In Vivo Applications of Brain Organoids

By Adara Anisman


Overview of In Vitro Brain Organoids 

In vitro 3D brain organoids (Figure 1) have been heralded as a faster, easier, and cheaper method for studying neurological diseases and screening potential drug therapies, as compared to traditional animal models1. Brain organoids grown from human stem cells are increasingly feasible to develop using emerging microfluidic and electrospinning technologies. This is good news, as up to 80% of drugs that pass preclinical tests fail in humans2; better research methods are clearly necessary.

In Vivo Applications of Brain Organoids Lead to Improved Research Avenues

Recent studies3,4 have opened new and fascinating research avenues into the in vivo applications of brain organoids, allowing them to develop within a biologically appropriate microenvironment with neuronal circuits, immune systems, and crucially vascular circulation. For example, brain organoids grown from human embryonic stem cells (hESCs) have been transplanted into a living immunodeficient mouse brain, where the cells successfully differentiated and developed synaptic connectivity with the mouse brain3. Host immune cells were found in the organoid graft, and immunostaining further indicated that vascularization of the organoid graft came from the host mouse’s own blood vessels. Most interesting, stimulating the organoid graft with light resulted in excitatory inputs received by the host brain, indicating functional communication between the human-ESC-derived organoid graft and the mouse-host brain. In another study, human brain organoids were grown from induced pluripotent stem cells (iPSCs), and the same donor’s endothelial cells (ECs) were used to vascularize the organoid prior to transplantation into mice4. However, no evidence of functional connectivity between graft and mouse brain was observed.


 The Implications of Brain Organoid Research: A Brighter Future

These astounding results provoke even more questions; to what degree will transplanted human brain organoids operate functionally in a rodent brain? What does this tell us about inter-species cellular compatibility and inter-species CNS compatibility? Will drug therapies administered to the host animal be able to take effect in a transplanted human brain organoid? How will we measure the efficacy of potential drug therapies when disease/symptoms may vary wildly between humans and rodents? What about the ethics; if we give rodents pieces of the human brain, at what point do they become more than mice? Clearly, the implications of this research are enormous. If we can successfully transplant a brain organoid into a rodent brain, why not a human one? Could this be the silver bullet of treating neurodegenerative disorders? Heaps of further research await.

Figure 1: Brain organogenesis in vitro5

 

References
  1. Koo, Y., Hawkins, B. T., & Yun, Y. (2018). Three-dimensional (3D) tetra-culture brain on chip platform for organophosphate toxicity screening. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-20876-2
  2. Perrin, S. Preclinical research: make mouse studies work. Nature 507, 423–425 (2014).
  3. Mansour, A. A. F., Gonçalves, J. T., Bloyd, C. W., Li, H., Fernandes, S., Quang, D., ... Gage, F. H. (2018). An in vivo model of functional and vascularized human brain organoids. Nature Biotechnology, 36(5), 432– 441. https://doi.org/10.1038/nbt.4127
  4. Pham, M. T., Pollock, K. M., Rose, M. D., Cary, W. A., Stewart, H. R., Zhou, P., ... Waldau, B. (2018). Generation of human vascularized brain organoids. NeuroReport, 29(7), 588–593. https://doi.org/10.1097/ wnr.0000000000001014
  5. Wang, Y., Wang, L., Guo, Y., Zhu, Y., & Qin, J. (2018, January 05). Engineering stem cell-derived 3D brain organoids in a perfusable organ-on-a-chip system. Retrieved January 31, 2021, from https://doi.org/10.1039/ C7RA11714K