EVALUATION OF UNK CELL CAPACITY TO INITIATE PREGNANCY-ASSOCIATED SPIRAL ARTERY REMODELLING
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Transient uterine Natural Killer (uNK) cells are the predominant leukocytes of early gestational human and murine uteri. Murine uNK cells promote changes in endometrial structure including initiation of perivascular smooth muscle reduction in spiral arteries. Less is known about human uNK cell functions due to sampling constraints. Xenogeneic engraftment of human lymphocyte progenitors to alymphoid mice has been useful in understanding human lymphocyte functions in vivo. Irradiation of recipients is required to create a niche for successful humanization of the mice but renders recipient mice sterile. The goal of my thesis was to develop a protocol enabling engraftment of human hematopoietic stem cells in alymphoid mice that would permit differentiation of functional human uNK cells. I then planned to evaluate human uNK cell functions and their regulation in vivo. Neonatal Rag2-/-Il2rg-/- mice, which lack T cells, B cells and NK cells were preconditioned with 5-fluorouracil and inoculated with syngeneic mouse bone marrow cells. As adults, inoculated female mice conceived and differentiated functional mouse uNK cells. In contrast, neonatally-preconditioned Rag2-/-Il2rg-/- mice inoculated with human cord blood hematopoietic stem cells conceived but differentiated non-lymphoid cells in sites normally occupied by uNK cells. Weekly injections of human IL-15, which is required for NK cell differentiation, proliferation and survival, did not promote uNK cell differentiation. Rather, treatment with IL-15 altered gestational uteri, even in mice receiving neither preconditioning nor hematopoietic stem cells. I was successful in developing a protocol that enables hematopoietic stem cell engraftment in neonatal mice without compromising mouse fertility. However, this model is apparently not suitable for in vivo studies of human uNK cell functions.