Abstract
Iron overload has been reported to contribute to bone marrow mesenchymal stem cells (BMSCs) damage, but the precise mechanism still remains elusive. Icariin, a major bioactive monomer belonging to flavonoid glucosides isolated from Herba Epimedii, has been shown to protect cells from oxidative stress induced apoptosis. The aim of this study was to investigate whether icariin protected against iron overload induced dysfunction of BMSCs and its underlying mechanism. In this study, we found that iron overload induced by 100 μM ferric ammonium citrate (FAC) caused apoptosis of BMSCs, promoted cleaved caspase-3 and BAX protein expressions while inhibited Bcl-2 protein expression, which effects were significantly attenuated by icariin treatment. In addition, iron overload induced significant depolarization of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation and inhibition of mitochondrial fusion/fission, which effects were also attenuated by icariin treatment. Meanwhile, we found that iron overload induced by 100 μM FAC significantly inhibited mitochondrial fission protein FIS1 and fusion protein MFN2 expressions, inhibited DRP1 and Cytochrome C protein translocation from the cytoplasm to mitochondria. Icariin at concentration of 1 μM was able to promote mitochondrial fission protein FIS1 and fusion protein MFN2 expressions, and increase DRP1 and cytochrome C protein translocation from the cytoplasm to mitochondria. Further, osteogenic differentiation and proliferation of BMSCs was significantly inhibited by iron overload, but icariin treatment rescued both osteogenic differentiation and proliferation of BMSCs. Further studies showed that icariin attenuated iron overload induced inactivation of the PI3K/AKT/mTOR pathway and activation of the ERK1/2 and JNK pathways. In summary, our study indicated that icariin was able to protect against iron overload induced dysfunction of BMSCs. These effects were potentially related to the modulation of mitochondrial fusion and fission, activation of the PI3K/AKT/mTOR pathway and inhibition of ERK1/2 and JNK pathways.
Highlights
Bone marrow mesenchymal stem cells (BMSCs) are well known for the ability to self-renewal and a latent ability to differentiate into cell types such as osteoblasts, adipocytes, myoblasts, and chondrocytes (Caplan, 1991; Ye et al, 2012)
We found that 10 μM. FAC (100 μM) ferric ammonium citrate (FAC) dramatically increased the apoptosis of BMSCs compared to control groups (Figures 1E,F)
We found that 1 μM icariin has the most significant effects in preventing BMSCs from FAC induced apoptosis (Figures 1E,F)
Summary
Bone marrow mesenchymal stem cells (BMSCs) are well known for the ability to self-renewal and a latent ability to differentiate into cell types such as osteoblasts, adipocytes, myoblasts, and chondrocytes (Caplan, 1991; Ye et al, 2012). The osteogenic differentiation of BMSCs is regulated by the well-known TGFβ/Smad and BMP signaling pathway, Wnt/β-catenin signaling pathway (Liu et al, 2014; Zhang et al, 2016). Some transcriptional factors such as Osterix and Runx have been proven to play important roles in regulating osteogenic differentiation of BMSCs (da Silva et al, 2018). Investigations have shown that in osteoporosis there is an increase in the adipocytes content, BMSCs obtained from the osteoporotic postmenopausal women are characterized by increased adipogenic potential (Rodriguez et al, 2009)
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