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Yang S, Soheilmoghaddam F, Pivonka P, Li J, Rudd S, Yeo T, Tu J, Zhu Y, Cooper-White JJ. Engineering Intervertebral Disc Regeneration: Biomaterials, Cell Sources and Animal Models. Cell Prolif 2025:e70046. [PMID: 40389238 DOI: 10.1111/cpr.70046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 03/28/2025] [Accepted: 04/15/2025] [Indexed: 05/21/2025] Open
Abstract
Intervertebral disc (IVD) degeneration is an age-related problem triggering chronic spinal issues, such as low back pain and IVD herniation. Standard surgical treatment for such spinal issues is the removal of the degenerated or herniated IVD and fusion of adjacent vertebrae to stabilise the joint and locally decompress the spinal cord and/or nerve roots to relieve pain. However, a key challenge of current surgical strategies is the increasing risk of adjacent segment degeneration due to the disruption of native biomechanics of the functional spinal unit, dominated by the loss of the IVD. In the past two decades, research has focused on developing a number of bioengineering approaches to repair and regenerate the IVD; in particular, tissue engineering of the IVD, using bioscaffolds and stem cells represents a promising area. This review highlights the current tissue engineering approaches utilising biomaterials, animal models and cell sources for IVD regeneration and discusses future opportunities.
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Affiliation(s)
- Sidong Yang
- Tissue Engineering and Microfluidics Laboratory (TE&M), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
- Department of Orthopaedic Surgery, Hebei Medical University Third Hospital, Shijiazhuang, China
- Hebei International Joint Research Centre for Spine Diseases, Shijiazhuang, China
| | - Farhad Soheilmoghaddam
- Tissue Engineering and Microfluidics Laboratory (TE&M), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
| | - Peter Pivonka
- School of Mechanical Medical & Process Engineering, Queensland University of Technology, Brisbane City, Queensland, Australia
| | - Joan Li
- Faculty of Medicine, The University of Queensland, St Lucia, Queensland, Australia
| | - Samuel Rudd
- School of Chemical Engineering, The University of Queensland, St Lucia, Queensland, Australia
| | - Trifanny Yeo
- Tissue Engineering and Microfluidics Laboratory (TE&M), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
- Institute for Health Innovation & Technology (iHealthtech), National University of Singapore, Singapore, Singapore
| | - Ji Tu
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Yibo Zhu
- School of Chemical Engineering, The University of Queensland, St Lucia, Queensland, Australia
| | - Justin J Cooper-White
- Tissue Engineering and Microfluidics Laboratory (TE&M), Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, Queensland, Australia
- School of Chemical Engineering, The University of Queensland, St Lucia, Queensland, Australia
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Cheng X, Wu L. Injectable smart-blended hydrogel cross-linked with Vanillin to accelerate differentiation of intervertebral disc-derived stem cells (IVDSCs) for promoting degenerative nucleolus pulposus in a rat model. Inflammopharmacology 2024:10.1007/s10787-024-01554-4. [PMID: 39207637 DOI: 10.1007/s10787-024-01554-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 08/09/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND The nucleus pulposus (NP) degradation is a primary factor in intervertebral disk degeneration (IVD) and a major contributor to low back pain. Intervertebral disk-derived stem cell (IVDSC) therapy presents a promising solution, yet identifying suitable cell carriers for NP transplantation remains challenging. The present study investigates this issue by developing smart injectable hydrogels incorporating vanillin (V) and hyaluronic acid (HA) encapsulated with IVDSCs to facilitate IVD regeneration. MATERIALS AND METHODS The hydrogel was cross linked by carbodiimide-succinimide (EDC-NHS) method. Enhanced mechanical properties were achieved by integrating collagen and HA into the hydrogel. The rheological analysis revealed the pre-gel viscoelastic and shear-thinning characteristics. RESULTS In vitro, cell viability was maintained up to 500 µg/mL, with a high proliferation rate observed over 14 days. The hydrogels supported multilineage differentiation, as confirmed by osteogenic and adipogenic induction. Anti-inflammatory effects were demonstrated by reduced cytokine release (TNF-α, IL-6, IL-1β) after 24 h of treatment. Gene expression studies indicated elevated levels of chondrocyte markers (Acan, Sox9, Col2). In vivo, hydrogel injection into the NP was monitored via X-ray imaging, showing a significant increase in disk height index (DHI%) after 8 weeks, alongside improved histologic scores. Biomechanical testing revealed that the hydrogel effectively mimicked NP properties, enhancing compressive stiffness and reducing neutral zone stiffness post-denucleation. CONCLUSION The results suggest that the synthesized VCHA-NP hydrogel can be used as an alternative to NPs, offering a promising path for IVD regeneration.
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Affiliation(s)
- Xiangyang Cheng
- Department of Orthopedics, Minhang Hospital, Fudan University, No.170, Xin Song Road, Shanghai, 201199, China
| | - Liang Wu
- Department of Orthopedics, Minhang Hospital, Fudan University, No.170, Xin Song Road, Shanghai, 201199, China.
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Zheng SK, Zhao XK, Wu H, He DW, Xiong L, Cheng XG. Oxidative stress-induced EGR1 upregulation promotes NR4A3-mediated nucleus pulposus cells apoptosis in intervertebral disc degeneration. Aging (Albany NY) 2024; 16:10216-10238. [PMID: 38943627 PMCID: PMC11236312 DOI: 10.18632/aging.205920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/16/2024] [Indexed: 07/01/2024]
Abstract
This study aimed to reveal the specific role of early growth response protein 1 (EGR1) and nuclear receptor 4A3 (NR4A3) in nucleus pulposus cells (NPCs) and the related molecular mechanism and to identify a new strategy for treating intervertebral disc degeneration (IVDD). Bioinformatics analysis was used to explore and predict IVDD-related differentially expressed genes, and chromatin immunoprecipitation sequencing (ChIP-seq) revealed NR4A3 as the EGR1 target gene. An in vitro NPC model induced by tributyl hydrogen peroxide (TBHP) and a rat model induced by fibrous ring acupuncture were established. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical staining, immunofluorescence staining, and flow cytometry were used to detect the effects of EGR1 and NR4A3 knockdown and overexpression on NPC apoptosis and the expression of extracellular matrix (ECM) anabolism-related proteins. Interactions between EGR1 and NR4A3 were analyzed via ChIP-qPCR and dual luciferase assays. EGR1 and NR4A3 expression levels were significantly higher in severely degenerated discs (SDD) than in mildly degenerated discs (MDD), indicating that these genes are important risk factors in IVDD progression. ChIP-seq and RNA-seq revealed NR4A3 as a direct downstream target of EGR1, and this finding was verified by ChIP-qPCR and dual luciferase reporter experiments. Remarkably, the rescue experiments showed that EGR1 promotes TBHP-induced NPC apoptosis and impairs ECM anabolism, dependent on elevated NR4A3 expression. In summary, the EGR1-NR4A3 axis mediates the progression of NPC apoptosis and ECM impairment and is a potential therapeutic target in IVDD.
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Affiliation(s)
- Si-Kuan Zheng
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xiao-Kun Zhao
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Hui Wu
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Ding-Wen He
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Long Xiong
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xi-Gao Cheng
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, Jiangxi 330006, China
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Shnayder NA, Ashhotov AV, Trefilova VV, Novitsky MA, Medvedev GV, Petrova MM, Narodova EA, Kaskaeva DS, Chumakova GA, Garganeeva NP, Lareva NV, Al-Zamil M, Asadullin AR, Nasyrova RF. High-Tech Methods of Cytokine Imbalance Correction in Intervertebral Disc Degeneration. Int J Mol Sci 2023; 24:13333. [PMID: 37686139 PMCID: PMC10487844 DOI: 10.3390/ijms241713333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/24/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
An important mechanism for the development of intervertebral disc degeneration (IDD) is an imbalance between anti-inflammatory and pro-inflammatory cytokines. Therapeutic and non-therapeutic approaches for cytokine imbalance correction in IDD either do not give the expected result, or give a short period of time. This explains the relevance of high-tech medical care, which is part of specialized care and includes the use of new resource-intensive methods of treatment with proven effectiveness. The aim of the review is to update knowledge about new high-tech methods based on cytokine imbalance correction in IDD. It demonstrates promise of new approaches to IDD management in patients resistant to previously used therapies, including: cell therapy (stem cell implantation, implantation of autologous cultured cells, and tissue engineering); genetic technologies (gene modifications, microRNA, and molecular inducers of IDD); technologies for influencing the inflammatory cascade in intervertebral discs mediated by abnormal activation of inflammasomes; senolytics; exosomal therapy; and other factors (hypoxia-induced factors; lysyl oxidase; corticostatin; etc.).
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Affiliation(s)
- Natalia A. Shnayder
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (A.V.A.); (V.V.T.)
- Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (M.M.P.); (E.A.N.); (D.S.K.)
| | - Azamat V. Ashhotov
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (A.V.A.); (V.V.T.)
| | - Vera V. Trefilova
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (A.V.A.); (V.V.T.)
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia;
| | - Maxim A. Novitsky
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia;
| | - German V. Medvedev
- R.R. Vreden National Medical Research Center for Traumatology and Orthopedics, 195427 Saint-Petersburg, Russia;
| | - Marina M. Petrova
- Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (M.M.P.); (E.A.N.); (D.S.K.)
| | - Ekaterina A. Narodova
- Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (M.M.P.); (E.A.N.); (D.S.K.)
| | - Daria S. Kaskaeva
- Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (M.M.P.); (E.A.N.); (D.S.K.)
| | - Galina A. Chumakova
- Department of Therapy and General Medical Practice with a Course of Postgraduate Professional Education, Altai State Medical University, 656038 Barnaul, Russia;
| | - Natalia P. Garganeeva
- Department of General Medical Practice and Outpatient Therapy, Siberian State Medical University, 634050 Tomsk, Russia;
| | - Natalia V. Lareva
- Department of Therapy of Faculty of Postgraduate Education, Chita State Medical Academy, 672000 Chita, Russia;
| | - Mustafa Al-Zamil
- Department of Physiotherapy, Faculty of Continuing Medical Education, Peoples’ Friendship University of Russia, 117198 Moscow, Russia;
| | - Azat R. Asadullin
- Department of Psychiatry and Addiction, Bashkir State Medical University, 450008 Ufa, Russia;
| | - Regina F. Nasyrova
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia; (A.V.A.); (V.V.T.)
- International Centre for Education and Research in Neuropsychiatry, Samara State Medical University, 443016 Samara, Russia
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Ohnishi T, Homan K, Fukushima A, Ukeba D, Iwasaki N, Sudo H. A Review: Methodologies to Promote the Differentiation of Mesenchymal Stem Cells for the Regeneration of Intervertebral Disc Cells Following Intervertebral Disc Degeneration. Cells 2023; 12:2161. [PMID: 37681893 PMCID: PMC10486900 DOI: 10.3390/cells12172161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 08/24/2023] [Accepted: 08/26/2023] [Indexed: 09/09/2023] Open
Abstract
Intervertebral disc (IVD) degeneration (IDD), a highly prevalent pathological condition worldwide, is widely associated with back pain. Treatments available compensate for the impaired function of the degenerated IVD but typically have incomplete resolutions because of their adverse complications. Therefore, fundamental regenerative treatments need exploration. Mesenchymal stem cell (MSC) therapy has been recognized as a mainstream research objective by the World Health Organization and was consequently studied by various research groups. Implanted MSCs exert anti-inflammatory, anti-apoptotic, and anti-pyroptotic effects and promote extracellular component production, as well as differentiation into IVD cells themselves. Hence, the ultimate goal of MSC therapy is to recover IVD cells and consequently regenerate the extracellular matrix of degenerated IVDs. Notably, in addition to MSC implantation, healthy nucleus pulposus (NP) cells (NPCs) have been implanted to regenerate NP, which is currently undergoing clinical trials. NPC-derived exosomes have been investigated for their ability to differentiate MSCs from NPC-like phenotypes. A stable and economical source of IVD cells may include allogeneic MSCs from the cell bank for differentiation into IVD cells. Therefore, multiple alternative therapeutic options should be considered if a refined protocol for the differentiation of MSCs into IVD cells is established. In this study, we comprehensively reviewed the molecules, scaffolds, and environmental factors that facilitate the differentiation of MSCs into IVD cells for regenerative therapies for IDD.
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Affiliation(s)
- Takashi Ohnishi
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; (T.O.); (K.H.); (A.F.); (N.I.)
| | - Kentaro Homan
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; (T.O.); (K.H.); (A.F.); (N.I.)
| | - Akira Fukushima
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; (T.O.); (K.H.); (A.F.); (N.I.)
| | - Daisuke Ukeba
- Department of Orthopedic Surgery, Hokkaido University Hospital, Sapporo 060-8648, Japan;
| | - Norimasa Iwasaki
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; (T.O.); (K.H.); (A.F.); (N.I.)
| | - Hideki Sudo
- Department of Advanced Medicine for Spine and Spinal Cord Disorders, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
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Kasamkattil J, Gryadunova A, Schmid R, Gay-Dujak MHP, Dasen B, Hilpert M, Pelttari K, Martin I, Schären S, Barbero A, Krupkova O, Mehrkens A. Human 3D nucleus pulposus microtissue model to evaluate the potential of pre-conditioned nasal chondrocytes for the repair of degenerated intervertebral disc. Front Bioeng Biotechnol 2023; 11:1119009. [PMID: 36865027 PMCID: PMC9971624 DOI: 10.3389/fbioe.2023.1119009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
Introduction: An in vitro model that appropriately recapitulates the degenerative disc disease (DDD) microenvironment is needed to explore clinically relevant cell-based therapeutic strategies for early-stage degenerative disc disease. We developed an advanced 3D nucleus pulposus (NP) microtissues (µT) model generated with cells isolated from human degenerating NP tissue (Pfirrmann grade: 2-3), which were exposed to hypoxia, low glucose, acidity and low-grade inflammation. This model was then used to test the performance of nasal chondrocytes (NC) suspension or spheroids (NCS) after pre-conditioning with drugs known to exert anti-inflammatory or anabolic activities. Methods: NPµTs were formed by i) spheroids generated with NP cells (NPS) alone or in combination with ii) NCS or iii) NC suspension and cultured in healthy or degenerative disc disease condition. Anti-inflammatory and anabolic drugs (amiloride, celecoxib, metformin, IL-1Ra, GDF-5) were used for pre-conditioning of NC/NCS. The effects of pre-conditioning were tested in 2D, 3D, and degenerative NPµT model. Histological, biochemical, and gene expression analysis were performed to assess matrix content (glycosaminoglycans, type I and II collagen), production and release of inflammatory/catabolic factors (IL-6, IL-8, MMP-3, MMP-13) and cell viability (cleaved caspase 3). Results: The degenerative NPµT contained less glycosaminoglycans, collagens, and released higher levels of IL-8 compared to the healthy NPµT. In the degenerative NPµT, NCS performed superior compared to NC cell suspension but still showed lower viability. Among the different compounds tested, only IL-1Ra pre-conditioning inhibited the expression of inflammatory/catabolic mediators and promoted glycosaminoglycan accumulation in NC/NCS in DDD microenvironment. In degenerative NPµT model, preconditioning of NCS with IL-1Ra also provided superior anti-inflammatory/catabolic activity compared to non-preconditioned NCS. Conclusion: The degenerative NPµT model is suitable to study the responses of therapeutic cells to microenvironment mimicking early-stage degenerative disc disease. In particular, we showed that NC in spheroidal organization as compared to NC cell suspension exhibited superior regenerative performance and that IL-1Ra pre-conditioning of NCS could further improve their ability to counteract inflammation/catabolism and support new matrix production within harsh degenerative disc disease microenvironment. Studies in an orthotopic in vivo model are necessary to assess the clinical relevance of our findings in the context of IVD repair.
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Affiliation(s)
- Jesil Kasamkattil
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Anna Gryadunova
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland,World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Raphael Schmid
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Max Hans Peter Gay-Dujak
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland,Department of Biomedicine, Institute of Anatomy, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Boris Dasen
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Morgane Hilpert
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Karoliina Pelttari
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Ivan Martin
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Stefan Schären
- Spine Surgery, University Hospital Basel, Basel, Switzerland
| | - Andrea Barbero
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Olga Krupkova
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland,*Correspondence: Olga Krupkova,
| | - Arne Mehrkens
- Spine Surgery, University Hospital Basel, Basel, Switzerland,Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
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Li L, Sheng K, Mannarino M, Jarzem P, Cherif H, Haglund L. o-Vanillin Modulates Cell Phenotype and Extracellular Vesicles of Human Mesenchymal Stem Cells and Intervertebral Disc Cells. Cells 2022; 11:cells11223589. [PMID: 36429018 PMCID: PMC9688801 DOI: 10.3390/cells11223589] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/02/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Human mesenchymal stem cell (hMSC) and extracellular vesicle (EV) therapy is a promising treatment for discogenic low back pain (LBP). Although promising, major obstacles remain to be overcome. Cellular senescence reduces self-renewal and multipotent potentials, and the senescence-associated secretory phenotype creates an inflammatory environment negatively affecting tissue homeostasis. Reducing senescence could therefore improve regenerative approaches. Ortho-Vanillin (o-Vanillin) has senolytic activity and anti-inflammatory properties and could be a valuable supplement to MSC and EV therapy. Here, we used direct co-culture experiments to evaluate proteoglycan synthesis, inflammatory mediators, and senescent cells in the presence or absence of o-Vanillin. EV release and transfer between hMSCs and intervertebral disc cells (DCs) was examined, and the effect on hMSC differentiation and DC phenotype was evaluated in the presence and absence of o-Vanillin. This study demonstrates that o-Vanillin affects cell communication, enhances hMSC differentiation and improves DC phenotype. Co-cultures of DCs and hMSCs resulted in increased proteoglycan synthesis, a decreased number of senescent cells and decreased release of the cytokines IL6 and 8. Effects that were further enhanced by o-Vanillin. o-Vanillin profoundly increased EV release and/or uptake by hMSCs and DCs. DC markers were significantly upregulated in both cell types in response to conditioned media of o-Vanillin treated donor cells. Collectively, this study demonstrates that o-Vanillin affects hMSC and DC crosstalk and suggests that combining hMSCs and senolytic compounds may improve the outcome of cell supplementation and EV therapy for LBP.
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Affiliation(s)
- Li Li
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
| | - Kai Sheng
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
- Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada
| | - Matthew Mannarino
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
| | - Peter Jarzem
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
| | - Hosni Cherif
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
| | - Lisbet Haglund
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
- Shriners Hospital for Children, Montreal, QC H4A 0A9, Canada
- Correspondence: ; Tel.: +1-514-934-1934 (ext. 35380)
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Regenerative Medicine: Pharmacological Considerations and Clinical Role in Pain Management. Curr Pain Headache Rep 2022; 26:751-765. [PMID: 36074255 PMCID: PMC9453705 DOI: 10.1007/s11916-022-01078-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/27/2022] [Indexed: 11/17/2022]
Abstract
Purpose of Review Low back pain affects at least 80% of individuals at some point in their lifetime and is the fifth most common reason for physician visits in the USA. Treatment of an acute episode of LBP generally includes rest, activity modification, physical therapy, NSAIDs, and patient education. Recent Findings A small percentage of patients will develop chronic pain lasting > 6 months duration. Platelet-rich plasma (PRP) is one of the main pillars of regenerative medicine, as its release of bioactive proteins supports the aim of RM of restoring the anatomical function in degenerative conditions. Mesenchymal stem cells (MSCs) are multipotent stem cells, multipotent progenitor cells, or marrow stromal cells found in various body tissues, including bone marrow, lung, and adipose tissue. Evidence from well-designed case–control or cohort studies for the use of PRP and MSCs in lumbar facet joint, lumbar epidural, and sacroiliac joint injections is currently described as level IV evidence. PRP and MSCs are used autogenously to help facilitate the healing process, and their injection has been studied in the long-term management of discogenic low back pain. PRP has been compared to steroid injections in the sacroiliac joint for chronic low back pain, with favorable results. MSCs have also been shown to be useful in intervertebral disc regeneration and treatment of chronic low back pain associated with degenerative disc disease. Summary Currently, the price for these treatments is extremely high, and thus the standard of care continues to be steroid injections and other treatments. This could change, however, with more robust data and research on the safety and long-term efficacy of biologics compared to other interventional management.
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Wang J, Xia D, Lin Y, Xu W, Wu Y, Chen J, Chu J, Shen P, Weng S, Wang X, Shen L, Fan S, Shen S. Oxidative stress-induced circKIF18A downregulation impairs MCM7-mediated anti-senescence in intervertebral disc degeneration. Exp Mol Med 2022; 54:285-297. [PMID: 35332256 PMCID: PMC8979962 DOI: 10.1038/s12276-022-00732-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 09/10/2021] [Accepted: 09/29/2021] [Indexed: 11/30/2022] Open
Abstract
Low back pain, triggered by intervertebral disc degeneration (IVDD), is one of the most common causes of disability and financial expenditure worldwide. However, except for surgical interventions, effective medical treatment to prevent the progression of IVDD is lacking. This study aimed to investigate the effects of circKIF18A, a novel circRNA, on IVDD progression and to explore its underlying mechanism in IVDD. In this study, we found that oxidative stress was positively correlated with nucleus pulposus cell (NPC) senescence in IVDD and that circKIF18A was downregulated in IVDD and attenuated senescent phenotypes such as cell cycle arrest and extracellular matrix degradation in NPCs. Mechanistically, circKIF18A competitively suppressed ubiquitin-mediated proteasomal degradation of MCM7, and the protective effects of circKIF18A on NPCs were partially mediated by MCM7 under oxidative stress. Intradiscal injection of adenoviral circKIF18A ameliorated IVDD in a rat model. This study revealed that circKIF18A regulates NPC degeneration by stabilizing MCM7 and identified a novel signaling pathway, the circKIF18A-MCM7 axis, for anti-senescence molecular therapy in IVDD. A non-coding circular RNA molecule that prevents spinal cells from undergoing premature ageing offers a new therapeutic target for treating intervertebral disc degeneration (IVDD), a major cause of lower back pain. Shuying Shen of Zhejiang University School of Medicine, China, and colleagues took samples from the soft, gelatinous central portion of the intervertebral disk, the so-called nucleus pulposus, and looked for circular RNAs with high expression levels in healthy individuals and low levels in people with IVDD. They identified a specific RNA in this way, and showed how this regulatory molecule promotes the activity of a protein involved in enhancing the proliferative capacity of nucleus pulposus tissues. In rats, injections of a gene therapy vector encoding this RNA helped ameliorate signs of IVDD, highlighting the potential for similar therapeutic strategies in people with IVDD.
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Affiliation(s)
- Jianle Wang
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China
| | - Dongdong Xia
- Department of Orthopedics, Ningbo First Hospital, 315010, Ningbo, Zhejiang, China
| | - Yan Lin
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China.,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China
| | - Wenbin Xu
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China
| | - Yaosen Wu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China.,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China
| | - Jiaoxiang Chen
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China.,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China
| | - Junjie Chu
- Department of Head and Neck Surgery, Institute of Micro-Invasive Surgery of Zhejiang University, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China
| | - Panyang Shen
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China.,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China
| | - Sheji Weng
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China.,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China
| | - Xiangyang Wang
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, 325088, Wenzhou, Zhejiang Province, China. .,Key Laboratory of Orthopaedics of Zhejiang Province, 325088, Wenzhou, Zhejiang Province, China.
| | - Lifeng Shen
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China. .,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China.
| | - Shunwu Fan
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China. .,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China.
| | - Shuying Shen
- Department of Orthopedics, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310020, Hangzhou, Zhejiang, China. .,Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, 310020, Hangzhou, Zhejiang, China.
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10
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Application of stem cells in the repair of intervertebral disc degeneration. Stem Cell Res Ther 2022; 13:70. [PMID: 35148808 PMCID: PMC8832693 DOI: 10.1186/s13287-022-02745-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 01/25/2022] [Indexed: 12/16/2022] Open
Abstract
Intervertebral disc degeneration (IDD) is a common disease that increases with age, and its occurrence is stressful both psychologically and financially. Stem cell therapy for IDD is emerging. For this therapy, stem cells from different sources have been proven in vitro, in vivo, and in clinical trials to relieve pain and symptoms, reverse the degeneration cascade, delay the aging process, maintain the spine shape, and retain mechanical function. However, further research is needed to explain how stem cells play these roles and what effects they produce in IDD treatment. This review aims to summarize and objectively analyse the current evidence on stem cell therapy for IDD.
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11
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The Proteolysis of ECM in Intervertebral Disc Degeneration. Int J Mol Sci 2022; 23:ijms23031715. [PMID: 35163637 PMCID: PMC8835917 DOI: 10.3390/ijms23031715] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/28/2022] [Accepted: 01/29/2022] [Indexed: 12/12/2022] Open
Abstract
Intervertebral disc (IVD) degeneration (IDD) is a pathological process that commonly occurs throughout the human life span and is a major cause of lower back pain. Better elucidation of the molecular mechanisms involved in disc degeneration could provide a theoretical basis for the development of lumbar disc intervention strategies. In recent years, extracellular matrix (ECM) homeostasis has received much attention due to its relevance to the mechanical properties of IVDs. ECM proteolysis mediated by a variety of proteases is involved in the pathological process of disc degeneration. Here, we discuss in detail the relationship between the IVD as well as the ECM and the role of ECM proteolysis in the degenerative process of the IVD. Targeting ECM proteolysis-associated proteases may be an effective means of intervention in IDD.
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12
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Combination of ultra-purified stem cells with an in situ-forming bioresorbable gel enhances intervertebral disc regeneration. EBioMedicine 2022; 76:103845. [PMID: 35085848 PMCID: PMC8801983 DOI: 10.1016/j.ebiom.2022.103845] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/18/2021] [Accepted: 01/13/2022] [Indexed: 12/14/2022] Open
Abstract
Background Lumbar intervertebral disc (IVD) herniations are associated with significant disability. Discectomy is the conventional treatment option for IVD herniations but causes a defect in the IVD, which has low self-repair ability, thereby representing a risk of further IVD degeneration. An acellular, bioresorbable, and good manufacturing practice (GMP)-compliant in situ-forming gel, which corrects discectomy-associated IVD defects and prevents further IVD degeneration had been developed. However, this acellular matrix-based strategy has certain limitations, particularly in elderly patients, whose tissues have low self-repair ability. The aim of this study was to investigate the therapeutic efficacy of using a combination of newly-developed, ultra-purified, GMP-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs) and the gel for IVD regeneration after discectomy in a sheep model of severe IVD degeneration. Methods RECs and nucleus pulposus cells (NPCs) were co-cultured in the gel. In addition, RECs combined with the gel were implanted into IVDs following discectomy in sheep with degenerated IVDs. Findings Gene expression of NPC markers, growth factors, and extracellular matrix increased significantly in the co-culture compared to that in each mono-culture. The REC and gel combination enhanced IVD regeneration after discectomy (up to 24 weeks) in the severe IVD degeneration sheep model. Interpretation These findings demonstrate the translational potential of the combination of RECs with an in situ-forming gel for the treatment of herniations in degenerative human IVDs. Funding Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd.
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13
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Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration. Int J Mol Sci 2021; 22:ijms222111355. [PMID: 34768786 PMCID: PMC8583205 DOI: 10.3390/ijms222111355] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 02/07/2023] Open
Abstract
Intervertebral discs (IVDs) have poor nutrient diffusion, because the nucleus pulposus (NP) lacks direct vascular supply and likely generates adenosine triphosphate by anaerobic glycolysis. Regulation of glycolysis is mediated by hypoxia-inducible factor-1α (HIF-1α), a transcription factor that responds to local oxygen tension. Constitutively active HIF-1α (CA HIF-1α) was created by point mutation and determined the protective role of HIF-1α in IVD degeneration. Under fluoroscopy, rat caudal IVD segments were stabbed by a needle puncture, and pcDNA3- HIF-1α wild-type (WT) or pcDNA3-CA HIF-1α was transfected into NP cell lines. The constitutive activity of CA HIF-1α was analyzed using a luciferase assay after cell lysis. Next, IVD tissue samples were retrieved from five patients with degenerative lumbar spinal stenosis at the time of surgery, and NP cells were cultured. NP cells were transfected with CA HIF-1α, and relevant gene expression was measured. HIF-1α protein levels in the nucleus were significantly higher, and transcriptional activity was 10.3-fold higher in NP cells with CA HIF-1α than in those with HIF-1α WT. Gene transfer of CA HIF-1α into NP cells enhanced the expression of Glut-1, Glut-3, aggrecan, type II collagen, and Sox9. Moreover, CA HIF-1α reduced the apoptosis of NP cells induced by the Fas ligand. The HIF-1α and collagen 2 expression levels were notably increased in the NP cells of the CA HIF-1α transfected segments in histology and immunohistochemistry study. Collectively, these results suggest that activation of HIF-1α signaling pathway may play a protective role against IVD degeneration and could be used as a future therapeutic agent.
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14
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Lee S, Chae DS, Song BW, Lim S, Kim SW, Kim IK, Hwang KC. ADSC-Based Cell Therapies for Musculoskeletal Disorders: A Review of Recent Clinical Trials. Int J Mol Sci 2021; 22:10586. [PMID: 34638927 PMCID: PMC8508846 DOI: 10.3390/ijms221910586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 01/04/2023] Open
Abstract
Recently published clinical trials involving the use of adipose-derived stem cells (ADSCs) indicated that approximately one-third of the studies were conducted on musculoskeletal disorders (MSD). MSD refers to a wide range of degenerative conditions of joints, bones, and muscles, and these conditions are the most common causes of chronic disability worldwide, being a major burden to the society. Conventional treatment modalities for MSD are not sufficient to correct the underlying structural abnormalities. Hence, ADSC-based cell therapies are being tested as a form of alternative, yet more effective, therapies in the management of MSDs. Therefore, in this review, MSDs subjected to the ADSC-based therapy were further categorized as arthritis, craniomaxillofacial defects, tendon/ligament related disorders, and spine disorders, and their brief characterization as well as the corresponding conventional therapeutic approaches with possible mechanisms with which ADSCs produce regenerative effects in disease-specific microenvironments were discussed to provide an overview of under which circumstances and on what bases the ADSC-based cell therapy was implemented. Providing an overview of the current status of ADSC-based cell therapy on MSDs can help to develop better and optimized strategies of ADSC-based therapeutics for MSDs as well as help to find novel clinical applications of ADSCs in the near future.
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Affiliation(s)
- Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary’s Hospital, Catholic Kwandong University, Gangneung 210-701, Korea;
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Il-Kwon Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
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15
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A comparative study of mesenchymal stem cell transplantation and NTG-101 molecular therapy to treat degenerative disc disease. Sci Rep 2021; 11:14804. [PMID: 34285277 PMCID: PMC8292352 DOI: 10.1038/s41598-021-94173-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Cellular replacement therapy using mesenchymal stem cells (MSCs) and/or the delivery of growth factors are at the forefront of minimally invasive biological treatment options for Degenerative Disc Disease (DDD). In this study, we compared the therapeutic potential of a novel drug candidate, NTG-101 to MSCs, including rat cartilage derived stem cells (rCDSCs), bone marrow stem cells (rBMSCs) and human Umbilical Cord Derived Mesenchymal Stem Cells (hUCMSCs) for the treatment of DDD. We induced DDD using a validated image-guided needle puncture injury in rat-tail IVDs. Ten weeks post-injury, animals were randomized and injected with MSCs, NTG-101 or vehicle. At the end of the study, histological analysis of the IVD-Nucleus Pulposus (NPs) injected with NTG-101 or rCDSCs showed a healthy or mild degenerative phenotype in comparison to vehicle controls. Immunohistochemical analysis revealed strong expression of aggrecan, collagen 2, brachyury and Oct4 in IVD-NPs injected with NTG-101. Our results also demonstrated suppression of inflammation induced p38 and NFκB resulting in inhibition of catabolic genes, but activation of Smad-2/3, Erk-1/2 and Akt-dependent signaling inducing anabolic genes in IVD-NP on treatment with NTG-101. In conclusion, a single injection of NTG-101 into the degenerative disc demonstrated superior benefits compared to stem cell transplantation.
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16
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Vadalà G, Ambrosio L, Russo F, Papalia R, Denaro V. Stem Cells and Intervertebral Disc Regeneration Overview-What They Can and Can't Do. Int J Spine Surg 2021; 15:40-53. [PMID: 34376495 DOI: 10.14444/8054] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Low back pain (LPB) is the main cause of disability worldwide with enormous socioeconomic burdens. A major cause of LBP is intervertebral disc degeneration (IDD): a chronic, progressive process associated with exhaustion of the resident cell population, tissue inflammation, degradation of the extracellular matrix and dehydration of the nucleus pulposus. Eventually, IDD may lead to serious sequelae including chronic LBP, disc herniation, segmental instability, and spinal stenosis, which may require invasive surgical interventions. However, no treatment is actually able to directly tackle IDD and hamper the degenerative process. In the last decade, the intradiscal injection of stem cells is raising as a promising approach to regenerate the intervertebral disc. This review aims to describe the rationale behind a regenerative stem cell therapy for IDD as well as the effect of stem cells following their implantation in the disc environment according to preclinical studies. Furthermore, actual clinical evidence and ongoing trials will be discussed, taking into account the future perspective and current limitations of this cutting-edge therapy. METHODS A literature analysis was performed for this narrative review. A database search of PubMed, Scopus and ClinicalTrials.gov was conducted using "stem cells" combined with "intervertebral disc", "degeneration" and "regeneration" without exclusion based on publication date. Articles were firstly screened on a title-abstract basis and, subsequently, full-text were reviewed. Both preclinical and clinical studies have been included. RESULTS The database search yielded recent publications from which the narrative review was completed. CONCLUSIONS Based on available evidence, intradiscal stem cell therapy has provided encouraging results in terms of regenerative effects and reduction of LBP. However, multicenter, prospective randomized trials are needed in order confirm the safety, efficacy and applicability of such a promising treatment.
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Affiliation(s)
- Gianluca Vadalà
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Luca Ambrosio
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Fabrizio Russo
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Rocco Papalia
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
| | - Vincenzo Denaro
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy
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17
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El-Kadiry AEH, Lumbao C, Rafei M, Shammaa R. Autologous BMAC Therapy Improves Spinal Degenerative Joint Disease in Lower Back Pain Patients. Front Med (Lausanne) 2021; 8:622573. [PMID: 33816523 PMCID: PMC8012529 DOI: 10.3389/fmed.2021.622573] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/26/2021] [Indexed: 01/08/2023] Open
Abstract
Spinal degenerative joint disease (DJD) is associated with lower back pain (LBP) arising from the degeneration of intervertebral discs (IVD), facet joints, intertransversarii muscles, and interspinous ligaments among other anatomical structures. To circumvent the socioeconomic burdens and often-problematic surgical options imposed by DJD therapy, cell-based biologic modalities like bone marrow aspirate concentrate (BMAC) have been investigated in pre-clinical and clinical settings, mostly for IVD degeneration (IDD), with encouraging outcomes. In this study, we evaluated the differences in therapeutic benefits of BMAC between IVD- and facet joint-originating chronic LBP. Eighteen patients diagnosed with chronic LBP met the selection criteria. Following discography and provocation testing, 13 patients tested positive and were assigned into IDD-associated LBP (1st arm), while the remaining 5 tested negative and were assigned into facetogenic LBP (2nd arm). Autologous BMAC was injected intradiscally in the 1st arm, while the 2nd arm received posterior spinal chain injections. No procedure-related serious events ensued. Clinical improvement was evaluated over 12 months based on pain and functionality questionnaires (VAS, BPI, RAND-36), opioid use, and changes in disc parameters assessed by magnetic resonance imaging (MRI). Ameliorated VAS and BPI scores differed significantly between both arms in favor of IDD patients who also took significantly less opioids. Average RAND-36 scores showed no significant difference between groups albeit a trend suggesting improvement was observed in IDD patients. MRI scans conducted on IDD patients demonstrated marked elevation in disc height and spinal canal space size without worsening disc quality. Overall, this is the first study investigating the potency of BMAC as an IDD treatment in Canada and the first globally for addressing facetogenic pain using cellular therapy.
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Affiliation(s)
- Abed El-Hakim El-Kadiry
- Laboratory of Thrombosis and Hemostasis, Research Center, Montreal Heart Institute, Montreal, QC, Canada
- Department of Biomedical Sciences, Université de Montréal, Montreal, QC, Canada
| | - Carlos Lumbao
- Canadian Centre for Regenerative Therapy, Toronto, ON, Canada
| | - Moutih Rafei
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology, Infectious Diseases, and Immunology, Université de Montréal, Montreal, QC, Canada
- Molecular Biology Program, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Riam Shammaa
- Canadian Centre for Regenerative Therapy, Toronto, ON, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
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18
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Binch ALA, Fitzgerald JC, Growney EA, Barry F. Cell-based strategies for IVD repair: clinical progress and translational obstacles. Nat Rev Rheumatol 2021; 17:158-175. [PMID: 33526926 DOI: 10.1038/s41584-020-00568-w] [Citation(s) in RCA: 158] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 12/21/2022]
Abstract
Intervertebral disc (IVD) degeneration is a major cause of low back pain, a prevalent and chronic condition that has a striking effect on quality of life. Currently, no approved pharmacological interventions or therapies are available that prevent the progressive destruction of the IVD; however, regenerative strategies are emerging that aim to modify the disease. Progress has been made in defining promising new treatments for disc disease, but considerable challenges remain along the entire translational spectrum, from understanding disease mechanism to useful interpretation of clinical trials, which make it difficult to achieve a unified understanding. These challenges include: an incomplete appreciation of the mechanisms of disc degeneration; a lack of standardized approaches in preclinical testing; in the context of cell therapy, a distinct lack of cohesion regarding the cell types being tested, the tissue source, expansion conditions and dose; the absence of guidelines regarding disease classification and patient stratification for clinical trial inclusion; and an incomplete understanding of the mechanisms underpinning therapeutic responses to cell delivery. This Review discusses current approaches to disc regeneration, with a particular focus on cell-based therapeutic strategies, including ongoing challenges, and attempts to provide a framework to interpret current data and guide future investigational studies.
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Affiliation(s)
- Abbie L A Binch
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland
| | - Joan C Fitzgerald
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland
| | - Emily A Growney
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland
| | - Frank Barry
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland.
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19
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Niu YT, Xie L, Deng RR, Zhang XY. In the presence of TGF-β1, Asperosaponin VI promotes human mesenchymal stem cell differentiation into nucleus pulposus like- cells. BMC Complement Med Ther 2021; 21:32. [PMID: 33446173 PMCID: PMC7807821 DOI: 10.1186/s12906-020-03169-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 11/26/2020] [Indexed: 03/15/2023] Open
Abstract
Background The regeneration of nucleus pulposus (NP) cells is an effective method to prevent intervertebral disc degeneration (IVDD). In this study, we investigated the role of Asperosaponin VI (ASA VI), isolated from a traditional Chinese medicine (TCM), the root of Dipsacus asper Wall, in promoting human mesenchymal stem cell (HMSC) proliferation and differentiation into NP-like cells and explored the possible mechanism of action. Methods The effects of ASA VI on HMSC viability and proliferation were determined by the XTT method and EDU staining. Then, Real-time qPCR, immunocytochemistry and immunofluorescence assays were used to measure the effect of ASA VI on the expression of extracellular matrix (ECM) components, such as COL2A1, aggrecan, SOX9, KRT19, PAX1, and glycosaminoglycans (GAGs), in NP cells. In addition, Western blot assay was used to measure the expression of p-ERK1/2 and p-smad2/3. Results ASA VI was able to promote the proliferation and differentiation of HMSCs into NP-like cells, and the optimum concentration was 1 mg/L. Western blot assay indicated that the possible mechanism might be related to the activation of p-ERK1 / 2 and p-Smad2 / 3. Conclusions ASA VI can promote the proliferation and differentiation of HMSCs into NP-like cells, which can potentially be used as a treatment for IVDD. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-020-03169-y.
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Affiliation(s)
- Yong-Tao Niu
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China
| | - Lin Xie
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China.
| | - Rong-Rong Deng
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China
| | - Xiao-Yu Zhang
- Department of Spine Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu, China
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Yoon SH, Kim DH, Cho S, Kim KJ. Evaluation of Bone Marrow-derived Stem Cells and Adipose-derived Stem Cells Co-cultured on Human Nucleus Pulposus Cells: A Pilot Study. Korean J Neurotrauma 2020; 16:138-146. [PMID: 33163421 PMCID: PMC7607015 DOI: 10.13004/kjnt.2020.16.e36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 11/15/2022] Open
Abstract
Objective We aimed to determine whether bone marrow-derived mesenchymal stem cells (BDMSCs) effectively attenuate the degeneration of human nucleus pulposus cells (NPCs). Methods Four NPC lines were obtained from 3 subjects who underwent spinal surgery for cervical disc herniation (n=1) or lumbar disc herniation (n=2). For co-culture wells without contact, BDMSCs and adipose-derived mesenchymal stem cells (ADMSCs) were seeded on tissue culture plates and maintained for 3 days. Senescence-associated β-gal (SA-β-gal) staining was represented as a percentage of the total number of stained cells (%). The cells with intracellular lipid droplets (LDs) were represented as the percentage of the number of cells with LDs. Glycosaminoglycan (GAG) secretion was measured at 450 nm, using a commercial kit, to analyze optical density. Results The ratio of cells stained with SA-β-gal to the total number of cells reduced significantly when co-cultured with BDMSCs and ADMSCs (p<0.001 vs. p<0.001). The proportion of NPCs containing LDs was lower when co-cultured with BDMSCs than with ADMSCs (p<0.001). The optical density related to GAG secretion was lower in BDMSCs and ADMSCs co-cultured with NPCs than in the controls (p<0.001 vs. p<0.001). Conclusion SA-β-gal staining showed significant attenuation of degenerative changes in NPCs co-cultured with BDMSCs. Moreover, the unexpected increase in LDs was significantly higher in NPCs co-cultured with ADMSCs than in those co-cultured with BDMSCs. However, GAG secretion was significantly decreased in NPCs co-cultured with MSCs.
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Affiliation(s)
- Sang Hoon Yoon
- Department of Neurosurgery, Armed Forces Capital Hospital, Seongnam, Korea
- Department of Neurosurgery & Spine Care, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dae Hee Kim
- Department of Neurosurgery, Armed Forces Capital Hospital, Seongnam, Korea
- Department of Neurosurgery & Spine Care, Seoul National University Bundang Hospital, Seongnam, Korea
- Neurosurgical Laboratory, Seoul National University Bundang Hospital, Seongnam, Korea
- Research Institute, Sociotech Co. Ltd., Seongnam, Korea
| | - Sam Cho
- Department of Neurosurgery, Armed Forces Capital Hospital, Seongnam, Korea
- Department of Neurosurgery & Spine Care, Seoul National University Bundang Hospital, Seongnam, Korea
- Research Institute, Sociotech Co. Ltd., Seongnam, Korea
| | - Ki-Jeong Kim
- Department of Neurosurgery & Spine Care, Seoul National University Bundang Hospital, Seongnam, Korea
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21
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Harmon MD, Ramos DM, Nithyadevi D, Bordett R, Rudraiah S, Nukavarapu SP, Moss IL, Kumbar SG. Growing a backbone - functional biomaterials and structures for intervertebral disc (IVD) repair and regeneration: challenges, innovations, and future directions. Biomater Sci 2020; 8:1216-1239. [PMID: 31957773 DOI: 10.1039/c9bm01288e] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Back pain and associated maladies can account for an immense amount of healthcare cost and loss of productivity in the workplace. In particular, spine related injuries in the US affect upwards of 5.7 million people each year. The degenerative disc disease treatment almost always arises due to a clinical presentation of pain and/or discomfort. Preferred conservative treatment modalities include the use of non-steroidal anti-inflammatory medications, physical therapy, massage, acupuncture, chiropractic work, and dietary supplements like glucosamine and chondroitin. Artificial disc replacement, also known as total disc replacement, is a treatment alternative to spinal fusion. The goal of artificial disc prostheses is to replicate the normal biomechanics of the spine segment, thereby preventing further damage to neighboring sections. Artificial functional disc replacement through permanent metal and polymer-based components continues to evolve, but is far from recapitulating native disc structure and function, and suffers from the risk of unsuccessful tissue integration and device failure. Tissue engineering and regenerative medicine strategies combine novel material structures, bioactive factors and stem cells alone or in combination to repair and regenerate the IVD. These efforts are at very early stages and a more in-depth understanding of IVD metabolism and cellular environment will also lead to a clearer understanding of the native environment which the tissue engineering scaffold should mimic. The current review focusses on the strategies for a successful regenerative scaffold for IVD regeneration and the need for defining new materials, environments, and factors that are so finely tuned in the healthy human intervertebral disc in hopes of treating such a prevalent degenerative process.
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Affiliation(s)
- Matthew D Harmon
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT, USA. and Department of Orthopedics Surgery, University of Connecticut Health, Farmington, CT, USA
| | - Daisy M Ramos
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT, USA. and Department of Orthopedics Surgery, University of Connecticut Health, Farmington, CT, USA
| | - D Nithyadevi
- Department of Orthopedics Surgery, University of Connecticut Health, Farmington, CT, USA
| | - Rosalie Bordett
- Department of Orthopedics Surgery, University of Connecticut Health, Farmington, CT, USA
| | - Swetha Rudraiah
- Department of Pharmaceutical Sciences, University of Saint Joseph, Hartford, CT, USA
| | - Syam P Nukavarapu
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT, USA. and Department of Orthopedics Surgery, University of Connecticut Health, Farmington, CT, USA and Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA
| | - Isaac L Moss
- Department of Orthopedics Surgery, University of Connecticut Health, Farmington, CT, USA
| | - Sangamesh G Kumbar
- Department of Materials Science and Engineering, University of Connecticut, Storrs, CT, USA. and Department of Orthopedics Surgery, University of Connecticut Health, Farmington, CT, USA and Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA
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22
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Fractalkine Regulates HEC-1A/JEG-3 Interaction by Influencing the Expression of Implantation-Related Genes in an In Vitro Co-Culture Model. Int J Mol Sci 2020; 21:ijms21093175. [PMID: 32365902 PMCID: PMC7246682 DOI: 10.3390/ijms21093175] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/24/2020] [Accepted: 04/29/2020] [Indexed: 12/15/2022] Open
Abstract
Embryo implantation is a complex process regulated by a network of biological molecules. Recently, it has been described that fractalkine (CX3CL1, FKN) might have an important role in the feto-maternal interaction during gestation since the trophoblast cells express fractalkine receptor (CX3CR1) and the endometrium cells secrete fractalkine. CX3CR1 controls three major signalling pathways, PLC-PKC pathway, PI3K/AKT/NFκB pathway and Ras-mitogen-activated protein kinases (MAPK) pathways regulating proliferation, growth, migration and apoptosis. In this study, we focused on the molecular mechanisms of FKN treatment influencing the expression of implantation-related genes in trophoblast cells (JEG-3) both in mono-and in co-culture models. Our results reveal that FKN acted in a concentration and time dependent manner on JEG-3 cells. FKN seemed to operate as a positive regulator of implantation via changing the action of progesterone receptor (PR), activin receptor and bone morphogenetic protein receptor (BMPR). FKN modified also the expression of matrix metalloproteinase 2 and 9 controlling invasion. The presence of HEC-1A endometrial cells in the co-culture contributed to the effect of fractalkine on JEG-3 cells regulating implantation. The results suggest that FKN may contribute to the successful attachment and implantation of embryo.
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Ukeba D, Sudo H, Tsujimoto T, Ura K, Yamada K, Iwasaki N. Bone marrow mesenchymal stem cells combined with ultra-purified alginate gel as a regenerative therapeutic strategy after discectomy for degenerated intervertebral discs. EBioMedicine 2020; 53:102698. [PMID: 32143180 PMCID: PMC7057222 DOI: 10.1016/j.ebiom.2020.102698] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 02/07/2020] [Accepted: 02/18/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Because the regenerative ability of intervertebral discs (IVDs) is restricted, defects caused by discectomy may induce insufficient tissue repair leading to further IVD degeneration. An acellular bioresorbable biomaterial based on ultra-purified alginate (UPAL) gel was developed to fill the IVD cavity and prevent IVD degeneration. However, an acellular matrix-based strategy may have limitations, particularly in the elderly population, who exhibit low self-repair capability. Therefore, further translational studies involving product combinations, such as UPAL gel plus bone marrow-derived mesenchymal stem cells (BMSCs), are required to evaluate the regenerative effects of BMSCs embedded in UPAL gel on degenerated IVDs. METHODS Rabbit BMSCs and nucleus pulposus cells (NPCs) were co-cultured in a three-dimensional (3D) system in UPAL gel. In addition, rabbit or human BMSCs combined with UPAL gel were implanted into IVDs following partial discectomy in rabbits with degenerated IVDs. FINDINGS Gene expression of NPC markers, growth factors, and extracellular matrix was significantly increased in the NPC and BMSC 3D co-culture compared to that in each 3D mono-culture. In vivo, whereas UPAL gel alone suppressed IVD degeneration as compared to discectomy, the combination of BMSCs and UPAL gel exerted a more potent effect to induce IVD regeneration. Similar IVD regeneration was observed using human BMSCs. INTERPRETATION These findings demonstrate the therapeutic potential of BMSCs combined with UPAL gel as a regenerative strategy following discectomy for degenerated IVDs. FUNDING Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Agency for Medical Research and Development, and the Mochida Pharmaceutical Co., Ltd.
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Affiliation(s)
- Daisuke Ukeba
- Faculty of Medicine and Graduate of Medicine, Department of Orthopedic Surgery, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Hideki Sudo
- Faculty of Medicine and Graduate of Medicine, Department of Orthopedic Surgery, Hokkaido University, Sapporo, Hokkaido, Japan; Faculty of Medicine and Graduate of Medicine, Department of Advanced Medicine for Spine and Spinal Cord Disorders, Hokkaido University, Sapporo, Hokkaido, Japan.
| | - Takeru Tsujimoto
- Faculty of Medicine and Graduate of Medicine, Department of Orthopedic Surgery, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Katsuro Ura
- Faculty of Medicine and Graduate of Medicine, Department of Orthopedic Surgery, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Katsuhisa Yamada
- Faculty of Medicine and Graduate of Medicine, Department of Orthopedic Surgery, Hokkaido University, Sapporo, Hokkaido, Japan; Faculty of Medicine and Graduate of Medicine, Department of Advanced Medicine for Spine and Spinal Cord Disorders, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Norimasa Iwasaki
- Faculty of Medicine and Graduate of Medicine, Department of Orthopedic Surgery, Hokkaido University, Sapporo, Hokkaido, Japan
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24
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Li G, Song Y, Liao Z, Wang K, Luo R, Lu S, Zhao K, Feng X, Liang H, Ma L, Wang B, Ke W, Yin H, Zhan S, Li S, Wu X, Zhang Y, Yang C. Bone-derived mesenchymal stem cells alleviate compression-induced apoptosis of nucleus pulposus cells by N6 methyladenosine of autophagy. Cell Death Dis 2020; 11:103. [PMID: 32029706 PMCID: PMC7005291 DOI: 10.1038/s41419-020-2284-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 01/17/2020] [Accepted: 01/20/2020] [Indexed: 12/28/2022]
Abstract
N6 methyladenosine (m6A) is one of the most prevalent epitranscriptomic modifications of mRNAs, and plays a critical role in various bioprocesses. Bone-derived mesenchymal stem cells (BMSCs) can attenuate apoptosis of nucleus pulposus cells (NPCs) under compression; however, the underlying mechanisms are poorly understood. This study showed that the level of m6A mRNA modifications was decreased, and the autophagic flux was increased in NPCs under compression when they were cocultured with BMSCs. We report that under coculture conditions, RNA demethylase ALKBH5-mediated FIP200 mRNA demethylation enhanced autophagic flux and attenuated the apoptosis of NPCs under compression. Specific silencing of ALKBH5 results in impaired autophagic flux and a higher proportion of apoptotic NPCs under compression, even when cocultured with BMSCs. Mechanistically, we further identify that the m6A "reader" YTHDF2 is likely to be involved in the regulation of autophagy, and lower m6A levels in the coding region of FIP200 lead to a reduction in YTHDF2-mediated mRNA degradation of FIP200, a core molecular component of the ULK1 complex that participates in the initiating process of autophagy. Taken together, our study reveals the roles of ALKBH5-mediated FIP200 mRNA demethylation in enhancing autophagy and reducing apoptosis in NPCs when cocultured with BMSCs.
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Affiliation(s)
- Gaocai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yu Song
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhiwei Liao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Kun Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rongjin Luo
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Saideng Lu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Kangcheng Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaobo Feng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hang Liang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Liang Ma
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Bingjin Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wencan Ke
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Huipeng Yin
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shengfeng Zhan
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shuai Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xinghuo Wu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yukun Zhang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Cao Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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25
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Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders. J Clin Med 2019; 9:jcm9010002. [PMID: 31861268 PMCID: PMC7019991 DOI: 10.3390/jcm9010002] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/11/2019] [Accepted: 12/12/2019] [Indexed: 12/13/2022] Open
Abstract
: Mesenchymal stromal cells (MSCs) are crucial elements in the bone marrow (BM) niche where they provide physical support and secrete soluble factors to control and maintain hematopoietic stem progenitor cells (HSPCs). Given their role in the BM niche and HSPC support, MSCs have been employed in the clinical setting to expand ex-vivo HSPCs, as well as to facilitate HSPC engraftment in vivo. Specific alterations in the mesenchymal compartment have been described in hematological malignancies, as well as in rare genetic disorders, diseases that are amenable to allogeneic hematopoietic stem cell transplantation (HSCT), and ex-vivo HSPC-gene therapy (HSC-GT). Dissecting the in vivo function of human MSCs and studying their biological and functional properties in these diseases is a critical requirement to optimize transplantation outcomes. In this review, the role of MSCs in the orchestration of the BM niche will be revised, and alterations in the mesenchymal compartment in specific disorders will be discussed, focusing on the need to correct and restore a proper microenvironment to ameliorate transplantation procedures, and more in general disease outcomes.
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26
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Luzzi S, Crovace AM, Del Maestro M, Giotta Lucifero A, Elbabaa SK, Cinque B, Palumbo P, Lombardi F, Cimini A, Cifone MG, Crovace A, Galzio R. The cell-based approach in neurosurgery: ongoing trends and future perspectives. Heliyon 2019; 5:e02818. [PMID: 31844735 PMCID: PMC6889232 DOI: 10.1016/j.heliyon.2019.e02818] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/11/2019] [Accepted: 11/06/2019] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Examination of the current trends and future perspectives of the cell-based therapies in neurosurgery. METHODS A PubMed/MEDLINE-based systematic review has been performed combining the main Medical Subject Headings (MeSH) regarding the cell- and tissue-based therapies with the "Brain", "Spinal Cord", "Spine" and "Skull" MeSH terms. Only articles in English published in the last 10 years and pertinent to neurosurgery have been selected. RESULTS A total of 1,173 relevant articles have been chosen. Somatic cells and gene-modification technologies have undergone the greatest development. Immunotherapies and gene therapies have been tested for the cure of glioblastoma, stem cells mainly for brain and spinal cord traumatic injuries. Stem cells have also found a rationale in the treatment of the cranial and spinal bony defects, and of the intervertebral disc degeneration, as well.Most of the completed or ongoing trials concerning the cell-based therapies in neurosurgery are on phase 2. Future perspectives involve the need to overcome issues related to immunogenicity, oncogenicity and routes for administration. Refinement and improvement of vector design and delivery are required within the gene therapies. CONCLUSION The last decade has been characterised by a progressive evolution of neurosurgery from a purely mechanical phase to a new biological one. This trend has followed the rapid and parallel development of translational medicine and nanotechnologies.The introduction of new technologies, the optimisation of the already existing ones, and the reduction of costs are among the main challenges of the foreseeable future.
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Affiliation(s)
- Sabino Luzzi
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Polo Didattico "Cesare Brusotti", Viale Brambilla, 74, Pavia, 27100, Italy
- Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi, 19, Pavia, 27100, Italy
| | - Alberto Maria Crovace
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Piazza G. Cesare, 11 – Policlinico di Bari, Bari, 70124, Italy
| | - Mattia Del Maestro
- Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi, 19, Pavia, 27100, Italy
- PhD School in Experimental Medicine, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Polo Didattico "Cesare Brusotti", Viale Brambilla, 74, Pavia, 27100, Italy
| | - Alice Giotta Lucifero
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Polo Didattico "Cesare Brusotti", Viale Brambilla, 74, Pavia, 27100, Italy
| | - Samer K. Elbabaa
- Pediatric Neurosurgery, Pediatric Neuroscience Center of Excellence, Arnold Palmer Hospital for Children, 1222 S. Orange Avenue, 2nd Floor, MP 154, Orlando, FL, 32806, USA
| | - Benedetta Cinque
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Paola Palumbo
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Francesca Lombardi
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Annamaria Cimini
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Maria Grazia Cifone
- Department of Life, Health & Environmental Sciences, University of L'Aquila, Building Delta 6, via Coppito, L'Aquila, 67100, Italy
| | - Antonio Crovace
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Piazza G. Cesare, 11 – Policlinico di Bari, Bari, 70124, Italy
| | - Renato Galzio
- Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Polo Didattico "Cesare Brusotti", Viale Brambilla, 74, Pavia, 27100, Italy
- Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Viale C. Golgi, 19, Pavia, 27100, Italy
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27
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Frapin L, Clouet J, Delplace V, Fusellier M, Guicheux J, Le Visage C. Lessons learned from intervertebral disc pathophysiology to guide rational design of sequential delivery systems for therapeutic biological factors. Adv Drug Deliv Rev 2019; 149-150:49-71. [PMID: 31445063 DOI: 10.1016/j.addr.2019.08.007] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 08/05/2019] [Accepted: 08/18/2019] [Indexed: 12/20/2022]
Abstract
Intervertebral disc (IVD) degeneration has been associated with low back pain, which is a major musculoskeletal disorder and socio-economic problem that affects as many as 600 million patients worldwide. Here, we first review the current knowledge of IVD physiology and physiopathological processes in terms of homeostasis regulation and consecutive events that lead to tissue degeneration. Recent progress with IVD restoration by anti-catabolic or pro-anabolic approaches are then analyzed, as are the design of macro-, micro-, and nano-platforms to control the delivery of such therapeutic agents. Finally, we hypothesize that a sequential delivery strategy that i) firstly targets the inflammatory, pro-catabolic microenvironment with release of anti-inflammatory or anti-catabolic cytokines; ii) secondly increases cell density in the less hostile microenvironment by endogenous cell recruitment or exogenous cell injection, and finally iii) enhances cellular synthesis of extracellular matrix with release of pro-anabolic factors, would constitute an innovative yet challenging approach to IVD regeneration.
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28
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Henriksson HB, Papadimitriou N, Hingert D, Baranto A, Lindahl A, Brisby H. The Traceability of Mesenchymal Stromal Cells After Injection Into Degenerated Discs in Patients with Low Back Pain. Stem Cells Dev 2019; 28:1203-1211. [PMID: 31237488 DOI: 10.1089/scd.2019.0074] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Low back pain is a major health issue and one main cause to this condition is believed to be intervertebral disc (IVD) degeneration. Stem cell therapy for degenerated discs using mesenchymal stromal cells (MSCs) has been suggested. The aim of the study was to investigate the presence and distribution pattern of autologous MSCs transplanted into degenerated IVDs in patients and explanted posttransplantation. IVD tissues from four patients (41, 45, 47, and 47 years of age) participating in a clinical feasibility study on MSC transplantation to degenerative discs were investigated. Three patients decided to undergo fusion surgery at time points 8 months and one patient at 28 months posttransplantation. Pretransplantation, MSCs from bone marrow aspirate were isolated by centrifugation in FICOLL® test tubes and cultured (passage 1). Before transplantation, MSCs were labeled with 1 mg/mL iron sucrose (Venofer®) and 1 × 106 MSCs were transplanted into degenerated IVDs. At the time point of surgery, IVD tissues were collected. IVD tissue samples were fixated, embedded in paraffin, and sections prepared. IVD samples were stained with Prussian Blue, by which iron deposits are visualized and examined (light microscopy). Immunohistochemistry (IHC), including SOX9 (sex determining region Y box 9), Coll2A1 (collagen 2A1), and cell viability (TUNEL) were performed. Cells positive for iron deposits were observed in IVD tissues (3/4 patients). The cells/iron deposits were observed in clusters and/or as solitary cells in regions in IVD tissue samples [regions of interest (ROIs)]. By IHC, SOX9- and Coll2A1-positive cells were detected in the same regions as the detected cells/iron deposits. A few nonviable cells were detected by TUNEL assay in ROIs. Results demonstrated that MSCs, labeled with iron sucrose, transplanted into degenerated IVDs were detectable 8 months posttransplantation. The detected cellular activity indicates that MSCs have differentiated into chondrocyte-like cells and that the injected MSCs and/or their progeny have survived since the cells were found in large cluster and as solitary cells which were distributed at different parts of the IVD.
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Affiliation(s)
- Helena Barreto Henriksson
- Department of Orthopedics, Institute for Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska Hospital, Gothenburg, Sweden.,Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Nikolaos Papadimitriou
- Department of Orthopedics, Institute for Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Orthopedics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Daphne Hingert
- Department of Orthopedics, Institute for Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Adad Baranto
- Department of Orthopedics, Institute for Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Orthopedics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anders Lindahl
- Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Helena Brisby
- Department of Orthopedics, Institute for Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Orthopedics, Sahlgrenska University Hospital, Gothenburg, Sweden
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Larson BL, Yu SN, Park H, Estes BT, Moutos FT, Bloomquist CJ, Wu PB, Welter JF, Langer R, Guilak F, Freed LE. Chondrogenic, hypertrophic, and osteochondral differentiation of human mesenchymal stem cells on three-dimensionally woven scaffolds. J Tissue Eng Regen Med 2019; 13:1453-1465. [PMID: 31115161 DOI: 10.1002/term.2899] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 04/30/2019] [Accepted: 05/09/2019] [Indexed: 12/18/2022]
Abstract
The development of mechanically functional cartilage and bone tissue constructs of clinically relevant size, as well as their integration with native tissues, remains an important challenge for regenerative medicine. The objective of this study was to assess adult human mesenchymal stem cells (MSCs) in large, three-dimensionally woven poly(ε-caprolactone; PCL) scaffolds in proximity to viable bone, both in a nude rat subcutaneous pouch model and under simulated conditions in vitro. In Study I, various scaffold permutations-PCL alone, PCL-bone, "point-of-care" seeded MSC-PCL-bone, and chondrogenically precultured Ch-MSC-PCL-bone constructs-were implanted in a dorsal, ectopic pouch in a nude rat. After 8 weeks, only cells in the Ch-MSC-PCL constructs exhibited both chondrogenic and osteogenic gene expression profiles. Notably, although both tissue profiles were present, constructs that had been chondrogenically precultured prior to implantation showed a loss of glycosaminoglycan (GAG) as well as the presence of mineralization along with the formation of trabecula-like structures. In Study II of the study, the GAG loss and mineralization observed in Study I in vivo were recapitulated in vitro by the presence of either nearby bone or osteogenic culture medium additives but were prevented by a continued presence of chondrogenic medium additives. These data suggest conditions under which adult human stem cells in combination with polymer scaffolds synthesize functional and phenotypically distinct tissues based on the environmental conditions and highlight the potential influence that paracrine factors from adjacent bone may have on MSC fate, once implanted in vivo for chondral or osteochondral repair.
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Affiliation(s)
- Benjamin L Larson
- Institute for Medical Engineering and Science, David H. Koch Institute for Integrative Cancer Research, and Media Lab, Massachusetts Institute of Technology, Cambridge, MA
| | - Sarah N Yu
- Institute for Medical Engineering and Science, David H. Koch Institute for Integrative Cancer Research, and Media Lab, Massachusetts Institute of Technology, Cambridge, MA
| | - Hyoungshin Park
- Institute for Medical Engineering and Science, David H. Koch Institute for Integrative Cancer Research, and Media Lab, Massachusetts Institute of Technology, Cambridge, MA
| | | | | | | | - Patrick B Wu
- Institute for Medical Engineering and Science, David H. Koch Institute for Integrative Cancer Research, and Media Lab, Massachusetts Institute of Technology, Cambridge, MA
| | - Jean F Welter
- Skeletal Research Center and Case Center for Multimodal Evaluation of Engineered Cartilage, Department of Biology, Case Western Reserve University, Cleveland, OH
| | - Robert Langer
- Institute for Medical Engineering and Science, David H. Koch Institute for Integrative Cancer Research, and Media Lab, Massachusetts Institute of Technology, Cambridge, MA
| | - Farshid Guilak
- Cytex Therapeutics, Inc., Durham, NC.,Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO.,Shriners Hospitals for Children-St. Louis, St. Louis, MO.,Center of Regenerative Medicine, Washington University in St. Louis, St. Louis, MO
| | - Lisa E Freed
- Institute for Medical Engineering and Science, David H. Koch Institute for Integrative Cancer Research, and Media Lab, Massachusetts Institute of Technology, Cambridge, MA
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Wangler S, Menzel U, Li Z, Ma J, Hoppe S, Benneker LM, Alini M, Grad S, Peroglio M. CD146/MCAM distinguishes stem cell subpopulations with distinct migration and regenerative potential in degenerative intervertebral discs. Osteoarthritis Cartilage 2019; 27:1094-1105. [PMID: 31002939 DOI: 10.1016/j.joca.2019.04.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 03/06/2019] [Accepted: 04/03/2019] [Indexed: 02/02/2023]
Abstract
OBJECTIVE This study aimed to characterize the mesenchymal stem cell (MSC) subpopulation migrating towards a degenerated intervertebral disc (IVD) and to assess its regenerative potential. DESIGN Based on initial screening for migration towards C-C motif chemokine ligand 5 (CCL5), the migration potential of CD146+ and CD146- mesenchymal stem cells (MSCs) was evaluated in vitro and in a degenerated organ culture model (degeneration by high-frequency loading in a bioreactor). Discogenic differentiation potential of CD146+ and CD146- MSCs was investigated by in vitro pellet culture assay with supplementation of growth and differentiation factor-6 (GDF6). Furthermore, trypsin degenerated IVDs were treated by either homing or injection of CD146+ or CD146- MSCs and glycosaminoglycan synthesis was evaluated by Sulphur 35 incorporation after 35 days of culture. RESULTS Surface expression of CD146 led to a higher number of migrated MSCs both in vitro and in organ culture. CD146+ and CD146- pellets responded with a similar up-regulation of anabolic markers. A higher production of sulfated glycosaminoglycans (sGAG)/DNA was observed for CD146+ pellets, while in organ cultures, sGAG synthesis rate was higher for IVDs treated with CD146- MSCs by either homing or injection. CONCLUSIONS The CD146+ MSC subpopulation held greater migration potential towards degenerative IVDs, while the CD146- cells induced a stronger regenerative response in the resident IVD cells. These findings were independent of the application route (injection vs migration). From a translational point of view, our data suggests that CD146+ MSCs may be suitable for re-population, while CD146- MSCs may represent the primary choice for stimulation of endogenous IVD cells.
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Affiliation(s)
- S Wangler
- AO Research Institute Davos, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland.
| | - U Menzel
- AO Research Institute Davos, Switzerland.
| | - Z Li
- AO Research Institute Davos, Switzerland.
| | - J Ma
- AO Research Institute Davos, Switzerland.
| | - S Hoppe
- Inselspital, University of Bern, Switzerland.
| | | | - M Alini
- AO Research Institute Davos, Switzerland.
| | - S Grad
- AO Research Institute Davos, Switzerland.
| | - M Peroglio
- AO Research Institute Davos, Switzerland.
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Inhibition of the Notch1 Pathway Promotes the Effects of Nucleus Pulposus Cell-Derived Exosomes on the Differentiation of Mesenchymal Stem Cells into Nucleus Pulposus-Like Cells in Rats. Stem Cells Int 2019; 2019:8404168. [PMID: 31249601 PMCID: PMC6526523 DOI: 10.1155/2019/8404168] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 02/17/2019] [Accepted: 03/19/2019] [Indexed: 12/15/2022] Open
Abstract
Stem cell therapies for intervertebral disc degeneration have been demonstrated as a promising strategy. Previous studies have shown that human nucleus pulposus cell- (NPC-) derived exosomes can induce the differentiation of mesenchymal stem cells (MSCs) into NP-like cells in vitro. However, the mechanism of MSC differentiation into NP-like cells with the induction of NPC exosomes is still unclear. Here, we verified the induction effects of NPC exosomes on the differentiation of MSCs into NP-like cells. In addition, the Notch1 pathway was downregulated in this process. Then, DAPT and soluble Jagged1 (SJAG) were applied to inhibit or enhance the expression of the Notch1 pathway, respectively, resulting in the upregulation or downregulation of collagen II, aggrecan, and Sox9 in MSCs. Knocking down of Notch1 protein facilitated the effects of NPC exosomes on the differentiation of MSCs into NP-like cells. NPC exosomes were more effective than an indirect coculture system in terms of the differentiation of MSCs into NP-like cells. Inhibition of NPC exosome secretion with Rab27a siRNA prevented the induction effects of an indirect coculture system on the differentiation of MSCs into NP-like cells. Transwell migration assays revealed that NPC exosomes could promote the migration of MSCs. Taken together, the Notch1 pathway was negatively associated with the differentiation of MSCs into NP-like cells with the treatments of NPC exosomes. Inhibition of the Notch1 pathway facilitates NPC exosome-induced differentiation of MSCs into NP-like cells in vitro. NPC exosomes play a key role in the differentiation of MSCs into NP-like cells in an indirect coculture system of NPCs and MSCs.
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Zhang ZQ, Wang CS, Yang P, Wang KZ. Mesenchymal Stem Cells Induced by Microencapsulated Chondrocytes on Repairing of Intervertebral Disc Degeneration. Orthop Surg 2018; 10:328-336. [PMID: 30485683 DOI: 10.1111/os.12411] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 12/22/2017] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To evaluate the therapeutic effects of mesenchymal stem cells induced by microencapsulated chondrocytes on repairing of intervertebral disc degeneration. METHODS Rabbit chondrocytes and bone marrow-derived mesenchymal stem cells (MSC) were derived. Chondrocytes were microencapsulated by a microcapsule generator to produce microencapsulated chondrocytes (MEC). MSC were then co-cultured with MEC (MSC-MEC) and the properties and the therapeutic effects on repairing of intervertebral disc degeneration were studied. For the in vitro study, cell proliferation, type II collagen, and glycosaminoglycan (GAG) were studied. The MSC induced by chondrocytes in the Transwell system (MSC-MLC) and pure MSC were used as the control group. For the in vivo studied, MSC-MEC were implanted into the intervertebral disc degenerated (IDD) models, and the radiological images, biomechanical properties, collagen II, and histology of the discs were studied. The IDD, MSC, and MSC-MLC groups were used as the control group. RESULTS In the in vitro study, no significant differences were found among the three groups, indicating that the microcapsule co-culture system will not affect the proliferation of MSC. The type II collagen quantity secreted by MSC-MEC was 23.57 ± 2.46 ng/μL, which was more than for MSC-MLC (15.14 ± 2.31 ng/μL) and MSC groups (4.17 ± 1.23 ng/μL, all P < 0.025). GAG secreted by MSC-MEC was 0.184 ± 0.006 mg/well, which was more than for the MSC-MLC (0.151 ± 0.011 mg/well) and MSC groups (0.023 ± 0.002 mg/well, all P < 0.025). In the in vivo study, no obvious degenerative or protrusive disc was found in the MSC-MEC group, while protrusive discs could be found in the MSC-MLC group, and both degenerative and protrusive discs were found in MSC and IDD groups, which indicated that the reparative effects of MSC-MEC on degenerated discs were better than for the control groups. Biomechanical properties of discs in the MSC-MEC group were maintained at all four time points (2nd, 4th, 8th, and 16th week after implantation). The compressive strength (CS) and the elastic modulus (EM) of MSC and IDD groups were consistently decreased. The CS of the MSC-MLC group was increased in the 4th week but decreased again in the 8th week, while the EM of the MSC-MLC group consistently decreased. Western blot results indicated that discs of the MSC-MEC group had more collagen II, which is an important component of discs. Histology staining showed that the nucleus pulposus of MSC-MEC was complete; no obvious fragment of component loss was found, while those of MSC-MLC, MSC, and IDD groups were widened, broken, and hollow. CONCLUSION The microencapsulation method for half-contact co-culturing improves the differentiation extent of MSC, and MSC induced by chondrocytes could also be used for treatment of IDD.
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Affiliation(s)
- Zi-Qi Zhang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Chun-Sheng Wang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pei Yang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Kun-Zheng Wang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Smith LJ, Silverman L, Sakai D, Le Maitre CL, Mauck RL, Malhotra NR, Lotz JC, Buckley CT. Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section. JOR Spine 2018; 1:e1036. [PMID: 30895277 PMCID: PMC6419951 DOI: 10.1002/jsp2.1036] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 09/09/2018] [Accepted: 09/10/2018] [Indexed: 12/28/2022] Open
Abstract
Intervertebral disc degeneration is strongly associated with chronic low back pain, a leading cause of disability worldwide. Current back pain treatment approaches (both surgical and conservative) are limited to addressing symptoms, not necessarily the root cause. Not surprisingly therefore, long-term efficacy of most approaches is poor. Cell-based disc regeneration strategies have shown promise in preclinical studies, and represent a relatively low-risk, low-cost, and durable therapeutic approach suitable for a potentially large patient population, thus making them attractive from both clinical and commercial standpoints. Despite such promise, no such therapies have been broadly adopted clinically. In this perspective we highlight primary obstacles and provide recommendations to help accelerate successful clinical translation of cell-based disc regeneration therapies. The key areas addressed include: (a) Optimizing cell sources and delivery techniques; (b) Minimizing potential risks to patients; (c) Selecting physiologically and clinically relevant efficacy metrics; (d) Maximizing commercial potential; and (e) Recognizing the importance of multidisciplinary collaborations and engaging with clinicians from inception through to clinical trials.
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Affiliation(s)
- Lachlan J. Smith
- Department of NeurosurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvania
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvania
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvania
| | - Lara Silverman
- DiscGenics Inc.Salt Lake CityUtah
- Department of NeurosurgeryUniversity of Tennessee Health Science CenterMemphisTennessee
| | - Daisuke Sakai
- Department of Orthopaedic Surgery, Surgical ScienceTokai University School of MedicineIseharaJapan
| | | | - Robert L. Mauck
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvania
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvania
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvania
| | - Neil R. Malhotra
- Department of NeurosurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvania
| | - Jeffrey C. Lotz
- Department of Orthopaedic SurgeryUniversity of CaliforniaSan FranciscoCalifornia
| | - Conor T. Buckley
- Trinity Centre for BioengineeringTrinity Biomedical Sciences Institute, Trinity College Dublin, The University of DublinDublinIreland
- School of EngineeringTrinity College Dublin, The University of DublinDublinIreland
- Advanced Materials and Bioengineering Research (AMBER) CentreRoyal College of Surgeons in Ireland & Trinity College Dublin, The University of DublinDublinIreland
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Lehmann TP, Jakub G, Harasymczuk J, Jagodziński PP. Transforming growth factor β mediates communication of co-cultured human nucleus pulposus cells and mesenchymal stem cells. J Orthop Res 2018; 36:3023-3032. [PMID: 29999195 DOI: 10.1002/jor.24106] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 07/01/2018] [Indexed: 02/04/2023]
Abstract
Intervertebral disc (IVD) consists of surrounding tissue annulus fibrosus and central nucleus pulposus, which are partially degenerative in scoliotic IVDs. Successful regeneration of scoliotic alterations requires cognition of critical paracrine mediators of cell-to-cell contact in the IVD. In this work, we hypothesized that transforming growth factor β (TGF-β) is involved in the intercellular communication of nucleus pulposus cells (NPCs) and mesenchymal stem cells (MSCs). We observed that in cultured NPCs TGF-β1 stimulated COL1A1 expression, encoding collagen I, and in MSCs stimulated COL1A1 and SOX9 expressions. We subsequently co-cultured NPCs and MSCs together using direct and indirect transwell systems. The expression of miR-140 and miR-145 were decreased in co-cultured NPCs. We observed that direct co-culture system stronger than the indirect system decreased expression of three miRNA. The expression of COL1A1, ACAN, encoding aggrecan, and SOX9 genes was increased in MSCs co-cultured with NPCs. Co-cultures were incubated with two inhibitors of TGF-β type I receptor: SB-431542 and SB-525334. In co-cultured NPCs, SB-431542 and SB-525334 annulated downregulation of miR-140 and miR-145. In MSCs these inhibitors diminished stimulation of COL1A1, ACAN, and SOX9. We concluded that stimulation of COL1A1, ACAN, and SOX9 in co-cultured MSCs and regulation of miR-140 and miR-145 in NPCs were TGF-β-dependent and TGF-β is involved in the communication of NPCs and MSCs in co-culture. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3023-3032, 2018.
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Affiliation(s)
- Tomasz P Lehmann
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, 60-781, Poland
| | - Głowacki Jakub
- Department of General Orthopaedics, Orthopaedic Oncology and Traumatology, Poznan University of Medical Sciences, Poznan, 61-545, Poland
| | - Jerzy Harasymczuk
- Department of Paediatric Surgery, Traumatology and Urology, Poznan University of Medical Sciences, Poznan, 61-545, Poland
| | - Paweł P Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, 60-781, Poland
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Aberrantly expressed messenger RNAs and long noncoding RNAs in degenerative nucleus pulposus cells co-cultured with adipose-derived mesenchymal stem cells. Arthritis Res Ther 2018; 20:182. [PMID: 30115120 PMCID: PMC6097446 DOI: 10.1186/s13075-018-1677-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023] Open
Abstract
Background Stem cell therapy is considered as a promising alternative to treat intervertebral disc degeneration (IDD). Extensive work had been done on identifying and comparing different types of candidate stem cells, both in vivo and in vitro. However, few studies have shed light on degenerative nucleus pulposus cells (NPCs), especially their biological behavior under the influence of exogenous stem cells, specifically the gene expression and regulation pattern. In the present study, we aimed to determine messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs), which are differentially expressed during the co-culturing process with adipose-derived mesenchymal stem cells (ASCs) and to explore the involved signaling pathways and the regulatory networks. Methods We compared degenerative NPCs co-cultured with ASCs with those cultured solely using lncRNA-mRNA microarray analysis. Based on these data, we investigated the significantly regulated signaling pathways based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Moreover, 23 micro RNAs (miRNAs), which were demonstrated to be involved in IDD were chosen; we investigated their theoretic regulatory importance associated with our microarray data. Results We found 632 lncRNAs and 1682 mRNAs were differentially expressed out of a total of 40,716 probes. We then confirmed the microarray data by real-time PCR. Furthermore, we demonstrated 197 upregulated, and 373 downregulated Gene Ontology terms and 176 significantly enriched pathways, such as the mitogen-activated protein kinase (MAPK) pathway. Also, a signal-net was constructed to reveal the interplay among differentially expressed genes. Meanwhile, a mRNA-lncRNA co-expression network was constructed for the significantly changed mRNAs and lncRNAs. Also, the competing endogenous RNA (ceRNA) network was built. Conclusion Our results present the first comprehensive identification of differentially expressed lncRNAs and mRNAs of degenerative NPCs, altered by co-culturing with ASCs, and outline the gene expression regulation pattern. These may provide valuable information for better understanding of stem cell therapy and potential candidate biomarkers for IDD treatment. Electronic supplementary material The online version of this article (10.1186/s13075-018-1677-x) contains supplementary material, which is available to authorized users.
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Zhang J, Jiang J, Huang R, Wang Y, Nie X, Gui R. Circular RNA expression profiles are significantly altered in mice bone marrow stromal cells after total body irradiation. Leuk Res 2018; 70:67-73. [DOI: 10.1016/j.leukres.2018.05.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/25/2018] [Accepted: 05/28/2018] [Indexed: 01/23/2023]
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Kim JS, Kwon D, Cha BH, Moon BK, Jeong Y, Han IB, Park H, Lee SH. Restoration of chondrogenic properties of degenerative nucleus pulposus cells by repeated co-culture with adipose-derived stem cells. J IND ENG CHEM 2018. [DOI: 10.1016/j.jiec.2017.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Han Z, Zhang Y, Gao L, Jiang S, Ruan D. Human Wharton's Jelly Cells Activate Degenerative Nucleus Pulposus Cells In Vitro. Tissue Eng Part A 2018; 24:1035-1043. [PMID: 29279046 DOI: 10.1089/ten.tea.2017.0340] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
To investigate the interaction between human Wharton's jelly cells (WJCs) and degenerative nucleus pulposus cells (NPCs), human WJCs were cocultured with degenerative NPCs with or without direct cell-cell contact. WJCs were isolated from the human umbilical cord and degenerative NPCs were isolated from the surgically obtained degenerative intervertebral disc tissue. The isolated WJCs positively expressed CD73, CD105, CD90, CD29, CD166, and human leukocyte antigen (HLA)-ABC, but negatively expressed CD34, CD45, and HLA-DR. After coculturing with three different WJCs:NPCs ratios for 7 days, the real-time polymerase chain reaction showed that the relative gene expression of nucleus pulposus (NP)-marker genes [aggrecan, type II collagen, and SRY-type HMG box-9 (SOX-9)] was significantly upgraded in all coculture groups (all p < 0.05 compared with control groups). Coculture either with or without cell-cell contact significantly activated the expression of NP-maker genes than controls, but coculture with cell-cell contact yielded a higher gene expression than coculture without cell-cell contact. In coculturing with cell-cell contact and WJCs:NPCs of 25:75, the relative gene expression of aggrecan, type II collagen, SOX-9 for WJCs yielded the highest increase by 721-, 1507-, and 1463-folds, respectively (all p < 0.05 compared with WJCs control). In contrast, the highest relative gene expression of aggrecan, type II collagen, SOX-9 for NPCs was 112-, 84-, and 109-folds, respectively, in coculture with cell-cell contact and in WJCs:NPCs of 75:25 (all p < 0.05 compared with NPCs control). In conclusion, the data indicated that coculturing human WJCs with degenerative NPCs induced the NP-like cell differentiation of WJCs and restored the biological status of degenerative NPCs and coculture WJCs and NPCs with direct cell-cell contact yielded more favorable gene expressions.
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Affiliation(s)
- Zhihua Han
- 1 Department of Orthopaedic Surgery, Navy General Hospital of PLA , Beijing, China .,2 Experimental Trauma and Orthopedic Surgery, Frankfurt Initiative for Regenerative Medicine, J.W. Goethe-University , Frankfurt, Germany
| | - Yan Zhang
- 1 Department of Orthopaedic Surgery, Navy General Hospital of PLA , Beijing, China .,3 Department of VIP Neurology, Navy General Hospital of PLA , Beijing, China
| | - Liang Gao
- 4 Center of Experimental Orthopaedics, Saarland University Medical Center , Homburg, Germany
| | - Shujun Jiang
- 3 Department of VIP Neurology, Navy General Hospital of PLA , Beijing, China
| | - Dike Ruan
- 1 Department of Orthopaedic Surgery, Navy General Hospital of PLA , Beijing, China
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Shim EK, Lee JS, Kim DE, Kim SK, Jung BJ, Choi EY, Kim CS. Autogenous Mesenchymal Stem Cells from the Vertebral Body Enhance Intervertebral Disc Regeneration via Paracrine Interaction: An in Vitro Pilot Study. Cell Transplant 2018; 25:1819-1832. [PMID: 27075568 DOI: 10.3727/096368916x691420] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Several in vivo studies have found that transplanting mesenchymal stem cells (MSCs) into degenerative intervertebral discs (IVDs) leads to regeneration of disc cells. Since the exact underlying mechanisms are not understood, we investigated the mechanisms of action of MSCs in regeneration of degenerative IVDs via paracrine actions. Human MSCs and degenerative disc cells from the same donor vertebrae were directly or indirectly cocultured. The multidifferentiation potential, cell proliferation, collagen synthesis, and mRNA expression levels were assessed. The proliferation rates of MSCs and degenerative disc cells were higher in the coculture system than in the monolayer cultures or in the conditioned medium of each cell type. During coculturing with nucleus pulposus (NP) cells, mRNA expression of the extracellular matrix (ECM) components aggrecan, versican (VCAN), SOX9, and type II and type VI collagen was significantly increased in MSCs, whereas mRNA expression for type V collagen was increased in MSCs cocultured with annulus fibrosus (AF) cells. In addition, the accumulation of total ECM collagen was greater in cocultured degenerative disc cells than in monocultured cells. During coculturing, MSCs downregulated the expression levels of various proinflammatory cytokine genes in degenerative NP [interleukin-1α ( IL-1α), IL-1β, IL-6, and tumor necrosis factor-α ( TNF-α)] and AF cells ( IL-1α and IL-6), which are involved in the degradation of ECM molecules. In association with the trophic effect of MSCs on degenerative disc cells, upregulation of growth factor mRNA expression was shown in MSCs cocultured with degenerative NP cells [epidermal growth factor ( EGF), insulin-like growth factor-1 ( IGF-1), osteogenic protein-1 ( OP-1), growth and differentiation factor-7 ( GDF-7), and transforming growth factor-β ( TGF-β)] or degenerative AF cells ( IGF-1, OP-1, and GDF-7). In terms of MSC-based clinical approaches to IVD regeneration, implanting MSCs into a degenerative IVD may both stimulate MSC differentiation into an NP- or AF-like phenotype and stimulate the biological activation of degenerative disc cells for self-repair.
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Affiliation(s)
- Eun-Kyung Shim
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, South Korea.,Department of Applied Life Science, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Jung-Seok Lee
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, South Korea
| | - Dong-Eun Kim
- Biomedical Research Institute, iBMT, Anyang, South Korea
| | - Seul Ki Kim
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, South Korea
| | - Byung-Joo Jung
- Department of Neurosurgery, Naeun Hospital, Anyang, South Korea
| | - Eun-Young Choi
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, South Korea
| | - Chang-Sung Kim
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, South Korea.,Department of Applied Life Science, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea
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Kumar H, Ha DH, Lee EJ, Park JH, Shim JH, Ahn TK, Kim KT, Ropper AE, Sohn S, Kim CH, Thakor DK, Lee SH, Han IB. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res Ther 2017; 8:262. [PMID: 29141662 PMCID: PMC5688755 DOI: 10.1186/s13287-017-0710-3] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 10/10/2017] [Accepted: 10/23/2017] [Indexed: 12/27/2022] Open
Abstract
Background Adipose tissue-derived mesenchymal stem cells (AT-MSCs) offer potential as a therapeutic option for chronic discogenic low back pain (LBP) because of their immunomodulatory functions and capacity for cartilage differentiation. The goal of this study was to assess the safety and tolerability of a single intradiscal implantation of combined AT-MSCs and hyaluronic acid (HA) derivative in patients with chronic discogenic LBP. Methods We performed a single-arm phase I clinical trial with a 12-month follow-up and enrolled 10 eligible chronic LBP patients. Chronic LBP had lasted for more than 3 months with a minimum intensity of 4/10 on a visual analogue scale (VAS) and disability level ≥ 30% on the Oswestry Disability Index (ODI). The 10 patients underwent a single intradiscal injection of combined HA derivative and AT-MSCs at a dose of 2 × 107 cells/disc (n = 5) or 4 × 107 cells/disc (n = 5). Safety and treatment outcomes were evaluated by assessing VAS, ODI, Short Form-36 (SF-36), and imaging (lumbar spine X-ray imaging and MRI) at regular intervals over 1 year. Results No patients were lost at any point during the 1-year clinical study. We observed no procedure or stem cell-related adverse events or serious adverse events during the 1-year follow-up period. VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses, and did not differ significantly between the two groups. Among six patients who achieved significant improvement in VAS, ODI, and SF-36, three patients (cases 4, 8, and 9) were determined to have increased water content based on an increased apparent diffusion coefficient on diffusion MRI. Conclusions Combined implantation of AT-MSCs and HA derivative in chronic discogenic LBP is safe and tolerable. However, the efficacy of combined AT-MSCs and HA should be investigated in a randomized controlled trial in a larger population. Trial registration ClinicalTrials.gov NCT02338271. Registered 7 January 2015.
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Affiliation(s)
- Hemant Kumar
- Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, South Korea
| | - Doo-Hoe Ha
- Department of Radiology, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, South Korea
| | - Eun-Jong Lee
- CHA Biotec®, Seongnam-si, Gyeonggi-do, 13488, South Korea
| | - Jun Hee Park
- Department of Neurosurgery, Shim Jeong Hospital, Seoul, 151715, South Korea
| | - Jeong Hyun Shim
- Department of Neurosurgery, Shim Jeong Hospital, Seoul, 151715, South Korea
| | - Tae-Keun Ahn
- Department of Orthopedic Surgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, South Korea
| | - Kyoung-Tae Kim
- Department of Neurosurgery, Kyungpook National University Hospital 130, Dongdeok-ro, Jung-gu, Daegu, 41944, Korea
| | - Alexander E Ropper
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Seil Sohn
- Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, South Korea
| | - Chung-Hun Kim
- Department of Plastic and Reconstructive Surgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, South Korea
| | | | - Soo-Hong Lee
- Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, 13496, South Korea.
| | - In-Bo Han
- Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, South Korea.
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Nakayama E, Matsumoto T, Kazama T, Kano K, Tokuhashi Y. Transplantation of dedifferentiation fat cells promotes intervertebral disc regeneration in a rat intervertebral disc degeneration model. Biochem Biophys Res Commun 2017; 493:1004-1009. [DOI: 10.1016/j.bbrc.2017.09.101] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 09/19/2017] [Indexed: 01/08/2023]
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Zhang Y, Guo W, Wang M, Hao C, Lu L, Gao S, Zhang X, Li X, Chen M, Li P, Jiang P, Lu S, Liu S, Guo Q. Co-culture systems-based strategies for articular cartilage tissue engineering. J Cell Physiol 2017; 233:1940-1951. [PMID: 28548713 DOI: 10.1002/jcp.26020] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 05/18/2017] [Indexed: 01/01/2023]
Abstract
Cartilage engineering facilitates repair and regeneration of damaged cartilage using engineered tissue that restores the functional properties of the impaired joint. The seed cells used most frequently in tissue engineering, are chondrocytes and mesenchymal stem cells. Seed cells activity plays a key role in the regeneration of functional cartilage tissue. However, seed cells undergo undesirable changes after in vitro processing procedures, such as degeneration of cartilage cells and induced hypertrophy of mesenchymal stem cells, which hinder cartilage tissue engineering. Compared to monoculture, which does not mimic the in vivo cellular environment, co-culture technology provides a more realistic microenvironment in terms of various physical, chemical, and biological factors. Co-culture technology is used in cartilage tissue engineering to overcome obstacles related to the degeneration of seed cells, and shows promise for cartilage regeneration and repair. In this review, we focus first on existing co-culture systems for cartilage tissue engineering and related fields, and discuss the conditions and mechanisms thereof. This is followed by methods for optimizing seed cell co-culture conditions to generate functional neo-cartilage tissue, which will lead to a new era in cartilage tissue engineering.
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Affiliation(s)
- Yu Zhang
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, People's Republic of China
| | - Weimin Guo
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, People's Republic of China
| | - Mingjie Wang
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, People's Republic of China
| | - Chunxiang Hao
- Institute of Anesthesia, Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Liang Lu
- Anhui Provincial Hospital, Hefei, People's Republic of China
| | - Shuang Gao
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, People's Republic of China
| | - Xueliang Zhang
- Shanxi Traditional Chinese, Taiyuan, People's Republic of China
| | - Xu Li
- School of Medicine, Naikai University, Tianjin, People's Republic of China
| | - Mingxue Chen
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, People's Republic of China
| | - Penghao Li
- School of Medicine, Naikai University, Tianjin, People's Republic of China
| | - Peng Jiang
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, People's Republic of China
| | - Shibi Lu
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, People's Republic of China
| | - Shuyun Liu
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, People's Republic of China
| | - Quanyi Guo
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, People's Republic of China
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Aker L, Ghannam M, Alzuabi MA, Jumah F, Alkhdour SM, Mansour S, Samara A, Cronk K, Massengale J, Holsapple J, Adeeb N, Oskouian RJ, Tubbs RS. Molecular Biology and Interactions in Intervertebral Disc Development, Homeostasis, and Degeneration, with Emphasis on Future Therapies: A Systematic Review. ACTA ACUST UNITED AC 2017. [DOI: 10.26632/ss.3.2017.1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Yao Y, Huang Y, Qian D, Zhang S, Chen Y, Bai B. Effect of Various Ratios of Co‐Cultured ATDC5 Cells and Chondrocytes on the Expression of Cartilaginous Phenotype in Microcavitary Alginate Hydrogel. J Cell Biochem 2017; 118:3607-3615. [DOI: 10.1002/jcb.26218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 06/13/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Yongchang Yao
- Department of Joint SurgeryThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510120China
- Guangdong key laboratory of orthopaedic technology and implant materialsGuangzhou510120China
| | - Yuyang Huang
- Department of Joint SurgeryThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510120China
- Guangdong key laboratory of orthopaedic technology and implant materialsGuangzhou510120China
| | - Dongyang Qian
- Department of Joint SurgeryThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510120China
- Guangdong key laboratory of orthopaedic technology and implant materialsGuangzhou510120China
| | - Shujiang Zhang
- Department of Joint SurgeryThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510120China
- Guangdong key laboratory of orthopaedic technology and implant materialsGuangzhou510120China
| | - Yi Chen
- Department of Joint SurgeryThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510120China
- Guangdong key laboratory of orthopaedic technology and implant materialsGuangzhou510120China
| | - Bo Bai
- Department of Joint SurgeryThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510120China
- Guangdong key laboratory of orthopaedic technology and implant materialsGuangzhou510120China
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Xiang H, Lin Y, Shen N, Wang Y, Wu X, Zhang G, Ma X, Chen B. Construction and assessment of bio-engineered intervertebral discs. Exp Ther Med 2017; 14:1929-1934. [PMID: 28962105 PMCID: PMC5609117 DOI: 10.3892/etm.2017.4764] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 02/24/2017] [Indexed: 11/05/2022] Open
Abstract
The present study assessed the value of bone marrow-mesenchymal stem cells (BM-MSCs) transformed by nucleus pulposus cells (NPs) for engineering of intervertebral discs. BM-MSCs and fetal NPs were cultured, planted onto polylactic acid-polyglycolic acid co-polymer (PLGA) and observed under inverted and scanning electron microscopes. PLGA scaffolds with adherent or suspended BM-MSCs and NPs were implanted into intervertebral discs of New Zealand white rabbits. Intervertebral signal intensity was evaluated by Thompson grading after 12 weeks. Proteoglycan and type II collagen were measured spectrophotometrically and immunohistochemically, respectively. Spindle or multi-angular BM-MSCs developed fibro-like phenotypesin co-culture with NPs and grew with a normal morphology when attached to PLGA scaffolds. A significant difference was observed in intervertebral proteoglycan expression and collagen II expression in the PLGA scaffold group vs. that in the control group implanted with BM-MSCs and NPs without a scaffold (3.93±0.31 vs. 3.52±0.26 mg/100 mg, 12.70±2.83 vs. 9.50±2.06, respectively). Thus, BM-MSCs can be co-cultured with NPs to enhance their differentiation into NPs for disc regeneration. In conclusion, PLGA scaffolds offer viable growing conditions and allow for the maintenance of mechanical properties and spatial structures of the engineered tissue, which meets the requirements of tissue-engineered discs that do not degenerate.
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Affiliation(s)
- Hongfei Xiang
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yazhou Lin
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Nana Shen
- Department of Rehabilitation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yan Wang
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xiaolin Wu
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Guoqing Zhang
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xuexiao Ma
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bohua Chen
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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Zhu Z, Chen G, Jiao W, Wang D, Cao Y, Zhang Q, Wang J. Identification of critical genes in nucleus pulposus cells isolated from degenerated intervertebral discs using bioinformatics analysis. Mol Med Rep 2017; 16:553-564. [PMID: 28586059 PMCID: PMC5482069 DOI: 10.3892/mmr.2017.6662] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 02/28/2017] [Indexed: 12/02/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is a pathological process, which may lead to lower back pain. The present study aimed to investigate the pathogenesis of IVD degeneration. GSE42611 was downloaded from Gene Expression Omnibus, including 4 nucleus pulposus samples isolated from degenerated IVDs and 4 nucleus pulposus samples separated from normal IVDs. The differentially expressed genes (DEGs) between the degenerated and normal samples were screened using the limma package in R. Functional and pathway enrichment analyses were conducted separately for the upregulated and downregulated genes, using Database for Annotation, Visualization and Integrated Discovery software. In addition, protein-protein interaction (PPI) networks were constructed using the Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. Finally, module analyses were conducted for the PPI networks using the MCODE plug-in in Cytoscape. A total of 558 DEGs were identified in the degenerated nucleus pulposus cells: 253 upregulated and 305 downregulated. Pathway enrichment analysis revealed that downregulated thrombospondin 1 (THBS1) was enriched in extracellular matrix-receptor interaction. Interleukin (IL)-6 in the PPI network for the upregulated genes and vascular endothelial growth factor A (VEGFA) in the PPI network for the downregulated genes had higher degrees. Additionally, four modules (µM1, µM2, µM3 and µM4) were identified from the PPI network for the upregulated genes. Four modules (dM1, dM2, dM3 and dM4) were identified from the PPI network for the downregulated genes. In the dM2 module, collagen genes and integrin subunit α4 (ITGA4) may interact with each other. Additionally, functional enrichment indicated that collagen genes were enriched in extracellular matrix organization. In conclusion, IL-6, VEGFA, THBS1, ITGA4 and collagen genes may contribute to the progression of IVD degeneration. These results suggested that the manipulation of these genes and their products may have potential as a novel therapeutic strategy for the treatment of patients with IVD.
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Affiliation(s)
- Zhuangchen Zhu
- Department of Orthopedics, Affiliated Hospital of Taishan Medical University, Tai'an, Shandong 271000, P.R. China
| | - Guang Chen
- Department of Orthopedics, Affiliated Hospital of Taishan Medical University, Tai'an, Shandong 271000, P.R. China
| | - Wei Jiao
- Department of Orthopedics, Affiliated Hospital of Taishan Medical University, Tai'an, Shandong 271000, P.R. China
| | - Defeng Wang
- Department of Orthopedics, Affiliated Hospital of Taishan Medical University, Tai'an, Shandong 271000, P.R. China
| | - Yan Cao
- Department of Orthopedics, Affiliated Hospital of Taishan Medical University, Tai'an, Shandong 271000, P.R. China
| | - Qingfu Zhang
- Department of Orthopedics, Affiliated Hospital of Taishan Medical University, Tai'an, Shandong 271000, P.R. China
| | - Junqin Wang
- Department of Orthopedics, Affiliated Hospital of Taishan Medical University, Tai'an, Shandong 271000, P.R. China
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Lu K, Li HY, Yang K, Wu JL, Cai XW, Zhou Y, Li CQ. Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Res Ther 2017; 8:108. [PMID: 28486958 PMCID: PMC5424403 DOI: 10.1186/s13287-017-0563-9] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 03/26/2017] [Accepted: 04/26/2017] [Indexed: 12/19/2022] Open
Abstract
Background The stem cell-based therapies for intervertebral disc degeneration have been widely studied. However, the mechanisms of mesenchymal stem cells interacting with intervertebral disc cells, such as nucleus pulposus cells (NPCs), remain unknown. Exosomes as a vital paracrine mechanism in cell–cell communication have been highly focused on. The purpose of this study was to detect the role of exosomes derived from bone marrow mesenchymal stem cells (BM-MSCs) and NPCs in their interaction with corresponding cells. Methods The exosomes secreted by BM-MSCs and NPCs were purified by differential centrifugation and identified by transmission electron microscope and immunoblot analysis of exosomal marker proteins. Fluorescence confocal microscopy was used to examine the uptake of exosomes by recipient cells. The effects of NPC exosomes on the migration and differentiation of BM-MSCs were determined by transwell migration assays and quantitative RT-PCR analysis of NPC phenotypic genes. Western blot analysis was performed to examine proteins such as aggrecan, sox-9, collagen II and hif-1α in the induced BM-MSCs. Proliferation and the gene expression profile of NPCs induced by BM-MSC exosomes were measured by Cell Counting Kit-8 and qRT-PCR analysis, respectively. Results Both the NPCs and BM-MSCs secreted exosomes, and these exosomes underwent uptake by the corresponding cells. NPC-derived exosomes promoted BM-MSC migration and induced BM-MSC differentiation to a nucleus pulposus-like phenotype. BM-MSC-derived exosomes promoted NPC proliferation and healthier extracellular matrix production in the degenerate NPCs. Conclusion Our study indicates that the exosomes act as an important vehicle in information exchange between BM-MSCs and NPCs. Given a variety of functions and multiple advantages, exosomes alone or loaded with specific genes and drugs would be an appropriate option in a cell-free therapy strategy for intervertebral disc degeneration.
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Affiliation(s)
- Kang Lu
- Department of Orthopedics, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Hai-Yin Li
- Department of Orthopedics, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Kuang Yang
- Department of Orthopedics, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Jun-Long Wu
- Department of Orthopedics, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Xiao-Wei Cai
- Department of Dermatology, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Yue Zhou
- Department of Orthopedics, XinQiao Hospital, Third Military Medical University, Chongqing, China
| | - Chang-Qing Li
- Department of Orthopedics, XinQiao Hospital, Third Military Medical University, Chongqing, China.
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Zhu LG, Feng MS, Zhan JW, Zhang P, Yu J. Effect of Static Load on the Nucleus Pulposus of Rabbit Intervertebral Disc Motion Segment in Ex vivo Organ Culture. Chin Med J (Engl) 2017; 129:2338-46. [PMID: 27647194 PMCID: PMC5040021 DOI: 10.4103/0366-6999.190666] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Background: The development of mechanically active culture systems helps increase the understanding of the role of mechanical stress in intervertebral disc (IVD) degeneration. Motion segment cultures allow for preservation of the native IVD structure, and adjacent vertebral bodies facilitate the application and control of mechanical loads. The purpose of this study was to establish loading and organ culture methods for rabbit IVD motion segments to study the effect of static load on the whole disc organ. Methods: IVD motion segments were harvested from rabbit lumbar spines and cultured in no-loading 6-well plates (control conditions) or custom-made apparatuses under a constant, compressive load (3 kg, 0.5 MPa) for up to 14 days. Tissue integrity, matrix synthesis, and the matrix gene expression profile were assessed after 3, 7, and 14 days of culturing and compared with those of fresh tissues. Results: The results showed that ex vivo culturing of motion segments preserved tissue integrity under no-loading conditions for 14 days whereas the static load gradually destroyed the morphology after 3 days. Proteoglycan contents were decreased under both conditions, with a more obvious decrease under static load, and proteoglycan gene expression was also downregulated. However, under static load, immunohistochemical staining intensity and collagen Type II alpha 1 (COL2A1) gene expression were significantly enhanced (61.54 ± 5.91, P = 0.035) and upregulated (1.195 ± 0.040, P = 0.000), respectively, compared with those in the controls (P < 0.05). In contrast, under constant compression, these trends were reversed. Our initial results indicated that short-term static load stimulated the synthesis of collagen Type II alpha 1; however, sustained constant compression led to progressive degeneration and specifically to a decreased proteoglycan content. Conclusions: A loading and organ culture system for ex vivo rabbit IVD motion segments was developed. Using this system, we were able to study the effects of mechanical stimulation on the biology of IVDs, as well as the pathomechanics of IVD degeneration.
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Affiliation(s)
- Li-Guo Zhu
- Spine Department 2, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102; Key Laboratory of Beijing of Palasy Technology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Min-Shan Feng
- Spine Department 2, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102; Key Laboratory of Beijing of Palasy Technology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Jia-Wen Zhan
- Key Laboratory of Beijing of Palasy Technology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102; General Orthopedics Department, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Ping Zhang
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Jie Yu
- Spine Department 2, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
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Bach FC, Miranda-Bedate A, van Heel FW, Riemers FM, Müller MC, Creemers LB, Ito K, Benz K, Meij BP, Tryfonidou MA. Bone Morphogenetic Protein-2, But Not Mesenchymal Stromal Cells, Exert Regenerative Effects on Canine and Human Nucleus Pulposus Cells. Tissue Eng Part A 2017; 23:233-242. [DOI: 10.1089/ten.tea.2016.0251] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Affiliation(s)
- Frances C. Bach
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Alberto Miranda-Bedate
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Ferdi W.M. van Heel
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Frank M. Riemers
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Margot C.M.E. Müller
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Laura B. Creemers
- Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Keita Ito
- Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | | | - Björn P. Meij
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Marianna A. Tryfonidou
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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Vedicherla S, Buckley CT. Cell-based therapies for intervertebral disc and cartilage regeneration- Current concepts, parallels, and perspectives. J Orthop Res 2017; 35:8-22. [PMID: 27104885 DOI: 10.1002/jor.23268] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/08/2016] [Indexed: 02/04/2023]
Abstract
Lower back pain from degenerative disc disease represents a global health burden, and presents a prominent opportunity for regenerative therapeutics. While current regenerative therapies such as autologous disc chondrocyte transplantation (ADCT), allogeneic juvenile chondrocyte implantation (NuQu®), and immunoselected allogeneic adipose derived precursor cells (Mesoblast) show exciting clinical potential, limitations remain. The heterogeneity of preclinical approaches and the paucity of clinical guidance have limited translational outcomes in disc repair, lagging almost a decade behind cartilage repair. Advances in cartilage repair have evolved to single step approaches with improved orthopedic repair and regeneration. Elements from cartilage regeneration endeavors could be adopted and applied to harness translatable approaches and deliver a clinically and economically feasible regenerative surgery for back pain. In this article, we trace the developments behind the translational success of cartilage repair, examine elements to consider in achieving disc regeneration, and the need for surgical redesign. We further discuss clinical parameters, objectives, and coordination required to deliver improved regenerative surgery. Cell source, processing, and delivery modalities are key issues to be addressed in considering surgical redesign. Advances in biomanufacturing, tissue cryobanking, and point of care cell processing technology may enable intraoperative solutions for single step procedures. To maximize translational success a triad partnership between clinicians, industry, and researchers will be critical in providing instructive clinical guidelines for design as well as practical and economic considerations. This will allow a consensus in research ventures and add regenerative surgery into the algorithm in managing and treating a debilitating condition such as back pain. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:8-22, 2017.
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Affiliation(s)
- Srujana Vedicherla
- Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.,School of Medicine, Trinity College Dublin, Ireland
| | - Conor T Buckley
- Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.,Department of Mechanical and Manufacturing Engineering, School of Engineering, Trinity College Dublin, Ireland
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