Potential roles for the kisspeptin/kisspeptin receptor system in implantation and placentation

Abstract

Background: Initially identified as suppressors of metastasis in various types of cancer, kisspeptins are a family of neuropeptides that are key regulators of the mammalian reproductive axis. Accumulating evidence has shown that kisspeptin is able to control both the pulsatile and surge GnRH release, playing fundamental roles in female reproduction, which include the secretion of gonadotropins, puberty onset, brain sex differentiation, ovulation and the metabolic regulation of fertility. Furthermore, recent studies have demonstrated the involvement of the kisspeptin system in the processes of implantation and placentation. This review summarizes the current knowledge of the pathophysiological role and utility of these local placental regulatory factors as potential biomarkers during the early human gestation.

Objective and rationale: A successful pregnancy, from the initiation of embryo implantation to parturition, is a complex process that requires the orchestration of a series of events. This review aims to concisely summarize what is known about the role of the kisspeptin system in implantation, placentation, early human pregnancy and pregnancy-related disorders, and to develop strategies for predicting, diagnosing and treating these abnormalities.

Search methods: Using the PubMed and Google Scholar databases, we performed comprehensive literature searches in the English language describing the advancement of kisspeptins and the kisspeptin receptor (KISS1R) in implantation, placentation and early pregnancy in humans, since its initial identification in 1996 and ending in July 2018.

Outcomes: Recent studies have shown the coordinated spatial and temporal expression patterns of kisspeptins and KISS1R during human pregnancy. The experimental data gathered recently suggest putative roles of kisspeptin signaling in the regulation of trophoblast invasion, embryo implantation, placentation and early pregnancy. Dysregulation of the kisspeptin system may negatively affect the processes of implantation as well as placentation. Clinical studies indicate that the circulating levels of kisspeptins or the expression levels of kisspeptin/KISS1R in the placental tissues may be used as potential diagnostic markers for women with miscarriage and gestational trophoblastic neoplasia.

Wider implications: Comprehensive research on the pathophysiological role of the kisspeptin/KISS1R system in implantation and placentation will provide a dynamic and powerful approach to understanding the processes of early pregnancy, with potential applications in observational and analytic screening as well as the diagnosis, prognosis and treatment of implantation failure and early pregnancy-related disorders.

Keywords: KISS1R; early pregnancy; gestational trophoblastic neoplasia; implantation; kisspeptin; miscarriage; placentation.

Figure 1

The major structure of kisspeptins in humans, the peptides encoded by the KISS1 gene. All kisspeptins are the products generated by the cleavage of a common precursor named prepro-kisspeptin. The prepro-kisspeptin is a 145-amino acid peptide, which is further cleaved into the following four peptides with lower molecular weights: KP-54, KP-14, KP-13 and KP-10. All kisspeptins contain the RF-amide motif that can bind and activate KISS1R. This figure is modified from Pinilla et al. (2012); Hu et al. (2017).

Figure 2

Kisspeptin/KISS1R signaling and potential functions at a glance. KISS1R is a seven-transmembrane domain, Gq/11-coupled receptor. Upon binding of kisspeptin, the intracellular portion of KISS1R phosphorylates Gq/11. The α-subunit of Gq/11 activates PLC, which subsequently cleaves PIP2 into IP3 and DAG. IP3 promotes intracellular Ca²⁺ release from the endoplasmic reticulum, while DAG activates a signaling cascade by phosphorylating PKC. PKC activation induces the phosphorylation of ERK1/2 and p38. In addition, activation of KISS1R recruits arrestin-1 and -2, which down-regulates and up-regulates phosphorylated ERK1/2 levels, respectively. The activation of KISS1R can also stimulate the phosphorylation of PI3K/Akt, and suppress the phosphorylation of PI3K/Akt by blocking the prometastatic chemokine receptor CXCR4 (the receptor for the chemokine stromal cell-derived factor 1) signaling. These signals act on downstream pathways, including NF-κB, MMPs and VEGF, to promote hormone secretion and apoptosis and inhibit metastasis, migration, angiogenesis and proliferation. DAG, diacylglycerol; ERK1/2, extracellular signal-regulated kinase; IP3, inositol 1,4,5-triphosphate; PI3K, phosphatidylinositol-3-kinase; MMPs, matrix metalloproteinases; NF-κB, nuclear factor κB; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; VEGF, vascular endothelial growth factor.

Figure 3

Flow diagram demonstrating the different cell lineage pathways involved in murine and human trophoblast differentiation and function. KISS1 is mainly expressed in cells of the villous pathway, while KISS1R is expressed in cells of both the villous and extravillous pathways. Modified from James et al. (2012).

Figure 4

A schematic diagram showing how the kisspeptin/KISS1R system regulates the processes of embryo implantation and placentation. Kisspeptin promotes embryo adhesion to the endometrium and stroma decidualization by up-regulating cell adhesion molecules and LIF, respectively. Kisspeptin inhibits trophoblast invasion and angiogenesis via the down-regulation of MMPs and VEGFA, respectively. VEGFA, vascular endothelial growth factor A; MMPs, matrix metalloproteinases; LIF, leukemia inhibitory factor.