika virus infection of cortical brain-like organs induces microcephaly by promoting apoptosis, inhibiting proliferation and disrupting neurosphere formation in neural stem cells.

The COVID-19 pandemic since 2020 has triggered neurological symptoms such as dizziness and muscle aches in addition to respiratory symptoms from SARS-CoV-2 infection.

In addition, brain-like organs can be used to simulate human brain damage caused by exogenous physical or chemical factors.

Studies of cellular interactions in multiple brain regions and lineages

The complex functions of the human brain depend on the coordination of neural circuits and different brain regions. Early in vitro studies of cellular interactions in brain regions or different lineages have mostly used two-dimensional cell co-cultures, but two-dimensional systems cannot effectively model the complexity of the three-dimensional environment in vivo.

Therefore, more and more studies have been conducted to artificially assemble organoids from different brain regions and lineages into “assembly-like” models. Compared with two-dimensional models, organoid assemblies can take advantage of cellular self-organization to achieve complex cell-cell interactions, and can be cultured for a long time with more mature physiological functions, which is of great significance for the analysis of neural circuits in the human brain and the simulation of psychiatric disorders.

Currently, many studies use the strategy of first differentiating brain region-specific organoids and then fusing them at specific time points to study brain interactions.

For example, to mimic the migration and integration of ventral forebrain interneurons into the cortex, some studies combined dorsal and ventral forebrain-like organs and observed tangential migration of interneurons and their integration with cortical glutamatergic neurons to form neural networks.

In addition to the assembly of different brain region-like organs, the fusion of brain-like organs with different spectrum-like organs has also received attention.

For example, brain-like organs can form neurovascular-like units together with vascular endothelial-like organs and supporting cells to mimic intracerebral blood vessel formation. Microglia-like cells differentiated in vitro can be integrated into cortical-like organs for studying neuron-glia interactions in Alzheimer's disease.

Organoid chip technology combining organoid and microfluidics is another way to study multi-system interactions. Microfluidic systems can connect different organoid models to form a microchip system, while simulating the functional perfusion that is missing in brain organoids to further mimic the in vivo microenvironment.

Several studies have indicated that brain-like organs cultured in microfluidic systems have higher physiological activity and maturation, possibly due to inhibition of glycolysis and endoplasmic reticulum stress-related pathways.

Drug screening and toxicological evaluation

Medical research into human diseases often faces many limitations, such as individual patient differences, unpredictability of results and time-consuming drug testing. Brain-like organs originating from patients with infectious diseases or neurological disorders show characteristics similar to clinical phenotypes and may be potential platforms for new drug testing.

Currently, there are deficiencies in the toxicity evaluation and preclinical studies of drugs. Due to the species differences between animal models and humans, it is difficult to accurately predict human neurotoxicity, resulting in the gradual emergence of toxic reactions of many drugs only after clinical trials or marketing.

Compared to the fully developed brain, brain-like organs are more sensitive to toxic substances and are suitable for neurotoxicity testing of different compounds.

Brain-like organs can be combined with microfluidic systems to form organoid chips. Due to its vascular-like perfusion system, it can better mimic the in vivo microenvironment and has unique advantages in drug screening and toxicology research.

brain transplant

Organ transplantation is an effective treatment for organ damage or failure, but research on organ transplantation targeting damaged brain regions has been greatly limited due to medical ethics, transplant rejection, scarcity of organ supply and demand, and the specificity of the structure and function of the human brain.

Brain-like organs originating from donors have sufficient cell supply potential and share the same genetic background as the host with less rejection, making them an ideal source for regeneration and repair of diseased or damaged brain tissues, and offering new possibilities for organ transplantation and regenerative medicine in the human brain.

Previous studies have demonstrated that it is feasible to transplant brain-like organs into rodent brains. Human-derived neurons are able to survive in the host brain, project to other brain regions and integrate into the host's neural network.

In organ repair, brain-like organs can be used to replace lost neurons or rebuild damaged neural networks. Stroke is the second leading cause of death worldwide, but effective treatments are scarce. Brain-like organs have a promising application as potential donors for stroke transplantation.

Brain-like organ transplants can also be used to repair complex sensory functional impairments. In neurodegenerative diseases, specific subpopulations of neurons (e.g., dopaminergic neurons or motor neurons) degenerate progressively, leading to disease-related neurological deficits.

Brain-like organ transplantation has been used as a potential treatment to repair brain damage caused by degenerative diseases. For example, the main pathological change in Parkinson's disease is the loss of dopaminergic neurons in the midbrain substantia nigra, leading to a significant decrease in dopamine release in the striatum.

Despite the shortcomings of transplanted brain-like organs in terms of functional maturity and cellular composition compared to host brain tissue, transplantation therapy using brain-like organs remains a promising approach for brain injury repair.