Abstract
BackgroundMesenchymal stem cells (MSCs) have become a promising treatment for spinal cord injury (SCI) due to the fact that they provide a favorable environment. Treatment using MSCs results in a better neurological functional improvement through the promotion of nerve cell regeneration and the modulation of inflammation. Many studies have highlighted that the beneficial effects of MSCs are more likely associated with their secreted factors. However, the identity of the factor that plays a key role in the MSC-induced neurological functional recovery following SCI as well as its molecular mechanism still remains unclear.MethodsA conditioned medium (collected from the MSCs) and hepatocyte growth factor (HGF) were used to test the effects on the differentiation of neural stem cells (NSCS) in the presence of BMP4 with or without a c-Met antibody. In SCI rats, Western blot, ELISA, immunohistochemistry, and hematoxylin-eosin staining were used to investigate the biological effects of MSC-conditioned medium and HGF on nerve cell regeneration and inflammation with or without the pre-treatment using a c-Met antibody. In addition, the possible molecular mechanism (cross-talk between HGF/c-Met and the BMP/Smad 1/5/8 signaling pathway) was also detected by Western blot both in vivo and in vitro.ResultsThe conditioned medium from bone marrow-derived MSCs (BMSCs) was able to promote the NSC differentiation into neurons in vitro and the neurite outgrowth in the scar boundary of SCI rats by inhibiting the BMP/Smad signaling pathway as well as reduces the secondary damage through the modulation of the inflammatory process. The supplementation of HGF showed similar biological effects to those of BMSC-CM, whereas a functional blocking of the c-Met antibody or HGF knockdown in BMSCs significantly reversed the functional improvement mediated by the BMSC-CM.ConclusionsThe MSC-associated biological effects on the recovery of SCI rats mainly depend on the secretion of HGF.
Highlights
A spinal cord injury (SCI) is a fatal neurological damage, often causing an incomplete or complete loss of neural function [1, 2]
bone marrow-derived MSCs (BMSCs)-conditioned medium (CM) counter-effects of BMP4 on Neural stem cells (NSCs) Based on previous studies, Bone morphogenetic proteins (BMPs) were considered to be one of the critical factors promoting the differentiation of NSCs into astrocytes following spinal cord injury [18, 21, 22]
To determine whether the BMSC-CM was able to negate the effects of BMP4 on NSCs, we first assayed the effects of BMP4 on NSCs
Summary
A spinal cord injury (SCI) is a fatal neurological damage, often causing an incomplete or complete loss of neural function [1, 2]. The injured lesion is not able to produce a sufficient amount of anti-inflammatory cytokines in comparison to the marked increased in pro-inflammatory cytokines, leading to an inflammatory cytokine imbalance [6, 7]. This imbalance results during over-reactive inflammation, which causes the loss of surviving nerve cells and poor functional outcomes. The identity of the factor that plays a key role in the MSC-induced neurological functional recovery following SCI as well as its molecular mechanism still remains unclear
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