Engineering the host-graft interface through astrocyte-driven mechanisms for stroke recovery
Embargo Date
2027-09-03
OA Version
Citation
Abstract
Stroke injuries in the adult mammalian brain create lesion cores that lack functional neural tissue and are often dominated by fibrotic scarring, which holds no neurological utility. Consequently, an exogenous source of cells is needed to promote repair. However, the optimal cell type and the impact of lesion heterogeneity on repair remain unclear. I hypothesized that lesion-specific factors, particularly the type and severity of the injury, influence the survival and behavior of transplanted grafts by prompting host astrocytes to secrete molecular signals that either support or hinder the survival and proliferation of grafted cells.I employed a suite of bioengineering approaches, including (i) cell preconditioning, (ii) Optical Coherence Tomography (OCT)-based lesion monitoring, and (iii) lesion environment priming to test my hypothesis. Neural progenitor cells and immature astrocytes were grafted into ischemic stroke lesions in the murine brain; then, the fate of the graft and host responses were analyzed using a RiboTag toolkit, which allowed for cell-type-specific transcriptomic profiling.
Our results demonstrate that graft identity and survival are significantly influenced by the lesion environment. Ischemic and hemorrhagic strokes elicit distinct molecular profiles. OCT imaging proved effective for real-time intravital lesion monitoring and was predictive of long-term graft survival. In sub-acute ischemic strokes, specific astrocyte-derived trophic factors were elevated in lesions that promoted graft survival and the reintroduction of these trophic factors increased graft survival. In contrast, hemorrhagic lesions were characterized by elevated inflammatory cytokines, T-cell and leukocyte recruitment, which hindered graft survival. Importantly, modulating the infiltration of cytokine-responsive immune cells resulted in marked improvements in graft outcomes.
This thesis highlights the essential role of the host microenvironment in determining cell graft fate and identifies molecular targets, particularly astrocyte-derived trophic factors and inflammation-related pathways, which can be modified to support neural repair. These findings lay the groundwork for enhancing the efficacy of glial cell therapies for stroke injuries.
Description
2025
License
Attribution-NoDerivatives 4.0 International