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

肥大细胞（MC）是过敏反应的主要应答者，也是先天免疫系统的重要细胞。我们最近发现，除了这些良好的功能，MC出现作为胚胎植入的关键调节剂，从而决定性地影响胎儿的生长和发育。MC缺陷型KitW-sh/W-sh小鼠表现出明显的着床受损表型，这可以通过先前用骨髓来源的肥大细胞（BMMC）重建来挽救。MC通过TGF-β/CtGF的相互作用积极影响囊胚植入所需的组织重塑。我们还表明，MC产生和分泌半乳糖凝集素-1（Gal-1），这是重要的胎盘与Gal-1基因敲除MC的MC-缺陷的动物重建的结果在晚期妊娠损失受损的胎盘和螺旋动脉重塑不足的结果。在这里，我们的目标是了解如何，最重要的是，通过介质和细胞相互作用MC的影响，首先，组织重塑必要的着床和植入，第二，螺旋动脉和胎盘的形成。本项目的主要目的是1）分离和表征子宫MCs，因为它们似乎与其他MCs不同，2）研究MCs的缺乏或MCs中假定的介质（如Gal-1）的缺乏如何影响子宫血流、螺旋动脉的形成和胎盘形成，3）解开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并从而胎盘形成，因为这两种细胞类型似乎具有相似性，相同介质的冗余功能和4）解决在缺乏子宫MC和子宫NK两者的小鼠中是否可以实现胎盘形成和妊娠。我们相信，我们的研究将有助于了解调控胚胎着床、胎盘形成和妊娠维持的基本机制，并揭示MC作为疾病调节剂的进一步作用。

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.