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Title: “Engineering immature astrocyte grafts for neural regeneration”

Advisory Committee: Timothy O’Shea, PhD – BU BME (Advisor) David Boas, PhD – BU BME, NPC (Chair) John Ngo, PhD – BU BME Darrell Kotton, MD – BUMC, CReM

Abstract: Stroke injuries in the mammalian adult results in the formation of an injury lesion core devoid of neural tissue and dominated by fibrotic scar tissue that serves no neurological function. In similar injuries in mammalian neonates, immature astrocytes coordinate a glia-based wound response that repopulates lesions with glia cells to enable effective neural regeneration. Cell graft strategies that promote glia repair are promising for new stroke treatments, however the types of transplanted cells required for lesion repair and neural circuit support is unknown. I hypothesize that grafting engineered immature astroglia at sub-acute time points after large ischemic and hemorrhagic strokes will direct the generation of vasculature with glial barrier functions and minimize fibrotic scarring in stroke lesion cores that will be necessary and sufficient to establish neural regeneration permissible environments that can sustain functional neuronal circuits. To test this hypothesis, I will (1) engineer immature astroglia with glia repair competency similar to neonate glia using hysteretic conditioning (HC) paradigms; (2) longitudinally track neurovascular recovery induced by grafts in and around lesion cores using intravital imaging methods, and (3) evaluate how graft-derived glia repair aids transplant neuron survival and host axon regeneration. This work will create novel methods for deriving immature astroglia grafts, optimize methodologies for longitudinal tracking of cell graft functions and stroke lesion remodeling, and provide new insights into the molecular mechanisms of effective neural regeneration in stroke lesions.