Mast cells rescue implantation defects caused by c-kit deficiency

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.

Adaptive Immune Responses During Pregnancy

“…Gal-1 secreted by MCs positively influences spiral artery formation and thus placentation, which finally allows the normal growth and development of the fetus within the uterus. 58 Another molecule influencing pregnancy at various checkpoints is the heme-degrading enzyme heme oxygenase-1 (HO-1). HO-1-deficient females were initially reported as sterile after observing that no progeny could be obtained after mating Hmox1 À/À females with Hmox1 À/À males.…”

In vivo visualization of uterine mast cells by two-photon microscopy

“…Not only do they contribute to innate and adaptive immune responses (Galli et al 2005, St John & Abraham 2013, but also they are directly involved in non-immunological processes including tissue remodeling and angiogenesis (Varayoud et al 2004, Bosquiazzo et al 2007, Theoharides et al 2010. Their effects are mainly mediated by granule-stored mediators such as metalloproteases, MC-specific proteases, tissue plasminogen activator (tPA), vascular endothelial growth factor (VEGF), transforming growth factor b (TGFb) (Galli et al 2005) and galectin 1 (Gal1, Woidacki et al 2013) that are released upon activation. We have recently reported that MCs migrate from the periphery to the uterus responding to hormonal fluctuations (Jensen et al 2010).…”

“…In a mouse model, Kit (c-Kit) deficiency, which is associated with a lack of MCs including uterine MCs (uMCs), was related to impaired implantation and placentation that negatively influenced fetal growth (Woidacki et al 2013). We found these effects to be mediated by Gal1 as bone marrow-derived MCs (BMMCs) from WT mice but not from Lgals1 (Gal1)-deficient mice could rescue the impaired reproductive phenotype (Woidacki et al 2013). The in vivo behavior of MCs at the fetal-maternal interface is, however, largely unknown.…”

“…The in vivo behavior of MCs at the fetal-maternal interface is, however, largely unknown. As there were some controversial reports on the role of MCs in pregnancy (Salamonsen et al 1996, Varayoud et al 2004, Menzies et al 2012, Woidacki et al 2013, it is of vital importance to localize uMCs at the fetal-maternal interface and to later dissect their behavior and interaction with other cells live.…”

“…Additionally, for rodents, a third population is described. These cells show characteristics of both mucosal and connective tissue-type MCs (Schwartz & Huff 1998, Michaloudi & Papadopoulos 1999, Woidacki et al 2013. Unfortunately, to the best of our knowledge, no model is currently available in which both types of MCs can be visualized in vivo.…”