Bone marrow mesenchymal stem cells (BMSCs) improved functional recovery of spinal cord injury partly by promoting axonal regeneration
Graphical abstract
Abstract graphy, potential therapeutic promise of BMSCs on spinal cord injury. BMSCs could improve neuron regeneration by vascular repair, differentiating into neurons, inhibiting neuron apoptosis and necrosis, anti-inflammatory effects, improving sensitivity to glutamate ligands, neurotrophic active effect, reducing the glial scar.
Introduction
Spinal cord injury (SCI) is a severe disease with a variety of pathogenic factors which lead to spinal cord structure and functional injury, finally resulting in the loss of voluntary movements and sensation below the damaged plane (Tran and Silver, 2015). SCI is also the enormous economic burden on the patients, their families, and the society. About 40–80 persons are suffering from spinal cord injury per million people every year in the world (Noonan et al., 2012). Epidemiological data showed that about three million people are living with traumatic SCI worldwide, and nearly 133–226 thousand incident cases were reported, globally in 2007 (Lee et al., 2014). The age of the SCI has increased from 28.7 years old in the 1970s to 42.2 during 2010–2014, which is noted for both sexes, all races, and all etiologies except acts of violence according to the survey of the United States (Chen et al., 2016). Current treatments for SCI are insufficient and cause severe side effects while the new therapy for SCI is urgently needed.
SCI has two major injury mechanisms including the primary and the secondary injury. Primary injury occurs quickly within a short time after injury (generally considered within 4 h), of which the effect is irreversible and the deformation and tearing of tissues caused by external forces directly. Then the neuronal axis is destroyed, starting from the damaged part to both sides. In a word, the primary injury could be divided into neural destroying and vascular structures injury (Sinescu et al., 2010). The secondary injury takes place in a few minutes to several days after the primary injury. It accompanied with a series of intracellular metabolisms, such as inflammatory cell infiltration, neurons apoptosis, and necrosis. The secondary injury caused by the tissue damage is even more severe compared with the primary injury (Fig. 1). After SCI, the blood-brain barrier (BBB) is disrupted, and an influx of inflammatory cells occurs, with the increased expression of matrix metalloproteinases (MMPs). Then the inflammatory cells, along with other resident microglia, produced generating toxic molecules, such as free oxygen, nitrosyl–derived radicals, MMPs, cytokines, and chemokines (Sinescu et al., 2010). It induced cell and neuron death more in the tissues surrounding the original injury site in turn (Wright et al., 2011). Subsequently, macrophages would clear the tissue debris at the lesion site, leading to the scar tissues filling with fluid-filled cysts. It could inhibit the regenerative sprouting of the lesion spinal cord by secreting the scar-associated neurite growth-inhibitory molecules (the chondroitin sulfate proteoglycans) (Schwab, 2002). At the same time, with the role of neurotoxic excitatory amino acids, oxygen free radical formation and calcium overload, furthermore resulting in the death of neurons and other cells.
Spinal cord injury destroys the nerve conduction pathway, leading to the loss of movement and sensory function below the injured plane, resulting in severe dysfunction and badly influenced the patient's life and psychology. Therefore, the ultimate goal of SCI treatment is to reconstruct the injured spinal cord and improve the motor, sensory and autonomic function (Lu, 2017). However, Nogo, a molecule expressed by myelin, the glial scars, and chondroitin sulfate proteoglycans (CSPGs) would be obstacles for the adult central nervous system (CNS) regeneration (Young, 2014). Adult central nervous system (CNS) regeneration needs neurons to survive in the damaged site, initiate new axonal growth, and ultimately establish new synaptic connections (Hao and Collins, 2017). There are five steps of the axon regeneration: retrograde signal transduction from the site of injury, entry of the signal into the nucleus, transcription and translation of the molecules essential for axon growth, axon growth itself, and synapse formation (Sakamoto and Kadomatsu, 2017). Therefore, the two main obstacles of the axonal regeneration for spinal cord repair are the diminished growth capacity of the adult neurons and the presence of inhibitory molecules in the scar at the lesion (Wu et al., 2015). An ideal treatment for spinal cord injury is to improve the two obstacles. Stem cell transplantation therapy represents an attractive alternative, especially for the treatment of patients suffering from SCI. The previous studies reported that bone marrow mesenchymal stem cells (BMSCs) secreted trophic factors that improved axonal regeneration and reduced cavity formation. Therefore, BMSCs could promote the intrinsic ability of the spinal cord to regeneration (Ide et al., 2016).
Section snippets
BMSCs and SCI
BMSCs are the most abundant cells in bone marrow, existing in the body connective tissue and organ stroma. BMSCs are still hematopoietic and functional support cells in the bone marrow. The characters of low immunogenic–no unique surface markers help BMSCs easily elude the immune surveillance (Zhang et al., 2015). Many studies have shown that BMSCs play an important role in the regulation of hematopoietic stem and progenitor cells (HSPCs) by different signal pathways, for example, the
BMSCs and axonal regeneration
BMSCs held therapeutic promise on axon regeneration after SCI. Nakano injected BMSCs three times per week into the cerebrospinal fluid (CSF)to examine the function of BMSCs for sub-acute (1–2 weeks post-injury) and chronic (4 weeks post-injury) SCI. After transplantation, numerous axons were found extending longitudinally in the astrocyte-devoid areas, where were no astrocytes or oligodendrocytes initially. The axons extended through the spinal cord lesion and filled with extracellular
Conclusion
It is still a challenging issue to control the apoptosis, glial scar formation and axonal degeneration of SCI. The stem cells, especially for BMSCs based therapies may provide a therapeutic potential for the injured spinal cord by promoting axonal regeneration and repair. The combinational strategies of BMSCs treatment for SCI, such as gene modified BMSCs, could focus on increasing intrinsic axon growth potential while simultaneously reducing the extrinsic inhibitors of axon extension. However,
Conflict of interest
The authors declare that they have no conflict of interest.
The work has not been published previously (except in the form of an abstract or as part of a published lecture or academic thesis or as an electronic preprint).
Acknowledgments
The study is supported by Zhejiang Provincial Natural Science Foundation of China under Grant No. LY15H090002 and the National Natural Science Foundation of China, Grant No. 81272158. The authors would like to thank Miss Yiyang Yue (Harvard University, [email protected]) for critical proofreading of the manuscript and language correction.
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Contribution: Manuscript preparation.
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Contribution: Manuscript review.
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Contribution: Study design, Manuscript preparation.