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

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Spiral artery wall:lumen ratio and lumen diameter from C57BL/6J, KitW-sh/W-sh and KitW-sh/W-sh, reconstituted with bone marrow derived mast cells (BMMC) on day 10 of pregnancy (Woidacki et al. 2013)

(Second founding period)

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 remodelling (Woidacki et al. 2013). 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
  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.

The project coordination and administration will be carried out by:

Prof. Dr. Ana Zenclussen (Project Leader)
Head of the Department for Experimental Obstetrics and Gynaecology
Medical Faculty
Otto-von-Guericke-University Magdeburg
Gerhart-Hauptmann-Str. 35
39108 Magdeburg

Reference

Woidacki K, Popovic M, Metz M, Schumacher A, Linzke N, Teles A, Poirier F, Fest S, Jensen F, Rabinovich GA, Maurer M, Zenclussen AC (2013): Mast cells rescue implantation defects caused by c-kit deficiency. Cell Death Dis 17;4:e462. doi: 10.1038/cddis.2012.214.

Mast cells as novel regulators of tolerance at the fetal-maternal interface: their role in pregnancy success as “Treg-helpers” and study of their therapeutic potential in spontaneous abortions

(First founding period)

Abstract:

Mast cells (MCs) are largely known as primary responders in allergic reactions and important cells of the innate immune system. However, recent studies reveal that MCs in fact also play a critical role in the Treg-dependent allograft tolerance by secreting interleukin-9 (IL)-9. In the light of this breaking role for MCs we embarked on a series of studies aiming to analyze whether MCs may be implicated in tolerance towards the semiallogenic fetus growing within the maternal uterus. We confirmed the presence of MCs at the fetal-maternal interface preferentially in maternal decidua (Fig. 1). Their peak is observed around implantation. Fetal rescue by means of antigen-specific Treg was associated with an augmented number of MCs as well as with enhanced expression of MC-related molecules (Tph-1, Mcpt-1 and Mcpt-5) at the fetal-maternal interface and in other organs. Treg treatment was further associated with an increase in the levels of well-known MC growth factors mSCF and IL-3, while IL-9 remained unaltered. Anti-IL-10 treatment abrogated the protective effect of Treg and down-regulated the levels of Mcpt-1, highlighting a possible function of IL-10 as MC regulator at the fetal-maternal interface. The strongest data in support of a role for MCs during pregnancy were provided by our experiments with MC-deficient KitW-sh/W-sh mice. Adult pregnant KitW-sh/W-sh females showed severely impaired implantation and pregnancy outcome as compared to their wild type counterparts. Reconstitution with BMMCs prior to pregnancy totally rescued the phenotype and was associated with the presence of MCs within the decidua (Fig. 2). Our results indicate that as already observed in transplantation, MCs and their associated molecules might contribute to Treg-induced tolerance at the fetal-maternal interface. Here, we aim to unravel the novel role of MCs as cells promoting tolerance towards the semiallogenic fetus and to elucidate whether this is achieved as the result of interplay between MCs and Treg.

The main aims of the present project are:

  1. to study the participation of MCs in reproductive processes such as ovulation, receptivity, implantation, trophoblast growth, placentation and pregnancy maintenance,
  2. to investigate the mechanisms as to why MC determine pregnancy success, especially focussing in the interactions of MC with Treg during pregnancy using intravital microscopy as well as with in vitro methods and
  3. to identify MCs and their metabolites as potential candidates for therapeutic approaches in a murine model of abortion, which may later help women suffering from spontaneous abortions, a still unsolved problem with social and economical consequences.

We do believe that our study will contribute to the knowledge of the basic mechanisms regulating immune tolerance during pregnancy and to bring to light a further role for MCs as disease modulators.

(Click the pictures to enlarge them)

Mast cells in placenta
Fig. 1: detection of mast cells (arrows) in decidua (maternal part of the fetal-maternal interface) and placenta (fetal part of the fetal-maternal interface) on day 14 of pregnancy (Magnification 10x, GIEMSA staining)
Mast cells in decidua
Fig. 2: detection of mast cells in decidua from mast cell deficient KitW-sh/W-sh mice after reconstitution with BMMCs on day 10 of pregnancy (Magnification 100x, Toluidinblue O staining)

The project coordination and administration will be carried out by:

Prof. Dr. Ana Zenclussen (Project Leader)
Head of the Department for Experimental Obstetrics and Gynaecology
Medical Faculty
Otto-von-Guericke-University Magdeburg
Gerhart-Hauptmann-Str. 35
39108 Magdeburg

This project was granted 2 PhD-positions. The 2 PhD students will be tutored and supported by Prof. Zenclussen, together with Dr. Federico Jensen (Post Doc), Katja Woidacki (PhD student) and Markus Scharm (Technical Assistant).

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