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Article ; Online: The role of the complement system in disc degeneration and Modic changes.

Heggli, Irina / Teixeira, Graciosa Q / Iatridis, James C / Neidlinger-Wilke, Cornelia / Dudli, Stefan

JOR spine

2024 Volume 7, Issue 1, Page(s) e1312

Abstract: Disc degeneration and vertebral endplate bone marrow lesions called Modic changes are prevalent spinal pathologies found in chronic low back pain patients. Their pathomechanisms are complex and not fully understood. Recent studies have revealed that ... ...

Abstract	Disc degeneration and vertebral endplate bone marrow lesions called Modic changes are prevalent spinal pathologies found in chronic low back pain patients. Their pathomechanisms are complex and not fully understood. Recent studies have revealed that complement system proteins and interactors are dysregulated in disc degeneration and Modic changes. The complement system is part of the innate immune system and plays a critical role in tissue homeostasis. However, its dysregulation has also been associated with various pathological conditions such as rheumatoid arthritis and osteoarthritis. Here, we review the evidence for the involvement of the complement system in intervertebral disc degeneration and Modic changes. We found that only a handful of studies reported on complement factors in Modic changes and disc degeneration. Therefore, the level of evidence for the involvement of the complement system is currently low. Nevertheless, the complement system is tightly intertwined with processes known to occur during disc degeneration and Modic changes, such as increased cell death, autoantibody production, bacterial defense processes, neutrophil activation, and osteoclast formation, indicating a contribution of the complement system to these spinal pathologies. Based on these mechanisms, we propose a model how the complement system could contribute to the vicious cycle of tissue damage and chronic inflammation in disc degeneration and Modic changes. With this review, we aim to highlight a currently understudied but potentially important inflammatory pathomechanism of disc degeneration and Modic changes that may be a novel therapeutic target.
Language	English
Publishing date	2024-02-02
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2572-1143
ISSN (online)	2572-1143
DOI	10.1002/jsp2.1312
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Impacts of priming on distinct immunosuppressive mechanisms of mesenchymal stromal cells under translationally relevant conditions.

Herger, Nick / Heggli, Irina / Mengis, Tamara / Devan, Jan / Arpesella, Leonardo / Brunner, Florian / Distler, Oliver / Dudli, Stefan

Stem cell research & therapy

2024 Volume 15, Issue 1, Page(s) 65

Abstract: Background: The multimodal properties of mesenchymal stromal cells (MSCs), particularly their ability to modulate immune responses is of high interest in translational research. Pro-inflammatory, hypoxic, and 3D culture priming are promising and often ... ...

Abstract	Background: The multimodal properties of mesenchymal stromal cells (MSCs), particularly their ability to modulate immune responses is of high interest in translational research. Pro-inflammatory, hypoxic, and 3D culture priming are promising and often used strategies to improve the immunosuppressive potency of MSCs, but the underlying mechanisms are not well understood. Therefore, the aims of this study were (i) to compare the effects of pro-inflammatory, hypoxic, and 3D culture priming on the in vitro immunosuppressive potential of MSCs, (ii) to assess if immunosuppressive priming effects are temporally preserved under standard and translationally relevant culture conditions, and (iii) to investigate if the three priming strategies engage the same immunosuppressive mechanisms. Methods: Functional in vitro T cell suppressive potency measurements were conducted to assess the impact of pro-inflammatory, hypoxic, and 3D culture priming on the immunosuppressive potential of human bone marrow-derived MSCs. Primed MSCs were either cultured under standard cell culture conditions or translationally relevant culture conditions, and their transcriptomic adaptations were monitored over time. Next-generation sequencing was performed to assess if different priming strategies activate distinct immunosuppressive mechanisms. Results: (i) Pro-inflammatory, hypoxic, and 3D culture priming induced profound transcriptomic changes in MSCs resulting in a significantly enhanced T cell suppressive potential of pro-inflammatory and 3D culture primed MSCs. (ii) Priming effects rapidly faded under standard cell culture conditions but were partially preserved under translationally relevant conditions. Interestingly, continuous 3D culture priming of MSCs maintained the immunosuppressive potency of MSCs. (iii) Next-generation sequencing revealed that priming strategy-specific differentially expressed genes are involved in the T cell suppressive capacity of MSCs, indicating that different priming strategies engage distinct immunosuppressive mechanisms. Conclusion: Priming can be a useful approach to improve the immunosuppressive potency of MSCs. However, future studies involving primed MSCs should carefully consider the significant impact of translationally relevant conditions on the preservation of priming effects. Continuous 3D culture could act as a functionalized formulation, supporting the administration of MSC spheroids for a sustainably improved immunosuppressive potency.
MeSH term(s)	Humans ; Mesenchymal Stem Cells ; Cell Culture Techniques ; Gene Expression Profiling ; High-Throughput Nucleotide Sequencing ; Hypoxia ; Immunosuppressive Agents
Chemical Substances	Immunosuppressive Agents
Language	English
Publishing date	2024-03-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-024-03677-5
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Article ; Online: The role of the bone in complex regional pain syndrome 1-A systematic review.

Kollmann, Gil / Wertli, Maria M / Dudli, Stefan / Distler, Oliver / Brunner, Florian

European journal of pain (London, England)

2023 Volume 27, Issue 7, Page(s) 794–804

Abstract: Objective: The aim of this systematic review was to appraise and analyse the knowledge on bone-related biochemical and histological biomarkers in complex regional pain syndrome 1 (CRPS 1).: Database: A total of 7 studies were included in the analysis ...

Abstract	Objective: The aim of this systematic review was to appraise and analyse the knowledge on bone-related biochemical and histological biomarkers in complex regional pain syndrome 1 (CRPS 1). Database: A total of 7 studies were included in the analysis (biochemical analyses n = 3, animal study n = 1, histological examination n = 3). Results: Two studies were classified as having a low risk of bias and five studies with a moderate risk of bias. Biochemical analysis indicated an increased bone turnover with increased bone resorption (elevated urinary levels of deoxypyridinoline) and bone formation (increased serum levels of calcitonin, osteoprotegerin and alkaline phosphatase). The animal study reported an increased signalling of proinflammatory tumour necrosis factor 4 weeks postfracture, which did, however, not contribute to local bone loss. Histological examination from biopsies revealed thinning and resorption of cortical bone, rarefication and reduction in trabecular bone and vascular modification in the bone marrow in acute CRPS 1, and replacement of the bone marrow by dystrophic vessels in chronic CRPS 1. Conclusion: The limited data reviewed revealed certain potential bone-related biomarkers in CRPS. Biomarkers hold the potential to identify patients who may benefit from treatments that influence bone turnover. Thus, this review identifies important areas for future research in CRPS1 patients.
MeSH term(s)	Animals ; Reflex Sympathetic Dystrophy ; Biomarkers ; Complex Regional Pain Syndromes/pathology
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-04-08
Publishing country	England
Document type	Systematic Review ; Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1390424-3
ISSN	1532-2149 ; 1090-3801
ISSN (online)	1532-2149
ISSN	1090-3801
DOI	10.1002/ejp.2116
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Book ; Online ; Thesis: Post-traumatic intervertebral disc degeneration

Dudli, Stefan

an in vitro study on the etiopathogenesis

2013

Author's details	by Stefan Dudli
Language	German
Size	Online-Ressource (Online-Ressource (1 Band)), Ill
Publisher	ETH
Publishing place	Zürich
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. 21207--Zürich, 2120
Database	Former special subject collection: coastal and deep sea fishing

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Article ; Online: Intervertebral disc microbiome in Modic changes: Lack of result replication underscores the need for a consensus in low-biomass microbiome analysis.

Mengis, Tamara / Zajac, Natalia / Bernhard, Laura / Heggli, Irina / Herger, Nick / Devan, Jan / Marcus, Roy / Brunner, Florian / Laux, Christoph / Farshad, Mazda / Distler, Oliver / Dudli, Stefan

JOR spine

2024 Volume 7, Issue 2, Page(s) e1330

Abstract: Introduction: The emerging field of the disc microbiome challenges traditional views of disc sterility, which opens new avenues for novel clinical insights. However, the lack of methodological consensus in disc microbiome studies introduces ... ...

Abstract	Introduction: The emerging field of the disc microbiome challenges traditional views of disc sterility, which opens new avenues for novel clinical insights. However, the lack of methodological consensus in disc microbiome studies introduces discrepancies. The aims of this study were to (1) compare the disc microbiome of non-Modic (nonMC), Modic type 1 change (MC1), and MC2 discs to findings from prior disc microbiome studies, and (2) investigate if discrepancies to prior studies can be explained with bioinformatic variations. Methods: Sequencing of 16S rRNA in 70 discs (24 nonMC, 25 MC1, and 21 MC2) for microbiome profiling. The experimental setup included buffer contamination controls and was performed under aseptic conditions. Methodology and results were contrasted with previous disc microbiome studies. Critical bioinformatic steps that were different in our best-practice approach and previous disc microbiome studies (taxonomic lineage assignment, prevalence cut-off) were varied and their effect on results were compared. Results: There was limited overlap of results with a previous study on MC disc microbiome. No bacterial genera were shared using the same bioinformatic parameters. Taxonomic lineage assignment using "amplicon sequencing variants" was more sensitive and detected 48 genera compared to 22 with "operational taxonomic units" (previous study). Increasing filter cut-off from 4% to 50% (previous study) reduced genera from 48 to 4 genera. Despite these differences, both studies observed dysbiosis with an increased abundance of gram-negative bacteria in MC discs as well as a lower beta-diversity. Conclusion: There is dysbiosis in MC discs. Bioinformatic parameters impact results yet cannot explain the different findings from this and a previous study. Therefore, discrepancies are likely caused by different sample preparations or true biologic differences. Harmonized protocols are required to advance understanding of the disc microbiome and its clinical implications.
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ISSN	2572-1143
ISSN (online)	2572-1143
DOI	10.1002/jsp2.1330
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Book ; Online: Post-traumatic intervertebral disc degeneration, an in vitro study on the etiopathogenesis

Dudli, Stefan

2013

Abstract: Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. ... ...

Abstract	Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. 21207
Keywords	BANDSCHEIBENSCHÄDEN (PATHOLOGIE) ; DEGENERATIVE ERSCHEINUNGEN (HISTOPATHOLOGIE) ; KRANKHEITSURSACHEN (MEDIZIN) ; PATHOGENESE + PATHOPHYSIOLOGIE (MEDIZIN) ; KNOCHENBRÜCHE (MEDIZIN)
Language	German
Publisher	Zürich, ETH
Publishing country	ch
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Thesis ; Online: Post-traumatic intervertebral disc degeneration

Dudli, Stefan

An in vitro study on the etiopathogenesis

2013

Keywords	PATHOGENESIS + PATHOPHYSIOLOGY (MEDICINE) ; DEGENERATION (HISTOPATHOLOGY) ; INTERVERTEBRAL DISCS (PATHOLOGY) ; KNOCHENBRÜCHE (MEDIZIN) ; FRACTURE OF BONES (MEDICINE) ; PATHOGENESE + PATHOPHYSIOLOGIE (MEDIZIN) ; BANDSCHEIBENSCHÄDEN (PATHOLOGIE) ; DEGENERATIVE ERSCHEINUNGEN (HISTOPATHOLOGIE) ; AETIOLOGY (MEDICINE) ; KRANKHEITSURSACHEN (MEDIZIN) ; info:eu-repo/classification/ddc/610 ; Medical sciences ; medicine
Language	English
Publisher	ETH
Publishing country	ch
Document type	Thesis ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Should Degenerated Intervertebral Discs of Patients with Modic Type 1 Changes Be Treated with Mesenchymal Stem Cells?

Herger, Nick / Bermudez-Lekerika, Paola / Farshad, Mazda / Albers, Christoph E / Distler, Oliver / Gantenbein, Benjamin / Dudli, Stefan

International journal of molecular sciences

2022 Volume 23, Issue 5

Abstract: Low back pain (LBP) has been among the leading causes of disability for the past 30 years. This highlights the need for improvement in LBP management. Many clinical trials focus on developing treatments against degenerative disc disease (DDD). The ... ...

Abstract	Low back pain (LBP) has been among the leading causes of disability for the past 30 years. This highlights the need for improvement in LBP management. Many clinical trials focus on developing treatments against degenerative disc disease (DDD). The multifactorial etiology of DDD and associated risk factors lead to a heterogeneous patient population. It comes as no surprise that the outcomes of clinical trials on intradiscal mesenchymal stem cell (MSC) injections for patients with DDD are inconsistent. Intradiscal MSC injections have demonstrated substantial pain relief and significant disability-related improvements, yet they have failed to regenerate the intervertebral disc (IVD). Increasing evidence suggests that the positive outcomes in clinical trials might be attributed to the immunomodulatory potential of MSCs rather than to their regenerative properties. Therefore, patient stratification for inflammatory DDD phenotypes may (i) better serve the mechanisms of action of MSCs and (ii) increase the treatment effect. Modic type 1 changes-pathologic inflammatory, fibrotic changes in the vertebral bone marrow-are frequently observed adjacent to degenerated IVDs in chronic LBP patients and represent a clinically distinct subpopulation of patients with DDD. This review discusses whether degenerated IVDs of patients with Modic type 1 changes should be treated with an intradiscal MSC injection.
MeSH term(s)	Bone Marrow/metabolism ; Humans ; Intervertebral Disc/metabolism ; Intervertebral Disc Degeneration/metabolism ; Low Back Pain/etiology ; Low Back Pain/therapy ; Mesenchymal Stem Cells/metabolism
Language	English
Publishing date	2022-02-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23052721
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Article: Bone marrow stromal cells in Modic type 1 changes promote neurite outgrowth.

Mengis, Tamara / Herger, Nick / Heggli, Irina / Devan, Jan / Spirig, José Miguel / Laux, Christoph J / Brunner, Florian / Farshad, Mazda / Distler, Oliver / Dudli, Stefan

Frontiers in cell and developmental biology

2023 Volume 11, Page(s) 1286280

Abstract: The pain in patients with Modic type 1 changes (MC1) is often due to vertebral body endplate pain, which is linked to abnormal neurite outgrowth in the vertebral body and adjacent endplate. The aim of this study was to understand the role of MC1 bone ... ...

Abstract	The pain in patients with Modic type 1 changes (MC1) is often due to vertebral body endplate pain, which is linked to abnormal neurite outgrowth in the vertebral body and adjacent endplate. The aim of this study was to understand the role of MC1 bone marrow stromal cells (BMSCs) in neurite outgrowth. BMSCs can produce neurotrophic factors, which have been shown to be pro-fibrotic in MC1, and expand in the perivascular space where sensory vertebral nerves are located. The study involved the exploration of the BMSC transcriptome in MC1, co-culture of MC1 BMSCs with the neuroblastoma cell line SH-SY5Y, analysis of supernatant cytokines, and analysis of gene expression changes in co-cultured SH-SY5Y. Transcriptomic analysis revealed upregulated brain-derived neurotrophic factor (BDNF) signaling-related pathways. Co-cultures of MC1 BMSCs with SH-SY5Y cells resulted in increased neurite sprouting compared to co-cultures with control BMSCs. The concentration of BDNF and other cytokines supporting neuron growth was increased in MC1 vs. control BMSC co-culture supernatants. Taken together, these findings show that MC1 BMSCs provide strong pro-neurotrophic cues to nearby neurons and could be a relevant disease-modifying treatment target.
Language	English
Publishing date	2023-10-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2023.1286280
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Machine Learning-Based Classification of 38 Years of Spine-Related Literature Into 100 Research Topics.

Sing, David C / Metz, Lionel N / Dudli, Stefan

Spine

2017 Volume 42, Issue 11, Page(s) 863–870

Abstract: Study design: Retrospective review.: Objective: To identify the top 100 spine research topics.: Summary of background data: Recent advances in "machine learning," or computers learning without explicit instructions, have yielded broad ... ...

Abstract	Study design: Retrospective review. Objective: To identify the top 100 spine research topics. Summary of background data: Recent advances in "machine learning," or computers learning without explicit instructions, have yielded broad technological advances. Topic modeling algorithms can be applied to large volumes of text to discover quantifiable themes and trends. Methods: Abstracts were extracted from the National Library of Medicine PubMed database from five prominent peer-reviewed spine journals (European Spine Journal [ESJ], The Spine Journal [SpineJ], Spine, Journal of Spinal Disorders and Techniques [JSDT], Journal of Neurosurgery: Spine [JNS]). Each abstract was entered into a latent Dirichlet allocation model specified to discover 100 topics, resulting in each abstract being assigned a probability of belonging in a topic. Topics were named using the five most frequently appearing terms within that topic. Significance of increasing ("hot") or decreasing ("cold") topic popularity over time was evaluated with simple linear regression. Results: From 1978 to 2015, 25,805 spine-related research articles were extracted and classified into 100 topics. Top two most published topics included "clinical, surgeons, guidelines, information, care" (n = 496 articles) and "pain, back, low, treatment, chronic" (424). Top two hot trends included "disc, cervical, replacement, level, arthroplasty" (+0.05%/yr, P < 0.001), and "minimally, invasive, approach, technique" (+0.05%/yr, P < 0.001). By journal, the most published topics were ESJ-"operative, surgery, postoperative, underwent, preoperative"; SpineJ-"clinical, surgeons, guidelines, information, care"; Spine-"pain, back, low, treatment, chronic"; JNS- "tumor, lesions, rare, present, diagnosis"; JSDT-"cervical, anterior, plate, fusion, ACDF." Conclusion: Topics discovered through latent Dirichlet allocation modeling represent unbiased meaningful themes relevant to spine care. Topic dynamics can provide historical context and direction for future research for aspiring investigators and trainees interested in spine careers. Please explore https://singdc.shinyapps.io/spinetopics. Level of evidence: N A.
MeSH term(s)	Humans ; Machine Learning ; Orthopedics/classification ; Orthopedics/trends ; Publications/classification ; Publications/trends ; Research/classification ; Research/trends
Language	English
Publishing date	2017-01-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	752024-4
ISSN	1528-1159 ; 0362-2436
ISSN (online)	1528-1159
ISSN	0362-2436
DOI	10.1097/BRS.0000000000002079
Database	MEDical Literature Analysis and Retrieval System OnLINE

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