Abstract
Mesenchymal stem cells (MSCs) constitute a promising therapy for spinal cord injury (SCI) because they can provide a favorable environment for the regrowth of neurons by inhibiting receptor-regulated Smads (R-Smads) expression in endogenous neural stem cells (NSCs). However, their mechanism of action and effect on the expression of inhibitory Smads (I-Smads) remain unclear. Herein, we demonstrated that extracellular vesicles (EVs) from MSCs were able to upregulate the Smad 6 expression by carrying TGF-β, and the Smad 6 knockdown in NSCs partially weakened the bone marrow MSC (BMSC)-EV-induced effect on neural differentiation. We found that the expression of Smad 6 did not reduced owing to the TGF-β type I receptor kinase inhibitor, SB 431,542, treatment in the acute phase of injury in rats with SCI, thereby indicating that the Smad 6 expression was not only mediated by TGF-β, but also by the inflammatory factors and bone morphogenetic proteins (BMPs) as well. However, in the later phase of SCI, the Smad 6 expression decreased by the addition of SB 431,542, suggesting that TGF-β plays a key role in the mediation of Smad 6 expression in this phase. In addition, immunohistochemistry staining; hematoxylin–eosin staining; and the Basso, Beattie, and Bresnahan (BBB) scores revealed that the early inhibition of TGF-β did not increase neuron regrowth. However, this inhibition increased the cavity and the caspase-3 expression at 24 h post-injury, leading to a worse functional outcome. Conversely, the later treatment with the TGF-β inhibitor promoted the regrowth of neurons around the cavity, resulting in a better neurological outcome. Together, these results indicate that Smad 6 acts as a feedback regulator to prevent the over-differentiation of NSCs to astrocytes and that BMSC-EVs can upregulate Smad 6 expression by carrying TGF-β.Graphical abstract
Highlights
Spinal cord injury (SCI) is often caused by primary mechanical injury to the spinal cord, followed by a series of molecular and cellular interactions
To determine whether bone marrow mesenchymal stem cells (BMSCs)-extracellular vesicles (EVs) were able to regulate the expression of inhibitory Smads (I-Smads) following SCI, we first examined the expression of Smad 6 in neural stem cells (NSCs) after adding BMSC-EVs
We added either the NF-κB or BMP4 inhibitor to NSCs, which did not reduce the expression of Smad 6, while the addition of SB 431,542 significantly reduced Smad 6 expression in NSCs cultured with BMSC-EVs, and either IL-6 or BMP4 (Fig. 8A, B). These results indicated that relatively low doses of IL-6 or BMP4 could be nearly completely inhibited by the BMSC-EVs, and as the low doses of IL-6 or BMP4 had a weaker effect on the upregulation of Smad 6 expression than transforming growth factor β (TGF-β) did, the addition of BMSCEVs was still able to upregulate Smad 6 expression in such a manner that IL-6 and BMP4-related signaling pathways were abolished (Fig. 8D, E)
Summary
Spinal cord injury (SCI) is often caused by primary mechanical injury to the spinal cord, followed by a series of molecular and cellular interactions. It results in necrosis, degeneration, and the demyelination of axons, as well as neuronal apoptosis, which results in the permanent impairment of neurological functions [1, 2]. In the early phase of injury, endogenous neural stem cells (eNSCs) are spontaneously activated and migrate into the injured cores [3]. These activated eNSCs have long been thought to assist in self-recovery by replacing lost nerve cells [4, 5]. Glial scars, which consist mainly of astrocytes, have proven to be advantageous
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
