Abstract
Umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are accessible, available in abundance, and have been shown to be a promising source that can regenerate cartilage in patients with osteoarthritis or other orthopedic diseases. Recently, a three-dimensional (3D) cell culture system was developed to mimic the naive tissue microenvironment. However, the efficacy of cells generated from the 3D spheroid culture system has not yet been elucidated. In the present study, we demonstrate the changes in superoxide dismutase 2 (SOD2) gene expression, an indicator of oxidative stress, on 3D spheroid MSCs. Moreover, siRNA transfection and neutralizing antibody investigations were performed to confirm the function of SOD2 and E-cadherin. Overall, we found that SOD2 siRNA transfection in the spheroid form of MSCs increases the expression of apoptotic genes and decreases the clearance of mitochondrial reactive oxygen species (ROS). As a result, we confirm that 3D spheroid formation increases E-cadherin and SOD2 expression, ultimately regulating the phosphoinositide 3-kinase (PI3K/pAkt/pNrf2 and pERK/pNrf2 signaling pathway. Additionally, we show that SOD2 expression on 3D spheroid MSCs affects the regeneration rates of destructive cartilage in an osteoarthritic model. We postulate that the impact of SOD2 expression on 3D spheroid MSCs reduces oxidative stress and apoptosis, and also promotes cartilage regeneration.
Highlights
Mesenchymal stems cell (MSCs), which are multipotent progenitor cells, can be isolated from adult bone marrow or other prenatal tissues
We propose that our 3D spheroid MSC culture system, containing aggregated cells tightly adhering to each other, can maintain intracellular functions that are similar to physiological conditions in vivo. 3D spheroid formation of MSCs transfected with siRNA superoxide dismutase 2 (SOD2) increased the expression of apoptotic related genes, caspase-3, poly (ADP-ribose) polymerase (PARP), and Bcl-2-associated X protein (BAX)
Having observed the association of enhanced SOD2 expression in 3D spheroid MSCs, we explored the influence of SOD2 in regeneration of cartilage in an monosodium iodoacetate (MIA)-induced OA rat model
Summary
Mesenchymal stems cell (MSCs), which are multipotent progenitor cells, can be isolated from adult bone marrow or other prenatal tissues. These promising cell sources have been previously shown to regenerate several tissues types, such as neurons, bone, and cartilage, regardless of origin [1,2]. Osteoarthritis is the main cause of joint pain and stiffness that results from the breakdown of cartilage tissue and underlying bone in joints. Surgeries such as joint replacement or osteotomy are necessary; they incur high costs [6]. The symptoms, namely joint swelling and difficulty of movement, develop over many years [7,8].
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