Clinical and experimental data have shown that stroke is a sexually dimorphic disease. Females, in particular, have a varying degree of ischemic sensitivity across the lifespan. During pregnancy a woman exchanges cells with her fetus and in many women small numbers of cells of fetal origin persist, presumably throughout life. Fetal cells can be found in the maternal brain years after delivery and these cells express both stem cell and mature neuronal markers. The development of murine models that can be used to track fetal cells long after delivery has opened up a new avenue of research for investigators. Recent experimental work showing that fetal cells traffic to areas of injury and inflammation and differentiate into a variety of cell types suggests that these cells may have unrecognized capacity for repair and regeneration. However, it is unknown if this trafficking represents an adaptive response or further compounds injury. We will investigate if fetal cells traffic to the brain after stroke and evaluate the long-term fate and differentiation of these cell in the maternal brain. We will then manipulate the amount of fetal cells present in the brain (by increasing parity), and determine if these cells are an important contributor to either ischemic sensitivity or functional recovery after stroke in aged female mice. Recent work has shown that fetal cells can engraft and differentiate into endothelial cells, smooth muscle cells, and cardiomyocytes after murine maternal myocardial infarction. We have recently demonstrated that after an experimental stroke, fetal cells from a prior pregnancy can be found in the injured brain of the mother (for feasibility). As fetal cells are suspected to have multilineage differentiation capabilities, they are thought to behave similarly to stem or progenitor cells. Thi work may have significant implications for cell replacement strategies in human neurodegenerative diseases such as ischemic stroke. We hypothesize that fetal progenitors are actively recruited to the maternal brain as part of the inflammatory response to ischemic stroke and participate in repair.
Events that occur during pregnancy can have lasting implications on both the mother and fetus for decades after parturition, in particular, fetal microchimerism, the bidirectional exchange and persistence of cells between a pregnant female and her fetus, has been shown to play a role in various disease pathologies but has not been well studied in the brain. We hypothesize that microchimeric cells (MCs) home to sites of injury as part of the immune response to stroke and display a stem cell phenotype with potential to aid in repair.
|Ritzel, Rodney M; Patel, Anita R; Spychala, Monica et al. (2017) Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk. Proc Natl Acad Sci U S A 114:E5673-E5682|
|Spychala, Monica S; Honarpisheh, Pedram; McCullough, Louise D (2017) Sex differences in neuroinflammation and neuroprotection in ischemic stroke. J Neurosci Res 95:462-471|