Enhanced Proliferation of Porcine Bone Marrow Mesenchymal Stem Cells Induced by Extracellular Calcium is Associated with the Activation of the Calcium-Sensing Receptor and ERK Signaling Pathway.

Jingjing Ye,Lina Wang,Xiaotong Zhu,Wei Ai,Yongliang Zhang,Ping Gao,Fenglin Zhang,Qianyun Xi,Gang Shu,Qingyan Jiang,Songbo Wang

doi:10.1155/2016/6570671

Abstract

Porcine bone marrow mesenchymal stem cells (pBMSCs) have the potential for application in regenerative medicine. This study aims to investigate the effects of extracellular calcium ([Ca2+]o) on pBMSCs proliferation and to explore the possible underlying mechanisms. The results demonstrated that 4 mM [Ca2+]o significantly promoted pBMSCs proliferation by reducing the G0/G1 phase cell percentage and by increasing the S phase cell proportion and the proliferation index of pBMSCs. Accordingly, [Ca2+]o stimulated the expression levels of proliferative genes such as cyclin A2, cyclin D1/3, cyclin E2, and PCNA and inhibited the expression of p21. In addition, [Ca2+]o resulted in a significant elevation of intracellular calcium and an increased ratio of p-ERK/ERK. However, inhibition of calcium-sensing receptor (CaSR) by its antagonist NPS2143 abolished the aforementioned effects of [Ca2+]o. Moreover, [Ca2+]o-induced promotion of pBMSCs proliferation, the changes of proliferative genes expression levels, and the activation of ERK1/2 signaling pathway were effectively blocked by U0126, a selective ERK kinase inhibitor. In conclusion, our findings provided evidence that the enhanced pBMSCs proliferation in response to [Ca2+]o was associated with the activation of CaSR and ERK1/2 signaling pathway, which may be useful for the application of pBMSCs in future clinical studies aimed at tissue regeneration and repair.

Highlights

Bone marrow mesenchymal stem cells (BMSCs) regulate hematopoietic and other stem cells niches and have multipotential capacities to differentiate toward osteocyte, chondrocyte, adipocyte, and myocyte [1], performing an important role in regenerative medicine, wound healing, and disease therapy [2]
Our results revealed that the enhanced porcine BMSCs (pBMSCs) proliferation in response to [Ca2+]o was associated with the activation of the calcium-sensing receptor (CaSR) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway
The proproliferation effects of [Ca2+]o have been reported in various cells such as rat bone marrow-derived progenitor cells [9], osteoblasts [10], preadipocytes [11], and porcine synoviumderived mesenchymal stromal cells [12]. In line with these results, we found that [Ca2+]o promoted pBMSCs proliferation in a dose-dependent manner, with the similar promotive effects observed when [Ca2+]o was greater than or equal to 4 mM

Summary

Introduction

Bone marrow mesenchymal stem cells (BMSCs) regulate hematopoietic and other stem cells niches and have multipotential capacities to differentiate toward osteocyte, chondrocyte, adipocyte, and myocyte [1], performing an important role in regenerative medicine, wound healing, and disease therapy [2]. Controlling the proliferation of pBMSCs is an attractive approach to determine the size of the pBMSCs pool and subsequently its possible influence on the maintenance of stem cell niches and multilineage differentiation potential. One of the most widely occurring second messengers, is an important cellular signaling component, which has been shown to play a pivotal role in controlling cell proliferation [6, 7]. Extracellular calcium ([Ca2+]o) modulates cell proliferation in various cells, such as myeloma cells

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