Mitochondrial Dynamics in Placenta-Derived Mesenchymal Stem Cells Regulate the Invasion Activity of Trophoblast.

Jin Seok,Gi Jin Kim,Jung Ok Lee,Sujin Jun

doi:10.3390/ijms21228599

Abstract

Mitochondrial dynamics are involved in many cellular events, including the proliferation, differentiation, and invasion/migration of normal as well as cancerous cells. Human placenta-derived mesenchymal stem cells (PD-MSCs) were known to regulate the invasion activity of trophoblasts. However, the effects of PD-MSCs on mitochondrial function in trophoblasts are still insufficiently understood. Therefore, the objectives of this study are to analyze the factors related to mitochondrial function and investigate the correlation between trophoblast invasion and mitophagy via PD-MSC cocultivation. We assess invasion ability and mitochondrial function in invasive trophoblasts according to PD-MSC cocultivation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and extracellular flux (XF) assay. Under PD-MSCs co-cultivation, invasion activity of a trophoblast is increased via activation of the Rho signaling pathway as well as Matrix metalloproteinases (MMPs). Additionally, the expression of mitochondrial function (e.g., reactive oxygen species (ROS), calcium, and adenosine triphosphate (ATP) synthesis) in trophoblasts are increased via PD-MSCs co-cultivation. Finally, PD-MSCs regulate mitochondrial autophagy factors in invasive trophoblasts via regulating the balance between PTEN-induced putative kinase 1 (PINK1) and parkin RBR E3 ubiquitin protein ligase (PARKIN) expression. Taken together, these results demonstrate that PD-MSCs enhance the invasion ability of trophoblasts via altering mitochondrial dynamics. These results support the fundamental mechanism of trophoblast invasion via mitochondrial function and provide a new stem cell therapy for infertility.

Highlights

Successful embryo implantation requires the dynamic invasion ability of trophoblasts
The proportion of stained cells was significantly increased in the placenta-derived mesenchymal stem cells (PD-mesenchymal stem cells (MSCs)) cocultivation group compared with trophoblasts cultured alone (Figure 1B, * p < 0.05)
We confirmed that effect of PD-MSCs cocultivation in invasion ability of other trophoblastic cell lines

Summary

Introduction

Successful embryo implantation requires the dynamic invasion ability of trophoblasts. When cytotrophoblasts, which are located in the inner layer of trophoblasts, make contact, the trophoblast begins to rapidly proliferate and secrete proteolytic enzymes to break the extracellular matrix (ECM) for invasion [1,2]. There have been many reports on the mechanisms of invasion and trophoblast regulatory factors, including matrix metalloproteinases (MMPs) and the Rho family (e.g., rho-associated protein kinase 1 (ROCK1), phospho-focal adhesion kinase (p-FAK) and Rho A/B/C) [3,4]. The abnormal invasion of trophoblasts results in embryo implantation failure and abnormal placental development, resulting in obstetric diseases such as intrauterine growth retardation (IUGR) and preeclampsia [5]. Several studies are underway to improve the invasion ability of trophoblast cells

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