Degeneration of intervertebral discs (IVDs) is associated with back pain and elevated levels of inflammatory cells. It has been hypothesised that discogenic pain is a direct result of vascular and neural ingrowth along annulus fissures, which may expose the avascular nucleus pulposus (NP) to the systemic circulation and induce an autoimmune reaction. In this study, we confirmed our previous observation of antibodies in human degenerated and posttraumatic IVDs cultured in vitro. We hypothesised that the presence of antibodies was due to an autoimmune reaction against specific proteins of the disc. Furthermore we identified antigens which possibly trigger an autoimmune response in degenerative disc diseases. We demonstrated that degenerated and post-traumatic IVDs contain IgG antibodies against typical extracellular proteins of the disc, particularly proteins of the NP. We identified IgGs against collagen type II and aggrecan, confirming an autoimmune reaction against the normally immune privileged NP. We also found specific IgGs against collagens types I and V, but not against collagen type III. In conclusion, this study confirmed the association between disc degeneration and autoimmunity, and may open the avenue for future studies on developing prognostic, diagnostic and therapymonitoring markers for degenerative disc diseases.
BackgroundHuman bone marrow-derived mesenchymal stem cells (MSC) are adult progenitor cells with great potential for application in cell-based therapies. From a cell-based therapy perspective, there are two limitations to MSC use: (1) these therapies require large numbers of cells, and long-term expansion of MSC in vitro promotes replicative senescence; and (2) patient variability is a challenge for defining MSC quality standards for transplantation. This study aimed to determine whether low or high oxidative status of MSC correlate with changes in cell expansion and differentiation potentials.MethodsWe investigated functional aspects of mitochondria, such as cell metabolic activity indicators and expression of antioxidant enzymes. Furthermore, we tested if senescence-induced changes in oxidative status of MSC could be counteracted by methylene blue (MB), an alternative mitochondrial electron transfer known to enhance cell bioenergetics.ResultsMSC isolated from donors of the same age showed distinctive behavior in culture and were grouped as weak (low colony-forming units (CFU) and a short life in vitro) and vigorous MSC (high CFU and a long life in vitro). In comparison to weak MSC, vigorous MSC had oxidative status characterized by lower mitochondrial membrane potential, lower mitochondrial activity, and fewer reactive oxygen species production, as well as reduced mitochondrial biogenesis. Vigorous MSC had a significantly higher expansion potential compared to weak MSC, while no differences were observed during differentiation. MB treatment significantly improved expansion and differentiation potential, however only in vigorous MSC.ConclusionsTogether, these results demonstrate the importance of mitochondrial function in MSC in vitro, and that cells with low oxidative status levels are better candidates for cell-based therapies.
Protein synthesis is a tightly regulated, energy-consuming process. The control of mRNA translation into protein is fundamentally important for the fine-tuning of gene expression; additionally, precise translational control plays a critical role in many cellular processes, including development, cellular growth, proliferation, differentiation, synaptic plasticity, memory, and learning. Eukaryotic translation initiation factor 4h (Eif4h) encodes a protein involved in the process of protein synthesis, at the level of initiation phase. Its human homolog, WBSCR1, maps on 7q11.23, inside the 1.6 Mb region that is commonly deleted in patients affected by the Williams-Beuren syndrome, which is a complex neurodevelopmental disorder characterized by cardiovascular defects, cerebral dysplasias and a peculiar cognitive-behavioral profile. In this study, we generated knockout mice deficient in Eif4h. These mice displayed growth retardation with a significant reduction of body weight that began from the first week of postnatal development. Neuroanatomical profiling results generated by magnetic resonance imaging analysis revealed a smaller brain volume in null mice compared with controls as well as altered brain morphology, where anterior and posterior brain regions were differentially affected. The inactivation of Eif4h also led to a reduction in both the number and complexity of neurons. Behavioral studies revealed severe impairments of fear-related associative learning and memory formation. These alterations suggest that Eif4h might contribute to certain deficits associated with Williams-Beuren syndrome.
The level of injury is linked with biochemical alterations and limitations in physical activity among individuals with spinal cord injury (SCI), which are crucial determinants of body composition. We searched five electronic databases from inception until 22 July 2021. The pooled effect estimates were computed using random-effects models, and heterogeneity was calculated using I2 statistics and the chi-squared test. Study quality was assessed using the Newcastle–Ottawa Scale. We pooled 40 studies comprising 4872 individuals with SCI (3991 males, 825 females, and 56 sex-unknown) in addition to chronic SCI (median injury duration 12.3 y, IQR 8.03–14.8). Individuals with tetraplegia had a higher fat percentage (weighted mean difference (WMD) 1.9%, 95% CI 0.6, 3.1) and lower lean mass (WMD −3.0 kg, 95% CI −5.9, −0.2) compared to those with paraplegia. Those with tetraplegia also had higher indicators of central adiposity (WMD, visceral adipose tissue area 0.24 dm2 95% CI 0.05, 0.43 and volume 1.05 L 95% CI 0.14, 1.95), whereas body mass index was lower in individuals with tetraplegia than paraplegia (WMD −0.9 kg/mg2, 95% CI −1.4, −0.5). Sex, age, and injury characteristics were observed to be sources of heterogeneity. Thus, individuals with tetraplegia have higher fat composition compared to paraplegia. Anthropometric measures, such as body mass index, may be inaccurate in describing adiposity in SCI individuals.
Tissue engineering is a field in progressive expansion and requires constant updates in methods and devices. One of the central fields is the development of biocompatible, biodegradable, and injectable scaffolds, such as collagen microcarriers. To enhance cell attachment and produce a cost-effective cell culture solution with local stimulation of cells, basic fibroblast growth factor (bFGF) or transforming growth factor-β1 (TGF-β1) was covalently immobilized on microcarriers either by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) or riboflavin/UV (RB/UV) light-mediated cross-linking. Collagen microcarriers cross-linked with bFGF or TGF-β1 were used for expansion and chondrogenic differentiation of human mesenchymal stem cells (MSCs). Evaluation methods included cell viability test, chondrogenic marker expression (aggrecan and collagen type I and type II), histological detection of proteoglycans, and immunohistochemical analysis. Cross-linking strengthened the collagen structure of the microcarriers and reduced collagenase-mediated degradation. MSCs effectively proliferated on microcarriers cross-linked with bFGF, especially by EDC/NHS cross-linking. Chondrogenic differentiation of MSCs was induced by TGF-β1 cross-linked on microcarriers, promoting gene expression and protein accumulation of aggrecan and collagen type I and type II, as well as proteoglycans. Cross-linking by RB/UV enhanced chondrogenesis more than any other group. In addition, cross-linking reduced scaffold shrinkage exerted by MSCs during chondrogenesis, a desirable feature for microcarriers if used as tissue defect filler. In conclusion, cross-linking of bFGF or TGF-β1 to collagen microcarriers supported in vitro proliferation and chondrogenesis, respectively. If translated in vivo and in clinical practice, such approach might lead a step closer to development of a cost-effective and locally acting device for cell-based therapy.
BackgroundIndividuals with a spinal cord injury (SCI), despite specialized rehabilitation and good health care, have a reduced life expectancy. Infectious diseases, such as pneumonias, infected pressure sores and urinary tract infections (UTI) have been identified as the leading causes of mortality. We hypothesise that a premature onset of immune frailty occurs in SCI, possibly caused also by recurrent urinary tract infections.A cross sectional study was performed comparing blood and urine samples between able bodied controls (n = 84) and persons with spinal cord injury (n = 85). The results were grouped according to age (below and above 60 years). Assessed were the abundancies of immune cells, the concentration of soluble biomarkers, the in vitro functioning of lymphocytes as well as phenotypic exhaustion of T-cells in blood and urine. Further, the leucocyte telomere length and the cytomegalovirus (CMV) serological status were compared between the groups.ResultsWe observed in people with SCI lower proportions of naïve T-cells, more memory T-cells, reduced T-cell proliferation and higher CMV prevalence compared to age-matched controls. SCI participants older than 60 years had a higher prevalence of UTI compared with SCI persons younger than 60 years.ConclusionThe immune system of people with SCI shows traits of an increased immunological strain and a premature onset of immune frailty. The role of UTI in the onset of immune frailty remains to be elucidated as we did not see significantly higher abundancies of circulating UTI-bacteria specific T-cell clones in persons with SCI. We assume that any impact of UTI on the immune system might be compartmentalized and locally restricted to the urinary tract.Electronic supplementary materialThe online version of this article (10.1186/s12979-017-0103-6) contains supplementary material, which is available to authorized users.
IntroductionChronic back pain is one of the most important socioeconomic problems that affects the global population. Elevated levels of inflammatory mediators, such as cytokines, have been correlated with pain, but their role in chronic back pain remains unclear. The effectiveness of anti-inflammatory drugs seems to be limited for chronic back pain. The authors wanted to investigate the levels of inflammatory mediators in long-term medically treated patients with persistent chronic back pain.MethodsCytokine plasma levels of patients with chronic back pain (n=23), compared to pain-free healthy controls (n=30), were investigated by immunoassay. Patients with chronic back pain were exposed to long-term conservative medical therapy with physiotherapy and anti-inflammatories, also combined with antidepressants and/or muscle-relaxants.ResultsThe patients with chronic back pain expressed lower levels of the chemokines MCP1, CCL5, and CXCL6 compared to pain-free healthy controls. Significantly lower concentrations of the anti-inflammatory cytokines, interleukin (IL)-4 and granulocyte-colony stimulating factor were also found. Interestingly, levels of proinflammatory cytokines (IL-2, IL-6, IL-1β, tumor necrosis factor alpha), IL-10, granulocyte-macrophage colony-stimulating factor, and stromal cell-derived factor 1 alpha showed no significant differences between both groups.ConclusionThis decrease of inflammatory mediators in medically treated patients with chronic back pain is of unclear origin and might be either a long-term side effect of medical therapy or related to chronic pain. Further longitudinal research is necessary to elucidate the underlying cause of these findings.
ObjectiveDuring degeneration of the intervertebral disc ingrowth of blood vessels and nerves into the disc are associated with back pain. Vascular endothelial growth factors promote vasculogenesis by binding to the membrane vascular endothelial growth factor receptor 1, while shorter soluble forms of this receptor can inhibit vascularization. We hypothesized that membrane and soluble receptor forms might change between stages of intervertebral disc degeneration.ResultsExpression of soluble and membrane forms of vascular endothelial growth factor receptor 1 in human degenerated intervertebral discs and healthy bovine caudal discs was assessed by qRT-PCR and immunoblot. Comparative microarray meta-analysis across disc degeneration grades showed that membrane and soluble forms of this receptor, together with other components of classic vascularization pathways, are constitutively expressed across human disc degeneration stages. Contrary to our hypothesis, we observed that expression of the classic vascularization pathway is stable across degeneration stages and we assume that soluble vascular endothelial growth factor receptor 1 does not contribute to prevent disc degeneration. However, we observed increased expression levels of genes involved in alternative vascularization signalling pathways in severely degenerated discs, suggesting that abnormal vascularization is part of the pathological progression of disc degeneration.Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3441-3) contains supplementary material, which is available to authorized users.
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