Chronic Versus Acute Transplantation of Neural Tissues for TBI-Induced Cortical Injuries

PROJECT SUMMARY/ABSTRACT
Injury to the cerebral cortex occurs frequently across the spectrum of severity in traumatic brain injury (TBI). No
therapies exist to counter the neurological and cognitive deficits caused by these injuries, which are
responsible for substantial disability after TBI. A promising strategy for restoring brain function after injury is
cell replacement. Neural tissues that connect with host cortex locally and function as supplementary cortical
processing modules are especially intriguing candidates for this approach. Currently available tissue substrates
that are suitable for translation, including human brain organoids derived from patient-matched stem cell lines,
do not fully recapitulate the architecture or micro-circuitry of cortex. However, they can still be used to
investigate outstanding questions regarding neural tissue integration with the host brain. One essential issue
that has not been examined systemically is the optimal timing of cell replacement after TBI. The overall
objective of the current proposal is to evaluate how the interplay between the timing of neural tissue
transplantation after TBI and the state of the cortical microenvironment affects anatomic and functional
outcomes. Our central hypothesis is that acute neural tissue transplantation after TBI and removal of the injury
perimeter will improve outcomes as a result of enhanced integration of graft neurons with host brain networks
and maintenance of host cortex integrity. To test this hypothesis, we will transplant human cortical organoids
into rat visual cortex in the chronic or acute setting after a controlled cortical impact injury and assess anatomic
and functional outcome measures. In Aim 1, organoids will be transplanted directly into a chronic injury cavity
or after resection of the glial scar at the border of the cavity. In Aim 2, organoid grafts will be inserted directly
into an acute injury cavity or after the injury margin as been removed. In both of these Aims, organoid health
and cell composition as well as host cortex integrity will be assessed histologically. The extent of formation of
graft efferents (green fluorescent protein tracing) and afferents (modified rabies virus system for retrograde
trans-synaptic tracing) also will be determined. Functional integration of organoid grafts with the host cortex will
be investigated using in vivo techniques for recording extracellular neural activity and visual stimulation of the
host animal. In Aim 3, we will examine how modulating the activity of organoids using optogenetic stimulation
impacts their connectivity and integration with the chronically or acutely injured brain. The proposed research is
innovative in its use of human brain organoids as structured neural tissues for cortical repair after TBI and
because it explicitly assesses how the timing of transplantation affects outcomes. We expect that the proposed
studies will elucidate conditions that result in improved outcomes after organoid transplantation while also
identifying the limitations of currently available neural tissue substrates. These expected outcomes will
advance the field of cortical repair after TBI by reinvigorating the concept of cell replacement therapy and
inspiring novel strategies for modulating graft integration with the brain to achieve specific therapeutic goals.

Grant Number: 5R01NS119472-05
NIH Institute/Center: NIH
Principal Investigator: HAN-CHIAO CHEN