Mast cells rescue implantation defects caused by c-kit deficiency

K Woidacki,F Poirier,A Schumacher,M Metz,A C Zenclussen,F Jensen,M Maurer,G A Rabinovich,A Teles,N Linzke,M Popovic,S Fest

doi:10.1038/cddis.2012.214

Abstract

Various physiologically relevant processes are regulated by the interaction of the receptor tyrosine kinase (c-Kit) and its ligand stem cell factor (SCF), with SCF known to be the most important growth factor for mast cells (MCs). In spite of their traditional role in allergic disorders and innate immunity, MCs have lately emerged as versatile modulators of a variety of physiologic and pathologic processes. Here we show that MCs are critical for pregnancy success. Uterine MCs presented a unique phenotype, accumulated during receptivity and expanded upon pregnancy establishment. KitW-sh/W-sh mice, whose MC deficiency is based on restricted c-Kit gene expression, exhibited severely impaired implantation, which could be completely rescued by systemic or local transfer of wild-type bone marrow-derived MCs. Transferred wild-type MCs favored normal implantation, induced optimal spiral artery remodeling and promoted the expression of MC proteases, transforming growth factor-β and connective tissue growth factor. MCs contributed to trophoblast survival, placentation and fetal growth through secretion of the glycan-binding protein galectin-1. Our data unveil unrecognized roles for MCs at the fetomaternal interface with critical implications in reproductive medicine.

Highlights

mast cells (MCs) are widely known as effector cells responsible for mediating allergic disorders and innate immunity
MC numbers were highest during the fertile phase of the cycle, namely in estrus when the female is sexually receptive and the endometrium is prepared for nidation (Figures 1a and b)
As mast cell deficiency in KitW-sh/W-sh is caused by a defective c-Kit signaling and c-Kit/c-Kit ligand interaction is important for oocyte development and folliculogenesis,[4] we monitored the estrous cycle in these mice

Summary

Introduction

MCs are widely known as effector cells responsible for mediating allergic disorders and innate immunity. Emerging evidence has identified a central role for these cells in the development and establishment of adaptive immune responses, as they are able to produce a variety of both proand anti-inflammatory mediators.[17] MCs are present in the myometrium, endometrium and cervix from humans and rodents, where they preferentially localize around blood vessels.[18,19,20,21,22] Little is known, about the functional contribution of MCs to uterine remodeling and, to Received 11.12.12; revised 13.12.12; accepted 13.12.12; Edited by RA Knight pregnancy establishment and the mechanisms underlying this effect. We undertook the present study using MC-deficient KitW-sh/W-sh mice, whose MC deficiency is caused by a defective c-Kit gene expression, to characterize the role of MCs in pregnancy success and to dissect the mechanisms underlying the modulatory functions of these cells

Methods

Results

Conclusion