Abstract
The present study aimed to investigate gene expression changes related to cell cycle activation in patients with spinal cord injury (SCI) and to further evaluate the difference between the upper and lower limbs of SCI patients. Fibroblasts were obtained from the upper and lower limbs of SCI patients and healthy subjects. To investigate gene expression profiling in the fibroblasts from SCI patients compared to the healthy subjects, RNA-Seq transcriptome analysis was performed. To validate the parasympathetic effects on cell cycle activation, fibroblasts from upper or lower limbs of SCI patients were treated with the anticholinergic agents tiotropium or acetylcholine, and quantitative RT-PCR and Western blot were conducted. Cell proliferation was significantly increased in the upper limbs of SCI patients compared with the lower limbs of SCI patients and healthy subjects. The pathway and genes involved in cell cycle were identified by RNA-Seq transcriptome analysis. Expression of cell-cycle-related genes CCNB1, CCNB2, PLK1, BUB1, and CDC20 were significantly higher in the upper limbs of SCI patients compared with the lower limbs of SCI patients and healthy subjects. When the fibroblasts were treated with tiotropium the upper limbs and acetylcholine in the lower limbs, the expression of cell-cycle-related genes and cell proliferation were significantly modulated. This study provided the insight that cell proliferation and cell cycle activation were observed to be significantly increased in the upper limbs of SCI patients via the parasympathetic effect.
Highlights
Spinal cord injury (SCI) initiates several primary and secondary mechanisms causing neuronal cell death, autonomic and immune dysfunction, sustained neurological deficits, and a significantly high risk of morbidity and mortality [1,2]
In the present study, increased cell proliferation and cell cycle activation were shown in the upper limbs of paraplegic patients with SCI, suggesting that the parasympathetic nervous system affected cell proliferation and the cell cycle above the neurological level of injury rather than below it
Whereas sympathetic hyperactivity is triggered by autonomic dysreflexia, resulting in systemic vasoconstriction below the level of the spinal cord lesion [20], parasympathetic activity is induced above the level of the lesion [21,22]
Summary
Spinal cord injury (SCI) initiates several primary and secondary mechanisms causing neuronal cell death, autonomic and immune dysfunction, sustained neurological deficits, and a significantly high risk of morbidity and mortality [1,2]. Cell-cycle-related genes and proteins that are upregulated immediately following SCI are associated with induced glial scar formation and chronic inflammation [6] and induce activation of both astroglia and microglia as well as the proliferation of these cells [7,8,9]. According to those effects, functional recovery and microglia-induced inflammatory responses were found to be significantly improved following the administration of a cell-cycle-inhibiting drug in a rat model of SCI [10,11]. Activation of the cell cycle contributes to the pathophysiology of SCI [6,7,8,9,13], but inhibition of the cell cycle should be neuroprotective in SCI [10,11,12]
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