Myles McCrary

Biomedical Engineering Ph.D. Thesis Defense

Date: April 22, 2019

Time: 1:00-2:00pm

Location: Woodruff Memorial Research Building Room- Conference Room 5101

Thesis Advisor: 

Ling Wei, MD

Emory University School of Medicine, Department of Anesthesiology

Thesis Committee: 

Robert Gross, MD, PhD

Emory University School of Medicine, Department of Neurosurgery

Luke Brewster, MD, PhD

Emory University School of Medicine, Department of Surgery

Michael Davis, PhD

Georgia Institute of Technology, Coulter Department of Biomedical Engineering

Shan Ping Yu, MD, PhD,

Emory University School of Medicine, Department of Anesthesiology

Cortical Transplantation of Brain-mimetic Glycosaminoglycan Scaffolds and Neural Progenitor Cells Promotes Regeneration after Ischemic Stroke in Mice

Ischemic stroke is a leading cause of mortality and morbidity, however, treatment options are very limited. Cellular therapy is an exciting avenue for replacing neural tissue lost to brain injury. Induced pluripotent stem cell derived neural progenitor cells (NPCs) are at the forefront brain regenerative medicine. NPCs can differentiate into and replace neurons and promote endogenous recovery mechanisms such as angiogenesis via trophic factor production and release. The stroke core region is hypothetically the ideal location for replacement of neural tissue since it is in situ, and following degradation, develops into a potential space where injections may be targeted with minimal compression of healthy peri-infarct tissue. However, the compromised cortical perfusion and degradation of the extracellular matrix following ischemia create an inhospitable environment resistant to cellular therapy. Overcoming these limitations are critical to clinical translation. Biomaterial approaches such as encapsulation with hydrogel may overcome these hurdles.

In this work, we investigated the ability of chondroitin-4-sulfate A (CS-A) to facilitate transplanted NPC survival, retention, and differentiation, the effects of CS-A encapsulation of NPCs on regenerative processes in the brain, and the extent to which CS-A could facilitate functional recovery of blood flow and behavioral outcomes after ischemic stroke in mice. Our findings indicate that injection of NPCs encapsulated in CS-A into the stroke core significantly improves angiogenesis, arteriogenesis, and blood flow after stroke compared to transplantation of non-encapsulated NPCs. Treatment with CS-A+NPCs also elicited a pro-regenerative microglial immune response. We found the improvements in vascular regeneration and remodeling were negated by blocking bFGF, suggesting that the sustained trophic signaling endowed by the CS-A hydrogel combined with NPC transplantation can promote brain tissue repair. However, further research and additional strategies are necessary to overcome the shortcomings of CS-A encapsulated NPC treatment prior to clinical translation. In summary, extending the regenerative and therapeutic potential of NPCs using angiogenic biomaterials such as CS-A may be a viable solution to overcoming limitations for cellular therapy in ischemic stroke.