Cortical Organoid Transplantation in TBI: Impact of Glial Scar Resection and Timing of Transplantation

Introduction: In the United States, over 1.5 million people experience traumatic brain injury (TBI) annually, with 43.3% of hospitalized patients developing long-term disabilities. Due to the brain’s limited capacity for regeneration, there are few effective treatments to restore structure and function to damaged cortex post-TBI. One promising approach is cellular transplantation, specifically using brain organoids. A potential barrier to that neural repair strategy is the formation of a glial scar at the border of the cortical cavity after TBI, creating an inhibitory environment that hinders axonal regrowth, and synapse formation.

Methods: This study aimed to assess the feasibility of transplanting human induced pluripotent stem cell (iPSC)-derived cortical organoids (COs) into injured cortex and determine the effects of transplantation timing and glial scar removal. Cortical injuries were induced in the visual cortex (V2) of rodents using a controlled cortical impactor (3mm diameter, 2.5m/s, 2mm depth). COs were transplanted one week or one-month post-injury. Two conditions were tested: glial scar removal (GS-) or leaving the scar intact (GS+). Glial scars were removed by aspirating a thin tissue layer around the injury site.

Results: Two months post-transplantation, we evaluated organoid survival, injury cavity size, and markers of inflammation around the injury site. In the GS- condition (n=4), organoid volume was increased, indicating better organoid survival. Enhanced organoid survival was also observed with transplantation one-week post-injury compared to one month after. Histological analysis revealed fewer GFAP+ cells, reduced Iba1+ signaling, and smaller injury cavities in both the GS- condition and one-week post-injury transplant animals, suggesting lower levels of inflammation in the host tissue surrounding the injury cavity in those conditions.

Conclusion : Our findings highlight the importance of earlier transplantation and direct contact of the organoid with healthy host tissue for organoid survival, reduced inflammation, and host tissue preservation. Future research will explore mechanisms of organoid-host interaction and strategizes to optimize repair.