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theses

Primary damage in traumatic brain injury (TBI) occurs instantaneously, and the only method of intervening is prevention. Secondary brain injury, however, involves a complex range of cellular and molecular processes that occur over a period of hours to months after the primary injury, resulting in both immediate cell death and damage, and long-term degenerative changes. Therapies that provide protection against secondary insults and/or restore neural function are critical to survival and functional recovery following TBI. Mesenchymal stromal cells (MSCs) have emerged as a promising therapy, acting as trophic mediators capable of responding to their micro-environment. Current delivery methods, however, limit sustained therapeutic benefit due to lack of long-term persistence, and migration away from the injury site. We have previously developed a method to immobilize MSCs in alginate micro-spheres, enabling greater control and localization. Herein, we evaluated alginate-encapsulated MSC therapy for the ability to target secondary injury components contributing to progressive damage following TBI. We demonstrated that encapsulated MSCs attenuated the neuro-inflammatory response in organotypic hippocampal slice culture (OHSC), more effectively than monolayer MSCs, and identified PGE2 as a key inflammatory mediator produced by MSCs. In contrast to monolayer MSCs, inflammatory signals were not required to stimulate PGE2 production by encapsulated MSCs. Further encapsulation-stimulated changes were revealed in a multiplex panel analyzing 27 MSC-produced cytokines and growth factors. We also determined that our encapsulated MSC treatment primarily targets astrocyte-mediated inflammation, and that constitutively increased levels of PGE2 produced by encapsulated MSCs may be a key contributor to their enhanced inflammatory modulation. Furthermore, encapsulated MSC treatment is capable of up-regulating astrocyte expression of several neurotrophic factors. In addition to modulating inflammation, encapsulated MSCs also prevented ischemia-induced cell death and neurite retraction in OHSC and cerebellar granule neuron cultures, and reduced astrocyte activation markers following in vitro ischemic injury. Overall, we have shown that encapsulated MSCs target multiple components of secondary injury following TBI, including inflammation and ischemia, and provide both anti-inflammatory and neuroprotective benefit. These results suggest that alginate encapsulation of MSCs may not only provide an improved delivery vehicle for transplantation but may also enhance MSC therapeutic benefit for TBI recovery.

ETD_6767

Ph.D.

Includes bibliographical references

by Elizabeth Carol Stucky

doi:10.7282/T3DF6T66

ETD doctoral

The author owns the copyright to this work.