Anin vivoplatform for rebuilding functional neocortical tissue

Abstract

Recent progress in cortical stem cell transplantation has demonstrated its potential to repair the brain. However, current transplant models have yet to demonstrate that the circuitry of transplant-derived neurons can encode useful function to the host. This is likely due to missing cell types within the grafts, abnormal proportions of cell types, abnormal cytoarchitecture, and inefficient vascularization. Here, we devised a transplant platform for testing neocortical tissue prototypes. Dissociated mouse embryonic telencephalic cells in a liquid scaffold were transplanted into aspiration-lesioned adult mouse cortices. The donor neuronal precursors differentiated into upper and deep layer neurons that exhibited synaptic puncta, projected outside of the graft to appropriate brain areas, became electrophysiologically active within one month post-transplant, and responded to visual stimuli. Interneurons and oligodendrocytes were present at normal densities in grafts. Grafts became fully vascularized by 1-week post-transplant and vessels in grafts were perfused with blood. With this paradigm, we could also organize cells into layers. Overall, we have provided proof of concept for an in vivo platform that can be used for developing and testing neocortical-like tissue prototypes.

Could an old brain be made young again?

“…Output measures of graft performance are those routinely used by laboratories, including ours. [ 5 - 8 , 10 , 11 , 13 , 15 , 16 ] These include measuring cell survival and cytoarchitecture, mapping of axonal and dendritic connections to and from the graft, and initial functional measures such as recording responses to sensory input and determining the appropriateness of these responses for the location of the graft (e.g., response to visual but not auditory stimuli when the graft is in the visual cortex). Most of these preclinical tests can be performed using adult immune-compromised mice as the hosts for human or primate fetal tissue grafts, although due to the size limitations of the mouse brain, some testing may require larger preclinical models.…”

“…Our laboratory has recently developed a platform for testing layered, vascularized, multicell type neocortical tissue prototypes in the adult mouse neocortex, which we have initially validated with transplanted mouse rather than human cells and using a commercially available, nonclinically relevant scaffold. [ 15 ] Nevertheless, functional blood vessels readily form, as do neuronal connections with the host that lead to graft-derived neurons in the visual cortex acquiring responsiveness to visual stimuli.…”