Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration

Nakazawa, Kenneth R.; Walter, Benjamin A.; Laudier, Damien M.; Krishnamoorthy, Divya; Mosley, Grace E.; Spiller, Kara L.; Iatridis, James C.

doi:10.1016/j.spinee.2017.09.018

Cited by 118 publications

(199 citation statements)

References 60 publications

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“…Thus, enhanced recruitment of macrophages via increased expression of MCP‐1 coupled with increased expression of PGE 2 could subsequently quell local tissue inflammation. However, in the context of the intact degenerate IVD relatively few blood vessels are found, and thus infiltration of exogenous macrophages is limited to only the periphery of the IVD (e.g., cartilaginous end‐plates) . Therefore, increased concentrations of MCP‐1 and PGE 2 , as observed by AD‐MSCs in the current study, may not be beneficial in the context of the degenerate IVD.…”

Section: Discussionmentioning

confidence: 68%

Differential Effector Response of Amnion‐ and Adipose‐Derived Mesenchymal Stem Cells to Inflammation; Implications for Intradiscal Therapy

Borem

Madeline

Bowman

et al. 2019

Journal Orthopaedic Research

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Intervertebral disc degeneration (IVDD) is a progressive condition marked by tissue destruction and inflammation. The therapeutic effector functions of mesenchymal stem cells (MSCs) makes them an attractive therapy for patients with IVDD. While several sources of MSCs exist, the optimal choice for use in the inflamed IVD remains a significant question. Adipose (AD)‐ and amnion (AM)‐derived MSCs have several advantages compared with other sources, however, no study has directly compared the impact of IVDD inflammation on their effector functions. Human MSCs were cultured in media with or without supplementation of interleukin‐1β (IL‐1β) and tumor necrosis factor‐α at concentrations reportedly produced by IVDD cells. MSC proliferation and production of pro‐ and anti‐inflammatory cytokines were quantified following 24 and 48 h of culture. Additionally, the osteogenic and chondrogenic potential of AD‐ and AM‐MSCs was characterized via histology and biochemical analysis following 28 days of culture. In inflammatory culture, AM‐MSCs produced significantly more anti‐inflammatory IL‐10 (14.47 ± 2.39 pg/ml; p = 0.004) and larger chondrogenic pellets (5.67 ± 0.26 mm2; p = 0.04) with greater percent area staining positively for glycosaminoglycan (82.03 ± 3.26%; p < 0.001) compared with AD‐MSCs (0.00 ± 0.00 pg/ml; 2.76 ± 0.18 mm2; 34.75 ± 2.49%; respectively). Conversely, AD‐MSCs proliferated more resulting in higher cell numbers (221,000 ± 8,021 cells; p = 0.048) and produced higher concentrations of pro‐inflammatory cytokines prostaglandin E2 (1,118.30 ± 115.56 pg/ml; p = 0.030) and IL‐1β (185.40 ± 7.63 pg/ml; p = 0.010) compared with AM‐MSCs (109,667 ± 5,696 cells; 1,291.40 ± 78.47 pg/ml; 144.10 ± 4.57 pg/ml; respectively). AD‐MSCs produced more mineralized extracellular matrix (3.34 ± 0.05 relative absorbance units [RAU]; p < 0.001) compared with AM‐MSCs (1.08 ± 0.06 RAU). Under identical inflammatory conditions, a different effector response was observed with AM‐MSCs producing more anti‐inflammatories and demonstrating enhanced chondrogenesis compared with AD‐MSCs, which produced more pro‐inflammatory cytokines and demonstrated enhanced osteogenesis. These findings may begin to help inform researchers which MSC source may be optimal for IVD regeneration. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2445–2456, 2019

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Section: Discussionmentioning

confidence: 68%

Differential Effector Response of Amnion‐ and Adipose‐Derived Mesenchymal Stem Cells to Inflammation; Implications for Intradiscal Therapy

Borem

Madeline

Bowman

et al. 2019

Journal Orthopaedic Research

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“…The presence of granulation tissue staining strongly for tumor necrosis factor‐α and advanced glycation end products has also been observed, suggesting that granulation tissue can accumulate as a result of disease as well as acute injury and that it is highly proinflammatory . Furthermore, granulation tissue in human IVDs has been further characterized to contain macrophages as well as other cells that exhibit increased proinflammatory and hypertrophic markers . The source of fibrotic cells in granulation tissue has not been identified.…”

Section: Cellular Responses To Injurymentioning

confidence: 99%

Annulus fibrosus cell phenotypes in homeostasis and injury: implications for regenerative strategies

Torre

Mroz

Bartelstein

et al. 2018

Annals of the New York Academy of Sciences

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Despite considerable efforts to develop cellular, molecular, and structural repair strategies and restore intervertebral disk function after injury, the basic biology underlying intervertebral disk healing remains poorly understood. Remarkably, little is known about the origins of cell populations residing within the annulus fibrosus, or their phenotypes, heterogeneity, and roles during healing. This review focuses on recent literature highlighting the intrinsic and extrinsic cell types of the annulus fibrosus in the context of the injury and healing environment. Spatial, morphological, functional, and transcriptional signatures of annulus fibrosus cells are reviewed, including inner and outer annulus fibrosus cells, which we propose to be referred to as annulocytes. The annulus also contains peripheral cells, interlamellar cells, and potential resident stem/progenitor cells, as well as macrophages, T lymphocytes, and mast cells following injury. Phases of annulus fibrosus healing include inflammation and recruitment of immune cells, cell proliferation, granulation tissue formation, and matrix remodeling. However, annulus fibrosus healing commonly involves limited remodeling, with granulation tissues remaining, and the development of chronic inflammatory states. Identifying annulus fibrosus cell phenotypes during health, injury, and degeneration will inform reparative regeneration strategies aimed at improving annulus fibrosus healing.

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“…Specific phenotypes of painful IVD degeneration have been introduced to help distinguish aging from painful IVD degeneration conditions, and these phenotypes often involve structural defects and pro‐inflammatory conditions . IVD injuries are known to precipitate a strong pro‐inflammatory responses with macrophage infiltration that can induce permanent alterations to IVD structure and function . Together, these findings demonstrate that IVD degeneration and pro‐inflammatory cytokines play important roles in back pain, but the relationships are complex and nonlinear.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting tumor necrosis factor‐alpha at time of induced intervertebral disc injury limits long‐term pain and degeneration in a rat model

et al. 2018

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Background: Painful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor-alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear. Purpose: Treatment strategies for low back pain require improved understanding of the complex relationships between pain, intradiscal pro-inflammatory cytokines, and structural IVD degeneration. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro-inflammatory cytokine expression. Methods: Lumbar IVDs were punctured anteriorly and injected with TNFα, anti-TNFα, or saline and compared with sham and naive controls. Hindpaw mechanical hyperalgesia was assayed weekly to determine pain over time. 6-weeks post-surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin-1 beta (IL-1β) expressions were assayed. Results: Intradiscal TNFα injection increased pain and IVD degeneration whereas anti-TNFα alleviated pain to sham level. Multivariate step-wise linear regression identified pain threshold was predicted by IVD degeneration and intradiscal TNFα expression. Pain threshold was also linearly associated with IVD height loss and IL-1β. Discussion: The significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. We concluded that TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Intradiscal TNFα inhibition following IVD injury may warrant investigation for its potential to alter downstream painful IVD degeneration processes.

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Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration

Cited by 118 publications

References 60 publications

Differential Effector Response of Amnion‐ and Adipose‐Derived Mesenchymal Stem Cells to Inflammation; Implications for Intradiscal Therapy

Differential Effector Response of Amnion‐ and Adipose‐Derived Mesenchymal Stem Cells to Inflammation; Implications for Intradiscal Therapy

Annulus fibrosus cell phenotypes in homeostasis and injury: implications for regenerative strategies

Inhibiting tumor necrosis factor‐alpha at time of induced intervertebral disc injury limits long‐term pain and degeneration in a rat model

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