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

肥大细胞（MCs）是过敏反应的主要应答者，也是先天免疫系统的重要细胞。我们最近的研究表明，除了这些功能外，MCs还是胚胎着床的关键调节剂，从而决定性地影响胎儿的生长发育。mc缺陷的KitW-sh/W-sh小鼠表现出明显的植入受损表型，可以通过先前的骨髓源性肥大细胞（BMMCs）重建来挽救。MCs通过TGF-β/CtGF相互作用积极影响胚泡着床所需的组织重塑。我们还证明了MCs产生并分泌半乳糖凝集素-1 (Gal-1)，这对胎盘发育很重要，因为mc缺陷动物的重组与Gal-1敲除MCs导致胎盘受损和螺旋动脉重构不足导致妊娠晚期丢失。在这里，我们的目标是了解介质和细胞相互作用是如何以及最重要的是通过哪些介质和细胞相互作用，MCs首先影响鉴定和植入所需的组织重塑，其次影响螺旋动脉的形成和胎盘形成。目前项目的主要目的是1)分离和描述子宫MCs似乎不同于其他MCs, 2)来研究缺乏MCs或者在MCs缺少公认的介质,如Gal-1,影响子宫血流,形成螺旋动脉和胎座,3)解开是否与子宫NK细胞和MCs如何交互,确保正确的螺旋动脉,从而形成胎座式这两种细胞类型似乎也有类似的,4)探讨子宫MCs和NKs均缺乏的小鼠是否能够实现胎盘和妊娠。我们相信我们的研究将有助于了解调节胚胎着床、胎盘和妊娠维持的基本机制，并揭示MCs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.