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Catabolic effects of endothelial cell-derived microparticles on disc cells: Implications in intervertebral disc neovascularization and degeneration.

ABSTRACT: Neovascularization of intervertebral discs, a phenomenon considered pathological since normal discs are primarily avascular structures, occurs most frequently in annulus fibrosus (AF) of degenerated discs. Endothelial cells (ECs) are involved in this process, but the mechanism of the interaction between AF and endothelial cells is unclear. In this study, we evaluated the effects on matrix catabolic activity of AF cells by the extracellular endothelial microparticles (EMPs) and soluble protein factors (SUP fraction) produced from ECs. Passage 1 human AF cells grown in monolayer cultures were treated for 72?h with 250?µg of EMPs or SUP fraction isolated from culture of the microvascular endothelial cell line, HEMC-I. Live-cell imaging revealed uptake of EMPs by AF cells. RT-PCR analysis demonstrated increased mRNA expression of MMP-1 (50.3-fold), MMP-3 (4.5-fold) and MMP-13 (5.5-fold) in AF cell cultures treated with EMPs compared to untreated control. Western analysis also demonstrated increased MMP protein expression in EMP-treated AF cells. AF cells treated with the SUP fraction also exhibited a dramatic increase in MMP mRNA and protein expression. Increased MMP expression is primarily due to EMP or SUP stimulation of AF cells since EMPs or SUP fraction alone contained negligible amount of MMPs. Interestingly, MMP activity was elevated in AF cell cultures treated with EMPs but not with SUP. This study revealed enhanced matrix catabolism as a molecular consequence of action of ECs on AF cells via EMPs, which might be expected during neo-angiogenesis of degenerating disc. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1466-1474, 2016.

SUBMITTER: Pohl PH

PROVIDER: S-EPMC5444459 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Catabolic effects of endothelial cell-derived microparticles on disc cells: Implications in intervertebral disc neovascularization and degeneration.

Pohl Pedro H I PH Lozito Thomas P TP Cuperman Thais T Yurube Takashi T Moon Hong J HJ Ngo Kevin K Tuan Rocky S RS St Croix Claudette C Sowa Gwendolyn A GA Rodrigues Luciano M R LM Kang James D JD Vo Nam V NV

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20160614 8

Neovascularization of intervertebral discs, a phenomenon considered pathological since normal discs are primarily avascular structures, occurs most frequently in annulus fibrosus (AF) of degenerated discs. Endothelial cells (ECs) are involved in this process, but the mechanism of the interaction between AF and endothelial cells is unclear. In this study, we evaluated the effects on matrix catabolic activity of AF cells by the extracellular endothelial microparticles (EMPs) and soluble protein fa ...[more]

PMID: 27246627

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Project description:As a controllable biological process, regulated cell death (RCD) extensively participates in cellular homeostasis, organismal development, and the pathogenesis of diseases. This review addresses the research gaps by synthesising the findings on the complexity of RCD modes and their role in disc degeneration, and summarises the preclinical strategies to alleviate disc degeneration and promote disc repair by regulating RCD.BackgroundIntervertebral disc degeneration (IDD) is the major source of chronic low back pain. As a controllable biological process, regulated cell death (RCD) extensively participates in the pathogenesis of IDD. Nevertheless, the initiation and progression of RCD remain unclear, and more importantly, the interaction between different RCD modes during IDD and therapy is far from well understood.MethodsLiterature search was performed using "regulated cell death AND intervertebral disc degeneration" in PubMed, Embase, and Web of Science. Meanwhile, relevant findings have been reviewed and quoted.ResultsIn this review, we discuss the inducing factors of IDD, various modes of RCD in intervertebral disc, the interactions between different RCD modes, as well as the obstacles to achieve disc regeneration. Meanwhile, the research gaps and perspective in studies that targeting RCD are also presented.ConclusionIncreasing evidence demonstrated the presence of different RCD modes in intervertebral disc during the progression of IDD. RCD in the resident disc cells is probably induced by the multiple factors such as abnormal mechanical loading, nutritional imbalance, inflammation microenvironment, circadian rhythm changes, withdraw of hormones, and other biomechanical factors. A better understanding of the fundamental mechanisms and the interactions between different RCD modes might contribute to the rescuing of disc degeneration and development of promising therapeutics.Translational potential statementThe Translational potential of this article. This review aims to demonstrate a better understanding of the fundamental mechanisms governing RCD, which might contribute to the rescuing of disc degeneration and to the development of promising therapeutics in a clinical setting.

Project description:Purpose To determine the repeatability of magnetic resonance (MR) elastography-derived shear stiffness measurements of the intervertebral disc (IVD) taken throughout the day and their relationship with IVD degeneration and subject age. Materials and Methods In a cross-sectional study, in vivo lumbar MR elastography was performed once in the morning and once in the afternoon in 47 subjects without current low back pain (IVDs = 230; age range, 20-71 years) after obtaining written consent under approval of the institutional review board. The Pfirrmann degeneration grade and MR elastography-derived shear stiffness of the nucleus pulposus and annulus fibrosus regions of all lumbar IVDs were assessed by means of principal frequency analysis. One-way analysis of variance, paired t tests, concordance and Bland-Altman tests, and Pearson correlations were used to evaluate degeneration, diurnal changes, repeatability, and age effects, respectively. Results There were no significant differences between morning and afternoon shear stiffness across all levels and there was very good technical repeatability between the morning and afternoon imaging results for both nucleus pulposus (R = 0.92) and annulus fibrosus (R = 0.83) regions. There was a significant increase in both nucleus pulposus and annulus fibrosus MR elastography-derived shear stiffness with increasing Pfirrmann degeneration grade (nucleus pulposus grade 1, 12.5 kPa ± 1.3; grade 5, 16.5 kPa ± 2.1; annulus fibrosus grade 1, 90.4 kPa ± 9.3; grade 5, 120.1 kPa ± 15.4), and there were weak correlations between shear stiffness and age across all levels (R ? 0.32). Conclusion Our results demonstrate that MR elastography-derived shear stiffness measurements are highly repeatable, weakly correlate with age, and increase with advancing IVD degeneration. These results suggest that MR elastography-derived shear stiffness may provide an objective biomarker of the IVD degeneration process. © RSNA, 2017 Online supplemental material is available for this article.

Project description:Background:Mesenchymal stem cells (MSCs) are becoming an increasingly attractive option for regenerative therapies due to their availability, self-renewal capacity, multilineage potential, and anti-inflammatory properties. Clinical trials are underway to test the efficacy of stem cell-based therapies for the repair and regeneration of the degenerate intervertebral disc (IVD), a major cause of back pain. Recently, both bone marrow-derived MSCs and adipose-derived stem cells (ASCs) have been assessed for IVD therapy but there is a lack of knowledge surrounding the optimal cell source and the response of transplanted cells to the low oxygen, pro-inflammatory niche of the degenerate disc. Here, we investigated several neurovascular factors from donor-matched MSCs and ASCs that may potentiate the survival and persistence of sensory nerve fibers and blood vessels present within painful degenerate discs and their regulation by oxygen tensions and inflammatory cytokines. Methods:Donor-matched ASCs and MSCs were conditioned with either IL-1? or TNF? under normoxic (21% O2) or hypoxic (5% O2) conditions. Expression and secretion of several potent neurovascular factors were assessed using qRT-PCR and human magnetic Luminex assay. Results:ASCs and MSCs expressed constitutive levels of key neurotrophic factors; and stimulation of ASCs with hypoxia triggered increased secretion of both angiogenic factors (Ang-2 and VEGF-A) and neurotrophic (NGF and NT-3) compared to MSCs. We also report increased transcriptional regulation of pain-associated neuropeptides in hypoxia stimulated ASCs compared to those in normoxic conditions. We demonstrate transcriptional and translational upregulation of NGF, NT-3, Ang-1, and FGF-2 in response to cytokines in ASCs in 21% and 5% O2. Conclusions:This work highlights fundamental differences between the neurovascular secretome of donor-matched ASCs and MSCs, demonstrating the importance of cell-selection for tissue specific regeneration to reduce ectopic sensory nerve and blood vessel survival and improve patient outcomes.

Dataset Information

Catabolic effects of endothelial cell-derived microparticles on disc cells: Implications in intervertebral disc neovascularization and degeneration.

Publications

Catabolic effects of endothelial cell-derived microparticles on disc cells: Implications in intervertebral disc neovascularization and degeneration.

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