Heterogeneity of Pericytes after Ischemic Stroke

Stroke is the number one leading cause of adult disability in the US. While medical intervention has significantly decreased mortality rate; stroke survivors still face devastating disability that affect their quality of life. With limited therapeutic interventions, promoting the brain repair and recovery remains an unmet need in medical sciences. While the brain has limited regeneration capability, its endogenous reactive and repair mechanism is not well-understood. Pericytes, a less-well-understood member of brain, are a heterogenous population of perivascular cell that regulate development and maintenance of structural elements of the blood brain barrier, vascular stability, and angiogenesis. Recent studies have confirmed their remarkable contractile ability, their control of cerebral blood flow and crosstalk with other cell types after injury. Due to its lack of exclusive markers, its overlapping markers with other cell types in the brain, including a newly identified population of perivascular fibroblasts and its heterogeneity, findings of brain pericyte after injury have been controversial. Through development of an array of novel molecular tools, coupled with the use of single cell RNA sequencing and novel pharmacological agents, this dissertation characterizes the post-stroke pericyte heterogeneity and its contribution to the brain repair processes. Pericyte population was characterized after stroke on the tissue level to understand their proliferative capacity and their association with the regenerative neurovascular niche. Using two novel molecular lineage-tracing models, subpopulations of pericyte were labeled and lineage-traced to delineate its contribution to the fibrotic scar. Using single cell RNA seq, the finding was confirmed and further characterized the molecular mechanism of pericyte contribution to (1) the brain fibrotic scar and (2) its role in establishing the regenerative neurovascular niche. Using the RNAseq dataseq as a guiding foundation, three specific manipulation studies were carried out to further delineate the heterogenous role of pericyte after stroke: Stat3 knockout in brain-specific pericyte, Loxl2/3 pathway inhibition by small molecule drugs and brain-specific pericyte ablation. These findings from these studies revealed the highly conserved nature of the brain’s fibrotic scar formation processes and the essential contribution of pericyte to the scar formation and maintenance. Pericyte heterogeneity, especially the fibrotic-scar-formation population and the peri-infarct population that associate with the neurovascular niche, needs to be taken into consideration when developing therapeutic treatment. Ultimately, these studies implicate the multi-faceted roles of pericyte in the brain repair and recovery processes, and provide further evidence to the growing body of research being done on the biology of pericyte in homeostasis and after injur