Origin and Life Cycle of the Uterine Natural Killer Cell: Novel Insights from Human Uterus Transplantation

子宫自然杀伤细胞(Unk)是一种非常重要的先天淋巴组织。 妊娠成功的决定因素。尽管进行了广泛的研究，但基本面 关于联合国系统中Unk细胞的起源和组成，知识差距仍然存在 子宫内膜与Unk分化的分子机制。这些差距 这在一定程度上是因为我们无法在人体模型中解决这些基本问题。 我们将尖端的下一代测序方法与Access相结合 向人类子宫移植接受者回答有关Unk贩运、功能的问题 和分化，这将促进我们对怀孕及其 复杂的问题。这一提议的中心前提是胎盘，因此 怀孕的命运，在一定程度上是由Unk细胞的分化决定的 在胚胎植入前填充母胎界面。在这里，我们建立在 这一前提并检验了以下假设：1)从外围设备派生的Unks 驻留在组织中的祖细胞群体拥有不同的转录特征， 2)活化T细胞核因子(NFAT)是一种关键的转录因子 促进未成熟子宫内膜NK细胞向成熟蜕膜NK细胞分化 细胞。子宫移植受者提供了一个回答基础问题的机会 关于人类Unk细胞生物学的问题，并将对 妊娠并发症的发病机制。

Uterine natural killer cells (uNK) are an innate lymphoid population that are critical determinants of pregnancy success. Despite extensive research, fundamental knowledge gaps remain regarding the origin and composition of uNK cells in the endometrium and the molecular mechanisms driving uNK differentiation. These gaps result in part from our inability to address these essential questions in a human model. We have combined cutting-edge next generation sequencing methodologies with access to human uterus transplant recipients to answer questions about uNK trafficking, function and differentiation that will advance our understanding of pregnancy and its complicatons. The central premise of this proposal is that placentation, and therefore pregnancy fate, is pre-determined in part by the differentiation of uNK cells which populate the maternal-fetal interface prior to embryo implantation. Herein, we build upon this premise and test the following hypotheses: 1) uNKs which derive from peripheral and tissue-resident progenitor populations possess distinct transcriptional signatures, and 2) the Nuclear Factor of Activated T cells (NFAT) is a key transcription factor that promotes the differentiation of immature endometrial NK cells into mature decidual NK cells. Uterus transplant recipients provide an opportunity to answer foundational questions about uNK cell biology in human beings and will yield new insights into the pathogenesis of pregnancy complications.