Mesenchymal stem cells in the treatment of spinal cord injury: Mechanisms, current advances and future challenges

Abstract

Spinal cord injury (SCI) has considerable impact on patient physical, mental, and financial health. Secondary SCI is associated with inflammation, vascular destruction, and subsequent permanent damage to the nervous system. Mesenchymal stem cells (MSCs) have anti-inflammatory properties, promoting vascular regeneration and the release neuro-nutrients, and are a promising strategy for the treatment of SCI. Preclinical studies have shown that MSCs promote sensory and motor function recovery in rats. In clinical trials, MSCs have been reported to improve the American Spinal Injury Association (ASIA) sensory and motor scores. However, the effectiveness of MSCs in treating patients with SCI remains controversial. MSCs promote tumorigenesis and ensuring the survival of MSCs in the hostile environment of SCI is challenging. In this article we examine the evidence on the pathophysiological changes occurring after SCI. We then review the underlying mechanisms of MSCs in the treatment of SCI and summarize the potential application of MSCs in clinical practice. Finally, we highlight the challenges surrounding the use of MSCs in the treatment of SCI and discuss future applications.

Keywords: axon regeneration; inflammatory factors; macrophages; mesenchymal stem cells; microglia; spinal cord injury.

Figure 1

MSCs in anti-inflammatory signaling pathways in SCI. MSCs reduce oxygen partial pressure at the site of injury through the IGF-1-Foxo3 signaling pathway.MSCs reduce NLRP3 expression through the P38 MAPK-MK2 pathway and MAPK-NF-κB pathway. MSCs bind to TLR on the surface of macrophages/microglia via Keap1, thereby reducing IL-6 and TNF-α expression by NF-κB; MSCs reduce neuropathic inflammation through the Notch-STAT3 pathway, which is beneficial for SCI repair.

Figure 2

MSCs promote nerve regenerative signaling pathways in SCI. MSCs promote tubulin expression through the MEK-EPR signaling pathway; MSCs inhibit TGF-β to produce glial scarring; MSCs inhibit neurocyte autophagy via the Lin12-Notch pathway; MSCs promote axon regeneration through Wnt/β-catenin; MSCs induce neuronal cell differentiation via the PI3K-mTOR pathway. MSCs induce neural regeneration via the IGF-1-Foxo3 signaling pathway.