Cerebral Organoids as 3-Dimensional Grafts in Traumatic Brain Injury

Traumatic brain injury results in the permanent loss of brain tissue, as the brain lacks a functional mechanism to regenerate the lost tissue. Researchers have sought to develop cell-based therapies to regenerate these tissues using several approaches, such as neural progenitor cells, mesenchymal stem cells, and direct astrocyte-to-neuron conversion. Each of these approaches has shown promise; however, each has limitations to regenerative potential. The recent emergence has led researchers to examine organoids’ potential as tissue grafts to regenerate the lost tissues in the brain following traumatic brain injury. In this dissertation, we sought to understand the interaction between the organoid and host following transplantation as a tissue graft. We additionally examined whether neuronal subtype composition in the organoid changes organoid-to-host interactions. To examine regenerative potential, we administered traumatic brain injuries to male NOD-SCID an immune-compromised mice line in the left motor cortex and acutely transplanted cortical organoids. For the examination of the neuronal subtype, we produced organoids enriched for glutamatergic, parvalbumin, and somatostatin neurons. We demonstrate that in transplantation of organoids following traumatic brain injury, the organoid selectively integrates into the efferent motor cortex pathway, modulates forelimb motor recovery, and that physiologically relevant neuronal subtype composition improves graft integration. The selective integration of the graft into efferent motor cortical pathways suggests the presence of an endogenous mechanism guiding this integration. We developed an in vitro model to examine the presence of an endogenous mechanism. In this dissertation, we establish organoids as a potential regenerative approach following traumatic brain injury. We additionally establish for the first time the presence of an endogenous mechanism guiding organoid integration into the brain.

Name thesis:degree_name

Doctor of Philosophy

Discipline thesis:degree_discipline

Molecular Biology

Grantor

Texas Woman's University

Year dc:date.issued

2025

Author dc:creator

• Gladen, Myles

Advisor dc:contributor.advisor

• Lybrand, Zane

Committee members dc:contributor.committeemember

• Hynds, DiAnna
• Na, Elisa
• Averitt, Dayna L
• Dulin, Jennifer

• Traumatic brain injury
• Neuroscience
• Organoids
• Regeneration
• Stem cells

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/11274/17403

OAI identifier oai:identifier

oai:twu-ir.tdl.org:11274/17403