Three-dimensional human axon tracts derived from cerebral organoids

Abstract

Reestablishing cerebral connectivity is a critical part of restoring neuronal network integrity and brain function after trauma, stroke, and neurodegenerative diseases. Creating transplantable axon tracts in the laboratory is a novel strategy for overcoming the common barriers limiting axon regeneration in vivo, including growth-inhibiting factors and the limited outgrowth capacity of mature neurons in the brain. We describe the generation and phenotype of three-dimensional human axon tracts derived from cerebral organoid tissue. These centimeter-long constructs are encased in an agarose shell that permits physical manipulation and are composed of discrete cellular regions spanned by axon tracts and dendrites, mirroring the separation of grey and white matter in the brain. Features of cerebral cortex also are emulated, as evidenced by the presence of neurons with different cortical layer phenotypes. This engineered neural tissue has the translational potential to reconstruct brain circuits by physically replacing discrete cortical neuron populations as well as long-range axon tracts in the brain.\n\neTOC BlurbRestoring axonal connectivity after brain damage is crucial for improving neurological and cognitive function. Cullen, et al. have generated anatomically inspired, three-dimensional human axon tracts projecting from cerebral organoids in a transplantable format that may facilitate the reconstruction of large-scale brain circuits.\n\nHighlightsO_LIA neural tissue engineering approach is applied to human cerebral organoids.\nC_LIO_LIThree-dimensional axon tracts are generated in a transplantable format.\nC_LIO_LIThe growth characteristics of the engineered axons are examined.\nC_LIO_LIThe cellular phenotypes of the organoid tissue and axons are characterized.\nC_LI