Neuroprotective Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells From Different Donors on Spinal Cord Injury in Mice

Abstract

Spinal cord injury (SCI) is caused by an external force, leading to severe dysfunction of the limbs below the injured segment. The inflammatory response plays a vital role in the prognosis of SCI. Human umbilical cord mesenchymal stem cell (hUCMSC) transplantation can promote repair of SCI by reducing the inflammatory response. We previously showed that hUCMSCs from 32 donors had different inhibitory abilities on BV2 cell proliferation. In this study, three experimental groups were established, and the mice were injected with different lines of hUCMSCs. Hind limb motor function, hematoxylin-eosin (H&E) staining, immunohistochemistry, Western blot (WB), qualitative real-time polymerase chain reaction (qRT-PCR), and RNA sequencing and correlation analysis were used to investigate the effects of hUCMSC transplantation on SCI mice and the underlying mechanisms. The results showed that the therapeutic effects of the three hUCMSC lines were positively correlated with their inhibitory abilities of BV2 cell proliferation rates in vitro. The MSC_A line had a better therapeutic effect on improving the hind limb motor function and greater effect on reducing the expression of glial fibrillary acidic protein (Gfap) and ionized calcium binding adaptor molecule 1 (Iba1) and increasing the expression of neuronal nuclei (NeuN). Differentially expressed genes including Zbtb16, Per3, and Hif3a were probably the key genes involved in the protective mechanism by MSC_A after nerve injury. qRT-PCR results further verified that Zbtb16, Per3, and Hif3a expressions reduced by SCI could be reversed by MSC_A application. These results suggest that the effect of hUCMSCs transplantation on acute SCI depends on their inhibitory abilities to inflammation reaction after nerve injury, which may help to shape future use of hUCMSCs combined with improving the effectiveness of clinical transformation.

Application of Human Umbilical Cord Mesenchymal Stem Cells in Rat Spinal Cord Injury Model

“…The neuroprotective effect of HUC-MSCs on SCI has been widely recognized, especially by inhibiting inflammatory response. 22,23 Levels of TGF-β secreted by the activated immune cells were increased during the inflammatory response. Zhou et al 24 found that IL-10 has a direct nutritional impact on spinal cord neurons: the Il-10 receptor that activates neurons can provide nutritional support for overcoming glutamate neurotoxicity in vitro.…”

Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases

“…In different subacute SCI mouse models, injection of human UC-MSCs into the center of the injury area decreased the local levels of several proinflammatory cytokines such as TNF-α, IFN-γ, IL-6, and IL-7, in addition to promoting the transition of macrophages to the M2 type, attenuating the local inflammatory response and resulting in tissue repair and motor-function recovery (Bao et al, 2018 ; Wu et al, 2020 ). Differences in the ability to inhibit the inflammatory response between human UC-MSCs from different donors are determinants of their effectiveness in the recovery of mice after SCI (Zhu et al, 2022 ). Intrathecal transplantation of human UC-MSCs in rats with subacute SCI promoted regeneration and remyelination, as well as reduced astrogliosis, decreased cavity and glial scar formation, and supported functional recovery (Yang et al, 2020 ; Cao et al, 2022 ).…”

Bridging the gap of axonal regeneration in the central nervous system: A state of the art review on central axonal regeneration

“…Post-translational tubulin modifications are relevant for axonal regeneration as it regulates cytoskeleton dynamics. A variety of post-translational modifications were described to occur following SCI, such as tyrosination, acetylation, and phosphorylation ( Zhu et al, 2022 ). Axon injury induces a gradient of tubulin deacetylation, reducing stable microtubules in proximity of the injury site, an effect that is necessary for growth cone dynamics and axon regeneration, and specific to peripheral neurons, failing to occur in central neurons.…”

“…α-Tubulin deacetylation in PNS axons is initiated by calcium influx at the site of injury, and requires protein kinase C (PKC)-mediated activation of the histone deacetylase 5 (HDAC5) ( Cho and Cavalli, 2012 ). Such a reduction in microtubule acetylation does not occur in the CNS, suggesting that tubulin modifications that accompany microtubule stability negatively impact the capacity of the axon to regenerate ( Zhu et al, 2022 ). In fact, HDAC5 knockdown and inhibition restricts growth cone dynamics and regeneration of dorsal root ganglion (DRG) neurons both in vitro and in vivo and in CGNs, whereas HDAC5 overexpression had the opposite effect ( Rivieccio et al, 2009 ; Gaub et al, 2010 ; Cho and Cavalli, 2012 ).…”

“…Accordingly, a popular preclinical strategy for altering the microtubule system toward axonal regeneration has been to stabilize microtubules by increasing microtubule acetylation and other tubulin modifications ( Zhu et al, 2022 ). Microtubule-stabilizing drugs, such as taxol and epothilones have shown to have a positive impact in the regenerative capacity of injured adult CNS axons, by reducing the inhibitory fibrotic lesion scar and enhancing the capacity of axons to grow ( Ertürk et al, 2007 ; Ruschel et al, 2015 ; Ruschel and Bradke, 2018 ; Sandner et al, 2018 ).…”