Mast cells as critical regulators of tissue remodeling during implantation and placentation: mechanisms of action and mediators

肥大细胞(Mast cell，MC)在很大程度上被认为是过敏反应的主要反应者，也是天然免疫系统的重要细胞。我们最近发现，除了这些特性良好的功能外，MC还是胚胎着床的关键调节因子，因此对胎儿的生长发育具有决定性的影响。MC缺陷的KitW-sh/W-sh小鼠表现出明显的着床障碍表型，这可以通过先前的骨髓来源肥大细胞(BMMCs)重建来挽救。MCs通过转化生长因子-β/结缔组织生长因子相互作用对胚泡着床所需的组织重塑产生积极影响。我们还证明了MC产生和分泌Galectin-1(Gal-1)，这对胎盘形成是重要的，因为MC缺失的动物由于Gal-1基因敲除MCs导致胎盘受损和螺旋动脉重塑不足而导致晚期妊娠丢失。在这里，我们的目标是了解如何以及最重要的是通过哪些介体和细胞相互作用首先影响着床和植入所需的组织重塑，其次影响螺旋动脉和胎盘的形成。本项目的主要目的是1)分离和鉴定子宫MC，因为它们似乎不同于其他MC；2)研究MC中缺少MC或缺少可能的介质，如GAL-1，如何影响子宫血流、螺旋动脉的形成和胎盘形成；3)了解MC是否以及如何与子宫NK细胞相互作用，以确保正确的螺旋动脉形成和胎盘形成，因为这两种细胞似乎具有相同的介体相似的多余功能；4)研究在缺乏子宫MCs和子宫NK的小鼠中是否可以实现胎盘和妊娠。我们相信，我们的研究将有助于了解胚胎着床、胎盘形成和妊娠维持的基本机制，并进一步揭示MC作为疾病调节器的作用。

Mast cells (MCs) are largely known as primary responders in allergic reactions and important cells of the innate immune system. We have recently showed that besides these well-characterized functions, MCs emerge as critical modulators of embryo implantation and thereby decisively influence fetal growth and development. MC-deficient KitW-sh/W-sh mice present a clear phenotype of impaired implantation, which can be rescued by previous reconstitution with bone marrow-derived mast cells (BMMCs). MCs positively influence tissue remodeling necessary for implantation of the blastocysts via TGF-β/CtGF interplay. We also demonstrated that MCs produce and secrete galectin-1 (Gal-1), which is of importance for placentation as reconstitution of MC-deficient animals with Gal-1 knockout MCs results in late pregnancy loss as results of impaired placentation and inadequate spiral artery remodeling. Here, we aim to understand how and most importantly through which mediators and cellular interactions MCs influence first, tissue remodeling necessary for nidation and implantation and second, formation of spiral arteries and placentation. The main aims of the present project are 1) to isolate and characterize uterine MCs as they seem to be different from other MCs, 2) to investigate how the absence of MCs or the deficiency of putative mediators in MCs, such as Gal-1, affect uterine blood flow, formation of spiral arteries and placentation, 3) to unravel whether and how MCs interact with uterine NK cells to ensure correct spiral artery formation and thereby placentation as these two cell types seem to have similar, redundant functions by the same mediators and 4) to address whether placentation and pregnancy can be achieved in mice lacking both, uterine MCs and uterine NKs. We do believe that our study will contribute to the knowledge of the basic mechanisms regulating embryo implantation, placentation and pregnancy maintenance and to bring to light a further role for MCs as disease modulators.