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Alonso-Frías P, Francés-Herrero E, Bueno-Fernandez C, Gómez-Álvarez M, Agustina-Hernández M, Cervelló I, Cozzolino M. Beneficial Effects of Infiltration of Platelet-Rich Plasma in the Endometrium. BIOLOGY 2025; 14:319. [PMID: 40282184 PMCID: PMC12024569 DOI: 10.3390/biology14040319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/14/2025] [Accepted: 03/15/2025] [Indexed: 04/29/2025]
Abstract
Platelet-rich plasma (PRP) is a concentrated product of autologous plasma platelets. It promotes the repair of tissues with low healing potential by providing supraphysiological amounts of essential growth factors and has recently become more popular in endometrial repair, achieving exciting clinical results. PRP treatment has proven to improve fertility outcomes in patients with a poor endometrial environment. However, the mechanism is not yet clear. Previous preclinical models also showed that PRP treatment decreased the expression of inflammatory markers and fibrosis, increased the endometrial proliferation rate and gene expression, and enhanced the pregnancy rate. The modulation of the endometrial immune environment and endometrial microbial community by PRP treatment appeared to be the key mechanism by which it improved endometrial receptivity. This review summarized the potential of adult PRP based on its composition and applications and the biological mechanisms and biological modifications in the endometrium after PRP instillation in preclinical models.
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Affiliation(s)
- Paula Alonso-Frías
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain; (P.A.-F.); (E.F.-H.); (M.G.-Á.); (M.A.-H.); (I.C.); (M.C.)
- Department of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Emilio Francés-Herrero
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain; (P.A.-F.); (E.F.-H.); (M.G.-Á.); (M.A.-H.); (I.C.); (M.C.)
- Department of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Clara Bueno-Fernandez
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain; (P.A.-F.); (E.F.-H.); (M.G.-Á.); (M.A.-H.); (I.C.); (M.C.)
| | - María Gómez-Álvarez
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain; (P.A.-F.); (E.F.-H.); (M.G.-Á.); (M.A.-H.); (I.C.); (M.C.)
| | - Marcos Agustina-Hernández
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain; (P.A.-F.); (E.F.-H.); (M.G.-Á.); (M.A.-H.); (I.C.); (M.C.)
| | - Irene Cervelló
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain; (P.A.-F.); (E.F.-H.); (M.G.-Á.); (M.A.-H.); (I.C.); (M.C.)
| | - Mauro Cozzolino
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), 46026 Valencia, Spain; (P.A.-F.); (E.F.-H.); (M.G.-Á.); (M.A.-H.); (I.C.); (M.C.)
- IVIRMA Global Research Alliance, IVI Roma, 00197 Rome, Italy
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Elmounedi N, Bahloul W, Keskes H. Current Therapeutic Strategies of Intervertebral Disc Regenerative Medicine. Mol Diagn Ther 2024; 28:745-775. [PMID: 39158834 DOI: 10.1007/s40291-024-00729-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2024] [Indexed: 08/20/2024]
Abstract
Intervertebral disc degeneration (IDD) is one of the most frequent causes of low back pain. No treatment is currently available to delay the progression of IDD. Conservative treatment or surgical interventions is only used to target the symptoms of IDD rather than treat the underlying cause. Currently, numerous potential therapeutic strategies are available, including molecular therapy, gene therapy, and cell therapy. However, the hostile environment of degenerated discs is a major problem that has hindered the clinical applicability of such approaches. In this regard, the design of drugs using alternative delivery systems (macro-, micro-, and nano-sized particles) may resolve this problem. These can protect and deliver biomolecules along with helping to improve the therapeutic effect of drugs via concentrating, protecting, and prolonging their presence in the degenerated disc. This review summarizes the research progress of diagnosis and the current options for treating IDD.
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Affiliation(s)
- Najah Elmounedi
- Cell Therapy and Experimental Surgery of Musculoskeletal System LR18SP11 Lab, Sfax Faculty of Medicine, Majida Boulila Road, 3029, Sfax, Tunisia.
| | - Walid Bahloul
- Cell Therapy and Experimental Surgery of Musculoskeletal System LR18SP11 Lab, Sfax Faculty of Medicine, Majida Boulila Road, 3029, Sfax, Tunisia
- Department of Orthopedics and Traumatology, CHU Habib Bourguiba, Sfax, Tunisia
| | - Hassib Keskes
- Cell Therapy and Experimental Surgery of Musculoskeletal System LR18SP11 Lab, Sfax Faculty of Medicine, Majida Boulila Road, 3029, Sfax, Tunisia
- Department of Orthopedics and Traumatology, CHU Habib Bourguiba, Sfax, Tunisia
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Peredo AP, Tsinman TK, Bonnevie ED, Jiang X, Smith HE, Gullbrand SE, Dyment NA, Mauck RL. Developmental morphogens direct human induced pluripotent stem cells toward an annulus fibrosus-like cell phenotype. JOR Spine 2024; 7:e1313. [PMID: 38283179 PMCID: PMC10810760 DOI: 10.1002/jsp2.1313] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 01/30/2024] Open
Abstract
Introduction Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs toward the AF fate remain unknown. Methods iPSC-derived sclerotome cells were treated with various combinations of developmental signals including transforming growth factor beta 3 (TGF-β3), connective tissue growth factor (CTGF), platelet derived growth factor BB (PDGF-BB), insulin-like growth factor 1 (IGF-1), or the Hedgehog pathway activator, Purmorphamine, and gene expression changes in major AF-associated ECM genes were assessed. The top performing combination treatments were further validated by using three distinct iPSC lines and by assessing the production of upregulated ECM proteins of interest. To conduct a broader analysis of the transcriptomic shifts elicited by each factor combination, and to compare genetic profiles of treated cells to mature human AF cells, a 96.96 Fluidigm gene expression array was applied, and principal component analysis was employed to identify the transcriptional signatures of each cell population and treatment group in comparison to native AF cells. Results TGF-β3, in combination with PDGF-BB, CTGF, or IGF-1, induced an upregulation of key AF ECM genes in iPSC-derived sclerotome cells. In particular, treatment with a combination of TGF-β3 with PDGF-BB for 14 days significantly increased gene expression of collagen II and aggrecan and increased protein deposition of collagen I and elastin compared to other treatment groups. Assessment of genes uniquely highly expressed by AF cells or SCL cells, respectively, revealed a shift toward the genetic profile of AF cells with the addition of TGF-β3 and PDGF-BB for 14 days. Discussion These findings represent an initial approach to guide human induced pluripotent stem cells toward an AF-like fate for cellular delivery strategies.
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Affiliation(s)
- Ana P. Peredo
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Tonia K. Tsinman
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Edward D. Bonnevie
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Xi Jiang
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Harvey E. Smith
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Sarah E. Gullbrand
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Nathaniel A. Dyment
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Robert L. Mauck
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
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Wang HS, Lin S, Yu HM. Exosome-mediated Repair of Intervertebral Disc Degeneration: The Potential Role of miRNAs. Curr Stem Cell Res Ther 2024; 19:798-808. [PMID: 37150986 DOI: 10.2174/1574888x18666230504094233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 05/09/2023]
Abstract
Intervertebral disc degeneration (IVDD) is a serious condition that manifests as low back pain, intervertebral disc protrusion, and spinal canal stenosis. At present, the main treatment methods for IVDD are surgical interventions such as discectomy, total disc replacement, and spinal fusion. However, these interventions have shown limitations, such as recurrent lumbar disc herniation after discectomy, lesions in adjacent segments, and failure of fixation. To overcome these shortcomings, researchers have been exploring stem cell transplantation therapy, such as mesenchymal stem cell (MSC) transplantation, but the treatment results are still controversial. Therefore, researchers are in search of new methods that are more efficient and have better outcomes. The exosomes from stem cells contain a variety of bioactive molecules that mediate cell interactions, and these components have been investigated for their potential therapeutic role in the repair of various tissue injuries. Recent studies have shown that MSC-derived miRNAs in exosomes and vesicles have therapeutic effects on nucleus pulposus cells, annulus fibrosus, and cartilage endplate. miRNAs play a role in many cell activities, such as cell proliferation, apoptosis, and cytokine release, by acting on mRNA translation, and they may have immense therapeutic potential, especially when combined with stem cell therapy. This article reviews the current status of research on intervertebral disc repair, especially with regard to the latest research findings on the molecular biological mechanisms of miRNAs in MSC-derived exosomes in intervertebral disc repair.
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Affiliation(s)
- Han-Shi Wang
- Department of Orthopaedic, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, Australia
| | - Hai-Ming Yu
- Department of Orthopaedic, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
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Zhang A, Cheng Z, Chen Y, Shi P, Gan W, Zhang Y. Emerging tissue engineering strategies for annulus fibrosus therapy. Acta Biomater 2023:S1742-7061(23)00337-9. [PMID: 37330029 DOI: 10.1016/j.actbio.2023.06.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 05/31/2023] [Accepted: 06/12/2023] [Indexed: 06/19/2023]
Abstract
Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. IVD herniation manifests as the nucleus pulposus (NP) protruding beyond the boundaries of the intervertebral disc due to disruption of the annulus fibrosus (AF). With a deepening understanding of the importance of the AF structure in the pathogenesis of intervertebral disc degeneration, numerous advanced therapeutic strategies for AF based on tissue engineering, cellular regeneration, and gene therapy have emerged. However, there is still no consensus concerning the optimal approach for AF regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions. STATEMENT OF SIGNIFICANCE: Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. However, there is still no consensus concerning the optimal approach for annulus fibrosus (AF) regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions.
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Affiliation(s)
- Anran Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhangrong Cheng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuhang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Pengzhi Shi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weikang Gan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yukun Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Muthu S, Jeyaraman M, Chellamuthu G, Jeyaraman N, Jain R, Khanna M. Does the Intradiscal Injection of Platelet Rich Plasma Have Any Beneficial Role in the Management of Lumbar Disc Disease? Global Spine J 2022; 12:503-514. [PMID: 33840260 PMCID: PMC9121148 DOI: 10.1177/2192568221998367] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
STUDY DESIGN Systematic review and meta-analysis. OBJECTIVES We performed this meta-analysis to evaluate whether intradiscal Platelet Rich Plasma(PRP) injection has any beneficial role in the management of lumbar disc disease. METHODS We conducted independent and duplicate electronic database searches including PubMed, Embase, and Cochrane Library till September 2020 for studies investigating the role of intradiscal PRP in the management of lumbar disc disease. The analysis was performed in the R platform using OpenMeta[Analyst] software. RESULTS 13 studies including 2 RCTs, 5 prospective, and 6 retrospective studies involving 319 patients were included in the meta-analysis. A single-arm meta-analysis of the included studies showed a beneficial effect of the intervention in terms of pain relief outcomes like VAS score (p < 0.001), pain component of SF-36 (p = 0.003) while such improvement was not seen in functional outcome measures like ODI score (p = 0.071), the physical component of SF-36 (p = 0.130) with significant heterogeneity noted among the included studies. No structural improvement in magnetic resonance imaging was observed (p = 0.106). No additional procedure-related adverse events were noted in the included studies (p = 0.662). CONCLUSION There is a paucity of high-quality studies to give conclusive evidence on the benefits of intradiscal PRP for lumbar disc disease. Although intradiscal PRP injection has shown some beneficial effect in controlling pain for lumbar disc disease, we could not find structural or functional improvement from the included studies. Hence, we recommend large double-blind double-arm randomized controlled studies to analyze the benefits of the intervention being analyzed.
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Affiliation(s)
- Sathish Muthu
- Indian Orthopaedic Rheumatology Association, Lucknow, Uttar Pradesh, India
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
| | - Madhan Jeyaraman
- Indian Orthopaedic Rheumatology Association, Lucknow, Uttar Pradesh, India
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
| | - Girinivasan Chellamuthu
- Indian Orthopaedic Rheumatology Association, Lucknow, Uttar Pradesh, India
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Indian Orthopaedic Rheumatology Association, Lucknow, Uttar Pradesh, India
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
| | - Rashmi Jain
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
| | - Manish Khanna
- Indian Orthopaedic Rheumatology Association, Lucknow, Uttar Pradesh, India
- Indian Stem Cell Study Group, Lucknow, Uttar Pradesh, India
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Lin H, Tian S, Peng Y, Wu L, Xiao Y, Qing X, Shao Z. IGF Signaling in Intervertebral Disc Health and Disease. Front Cell Dev Biol 2022; 9:817099. [PMID: 35178405 PMCID: PMC8843937 DOI: 10.3389/fcell.2021.817099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 12/27/2021] [Indexed: 11/18/2022] Open
Abstract
Low back pain (LBP) is a common musculoskeletal symptom, which brings a lot of pain and economic loss to patients. One of the most common causes of LBP is intervertebral disc degeneration (IVDD). However, pathogenesis is still debated, and therapeutic options are limited. Insulin-like growth factor (IGF) signaling pathways play an important role in regulating different cell processes, including proliferation, differentiation, migration, or cell death, which are critical to the homeostasis of tissues and organs. The IGF signaling is crucial in the occurrence and progression of IVDD. The activation of IGF signaling retards IVDD by increasing cell proliferation, promoting extracellular matrix (ECM) synthesis, inhibiting ECM decomposition, and preventing apoptosis and senescence of disc cells. However, abnormal activation of IGF signaling may promote the process of IVDD. IGF signaling is currently considered to have a promising treatment prospect for IVDD. An in-depth understanding of the role of IGF signaling in IVDD may help find a novel approach for IVDD treatment.
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Affiliation(s)
- Hui Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuo Tian
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yizhong Peng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Wu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Xiao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangcheng Qing
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zengwu Shao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ekram S, Khalid S, Salim A, Khan I. Regulating the fate of stem cells for regenerating the intervertebral disc degeneration. World J Stem Cells 2021; 13:1881-1904. [PMID: 35069988 PMCID: PMC8727226 DOI: 10.4252/wjsc.v13.i12.1881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/12/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden. The etiology of intervertebral disc (IVD) degeneration is complicated, and its mechanism is still not completely understood. Factors such as aging, systemic inflammation, biochemical mediators, toxic environmental factors, physical injuries, and genetic factors are involved in the progression of its pathophysiology. Currently, no therapy for restoring degenerated IVD is available except pain management, reduced physical activities, and surgical intervention. Therefore, it is imperative to establish regenerative medicine-based approaches to heal and repair the injured disc, repopulate the cell types to retain water content, synthesize extracellular matrix, and strengthen the disc to restore normal spine flexion. Cellular therapy has gained attention for IVD management as an alternative therapeutic option. In this review, we present an overview of the anatomical and molecular structure and the surrounding pathophysiology of the IVD. Modern therapeutic approaches, including proteins and growth factors, cellular and gene therapy, and cell fate regulators are reviewed. Similarly, small molecules that modulate the fate of stem cells for their differentiation into chondrocytes and notochordal cell types are highlighted.
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Affiliation(s)
- Sobia Ekram
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Shumaila Khalid
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Sindh, Pakistan.
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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: 15] [Impact Index Per Article: 3.0] [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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Intervertebral Disc Diseases PART 2: A Review of the Current Diagnostic and Treatment Strategies for Intervertebral Disc Disease. Int J Mol Sci 2020; 21:ijms21062135. [PMID: 32244936 PMCID: PMC7139690 DOI: 10.3390/ijms21062135] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/12/2020] [Accepted: 03/18/2020] [Indexed: 12/25/2022] Open
Abstract
With an aging population, there is a proportional increase in the prevalence of intervertebral disc diseases. Intervertebral disc diseases are the leading cause of lower back pain and disability. With a high prevalence of asymptomatic intervertebral disc diseases, there is a need for accurate diagnosis, which is key to management. A thorough understanding of the pathophysiology and clinical manifestation aids in understanding the natural history of these conditions. Recent developments in radiological and biomarker investigations have potential to provide noninvasive alternatives to the gold standard, invasive discogram. There is a large volume of literature on the management of intervertebral disc diseases, which we categorized into five headings: (a) Relief of pain by conservative management, (b) restorative treatment by molecular therapy, (c) reconstructive treatment by percutaneous intervertebral disc techniques, (d) relieving compression and replacement surgery, and (e) rigid fusion surgery. This review article aims to provide an overview on various current diagnostic and treatment options and discuss the interplay between each arms of these scientific and treatment advancements, hence providing an outlook of their potential future developments and collaborations in the management of intervertebral disc diseases.
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11
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Du J, Long R, Nakai T, Sakai D, Benneker L, Zhou G, Li B, Eglin D, Iatridis J, Alini M, Grad S, Li Z. Functional cell phenotype induction with TGF-β1 and collagen-polyurethane scaffold for annulus fibrosus rupture repair. Eur Cell Mater 2020; 39:1-17. [PMID: 31899537 PMCID: PMC7027376 DOI: 10.22203/ecm.v039a01] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Appropriate cell sources, bioactive factors and biomaterials for generation of functional and integrated annulus fibrosus (AF) tissue analogues are still an unmet need. In the present study, the AF cell markers, collagen type I, cluster of differentiation 146 (CD146), mohawk (MKX) and smooth muscle protein 22α (SM22α) were found to be suitable indicators of functional AF cell induction. In vitro 2D culture of human AF cells showed that transforming growth factor β1 (TGF-β1) upregulated the expression of the functional AF markers and increased cell contractility, indicating that TGF-β1-pre-treated AF cells were an appropriate cell source for AF tissue regeneration. Furthermore, a tissue engineered construct, composed of polyurethane (PU) scaffold with a TGF-β1-supplemented collagen type I hydrogel and human AF cells, was evaluated with in vitro 3D culture and ex vivo preclinical bioreactor-loaded organ culture models. The collagen type I hydrogel helped maintaining the AF functional phenotype. TGF-β1 supplement within the collagen I hydrogel further promoted cell proliferation and matrix production of AF cells within in vitro 3D culture. In the ex vivo IVD organ culture model with physiologically relevant mechanical loading, TGF-β1 supplement in the transplanted constructs induced the functional AF cell phenotype and enhanced collagen matrix synthesis. In conclusion, TGF-β1-containing collagen-PU constructs can induce the functional cell phenotype of human AF cells in vitro and in situ. This combined cellular, biomaterial and bioactive agent therapy has a great potential for AF tissue regeneration and rupture repair.
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Affiliation(s)
- J. Du
- AO Research Institute Davos, Davos, Switzerland
| | - R.G. Long
- AO Research Institute Davos, Davos, Switzerland,Icahn School of Medicine at Mount Sinai, New York, USA,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland
| | - T. Nakai
- Tokai University School of Medicine, Isehara, Japan,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland
| | - D. Sakai
- Tokai University School of Medicine, Isehara, Japan,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland
| | - L.M. Benneker
- Inselspital, University of Bern, Bern, Switzerland,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland
| | - G. Zhou
- Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Department of Medical Cell Biology and Genetics, Health Sciences Centre, Shenzhen University, Shenzhen, China
| | - B. Li
- Orthopaedic Institute, Medical College, Soochow University, Suzhou, Jiangsu, China
| | - D. Eglin
- AO Research Institute Davos, Davos, Switzerland,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland
| | - J.C. Iatridis
- Icahn School of Medicine at Mount Sinai, New York, USA,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland
| | - M. Alini
- AO Research Institute Davos, Davos, Switzerland,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland
| | - S. Grad
- AO Research Institute Davos, Davos, Switzerland,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland
| | - Z. Li
- AO Research Institute Davos, Davos, Switzerland,Collaborative Research Program Annulus Fibrosus Repair, AO Foundation, Davos, Switzerland,Address for correspondence: Zhen Li, PhD, AO Research Institute Davos, Clavadelerstrasse 8, 7270, Davos Platz, Switzerland. Telephone number: +41 814142325
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12
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The effects of simulated +Gz and microgravity on intervertebral disc degeneration in rabbits. Sci Rep 2019; 9:16608. [PMID: 31719640 PMCID: PMC6851093 DOI: 10.1038/s41598-019-53246-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 10/01/2019] [Indexed: 01/07/2023] Open
Abstract
The overall objective of this study was to test the hypothesis that +Gz (hypergravity/positive acceleration) and microgravity can both aggravate intervertebral disc degeneration (IVDD). Due to +Gz and microgravity, many pilots develop IVDD. However, the lack of animal models of IVDD under conditions of simulated +Gz and microgravity has hampered research on the onset and prevention of IVDD. Rabbits were randomly allotted to a control group, microgravity group, +Gz group, or mixed (+Gz + microgravity) group. A tail-suspension model was utilized to simulate a microgravity environment and an animal centrifuge to mimic +Gz conditions. After exposure to the above conditions for 4, 8, and 24 weeks, the body weights (BW) of animals in the control group gradually increased over time, while those of animals in the microgravity and mixed groups both decreased (p < 0.001). As compared with the control group, the proteoglycan content of animals in the other three groups was significantly reduced (F = 192.83, p < 0.001). The imageological, histopathological, and immunohistochemical changes to the L6-S1 intervertebral disc samples suggests that the effects of +Gz and microgravity can aggravate IVDD over time. The mixed effects of +Gz and microgravity had the greatest effect on degeneration and +Gz had a particularly greater effect than microgravity.
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13
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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: 65] [Impact Index Per Article: 10.8] [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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14
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Abstract
Development of the axial skeleton is a complex, stepwise process that relies on intricate signaling and coordinated cellular differentiation. Disruptions to this process can result in a myriad of skeletal malformations that range in severity. The notochord and the sclerotome are embryonic tissues that give rise to the major components of the intervertebral discs and the vertebral bodies of the spinal column. Through a number of mouse models and characterization of congenital abnormalities in human patients, various growth factors, transcription factors, and other signaling proteins have been demonstrated to have critical roles in the development of the axial skeleton. Balance between opposing growth factors as well as other environmental cues allows for cell fate specification and divergence of tissue types during development. Furthermore, characterization of progenitor cells for specific cell lineages has furthered the understanding of specific spatiotemporal cues that cells need in order to initiate and complete development of distinct tissues. Identifying specific marker genes that can distinguish between the various embryonic and mature cell types is also of importance. Clinically, understanding developmental clues can aid in the generation of therapeutics for musculoskeletal disease through the process of developmental engineering. Studies into potential stem cell therapies are based on knowledge of the normal processes that occur in the embryo, which can then be applied to stepwise tissue engineering strategies.
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Affiliation(s)
| | | | - Rosa Serra
- Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States.
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15
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Séguin CA, Chan D, Dahia CL, Gazit Z. Latest advances in intervertebral disc development and progenitor cells. JOR Spine 2018; 1:e1030. [PMID: 30687811 PMCID: PMC6338208 DOI: 10.1002/jsp2.1030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 07/23/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022] Open
Abstract
This paper is a concise review aiming to assemble the most relevant topics presented by the authors at ORS-Philadelphia Spine Research Society Fourth International Spine Research Symposium. It centers on the latest advances in disc development, its main structural entities, and the populating cells, with emphasis on the advances in pivotal molecular pathways responsible for forming the intervertebral discs (IVD). The objective of finding and emphasizing pathways and mechanisms that function to control tissue formation is to identify and to explore modifications occurring during normal aging, disease, and tissue repair. Thus, to comprehend that the cellular and molecular basis of tissue degeneration are crucial in the study of the dynamic interplay that includes cell-cell communication, gene regulation, and growth factors required to form a healthy and functional tissue during normal development.
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Affiliation(s)
- Cheryle A Séguin
- Schulich School of Medicine and Dentistry Bone and Joint Institute, The University of Western Ontario London ON Canada
| | - Danny Chan
- School of Biomedical Sciences LKS Faculty of Medicine, The University of Hong Kong Hong Kong China
| | - Chitra L Dahia
- Hospital for Special Surgery Weill Cornell Medical College New York New York
| | - Zulma Gazit
- Department of Surgery Regenerative Medicine Institute, Cedars-Sinai Medical Center Los Angeles California
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16
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Kennon JC, Awad ME, Chutkan N, DeVine J, Fulzele S. Current insights on use of growth factors as therapy for Intervertebral Disc Degeneration. Biomol Concepts 2018; 9:43-52. [PMID: 29779014 DOI: 10.1515/bmc-2018-0003] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 03/23/2018] [Indexed: 02/07/2023] Open
Abstract
Chronic low back pain is a critical health problem and a leading cause of disability in aging populations. A major cause of low back pain is considered to be the degeneration of the intervertebral disc (IVD). Recent advances in therapeutics, particularly cell and tissue engineering, offer potential methods for inhibiting or reversing IVD degeneration, which have previously been impossible. The use of growth factors is under serious consideration as a potential therapy to enhance IVD tissue regeneration. We reviewed the role of chosen prototypical growth factors and growth factor combinations that have the capacity to improve IVD restoration. A number of growth factors have demonstrated potential to modulate the anabolic and anticatabolic effects in both in vitro and animal studies of IVD tissue engineering. Members of the transforming growth factor-β superfamily, IGF-1, GDF-5, BMP-2, BMP-7, and platelet-derived growth factor have all been investigated as possible therapeutic options for IVD regeneration. The role of growth factors in IVD tissue engineering appears promising; however, further extensive research is needed at both basic science and clinical levels before its application is appropriate for clinical use.
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Affiliation(s)
- Justin C Kennon
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA, USA
| | - Mohamed E Awad
- Department of Oral Biology, Augusta University, Augusta, GA, USA
| | - Norman Chutkan
- Banner University Medical Center, University of Arizona College of Medicine - Phoenix, The CORE Institute, Phoenix, AZ, USA
| | - John DeVine
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA, USA
| | - Sadanand Fulzele
- Department of Orthopaedic Surgery, Augusta University, Augusta, GA, USA.,Institute of Regenerative and Reparative Medicine, Augusta University, Augusta, GA, USA
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17
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Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review. Gene Ther 2018; 25:67-82. [DOI: 10.1038/s41434-018-0004-0] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 11/30/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022]
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18
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Elsaadany M, Winters K, Adams S, Stasuk A, Ayan H, Yildirim-Ayan E. Equiaxial Strain Modulates Adipose-derived Stem Cell Differentiation within 3D Biphasic Scaffolds towards Annulus Fibrosus. Sci Rep 2017; 7:12868. [PMID: 28993681 PMCID: PMC5634474 DOI: 10.1038/s41598-017-13240-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 09/19/2017] [Indexed: 12/14/2022] Open
Abstract
Recurrence of intervertebral disc (IVD) herniation is the most important factor leading to chronic low back pain and subsequent disability after discectomy. Efficacious annulus fibrosus (AF) repair strategy that delivers cells and biologics to IVD injury site is needed to limit the progression of disc degeneration and promote disc self-regeneration capacities after discectomy procedures. In this study, a biphasic mechanically-conditioned scaffold encapsulated with human adipose-derived stem cells (ASCs) is studied as a potential treatment strategy for AF defects. Equiaxial strains and frequencies were applied to ASCs-encapsulated scaffolds to identify the optimal loading modality to induce AF differentiation. Equiaxial loading resulted in 2–4 folds increase in secretion of extracellular matrix proteins and the reorganization of the matrix fibers and elongations of the cells along the load direction. Further, the equiaxial load induced region-specific differentiation of ASCs within the inner and outer regions of the biphasic scaffolds. Gene expression of AF markers was upregulated with 5–30 folds within the equiaxially loaded biphasic scaffolds compared to unstrained samples. The results suggest that there is a specific value of equiaxial strain favorable to differentiate ASCs towards AF lineage and that ASCs-embedded biphasic scaffold can potentially be utilized to repair the AF defects.
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Affiliation(s)
| | - Kayla Winters
- Department of Bioengineering, University of Toledo, Toledo, OH, USA
| | - Sarah Adams
- Department of Bioengineering, University of Toledo, Toledo, OH, USA
| | - Alexander Stasuk
- Department of Bioengineering, University of Toledo, Toledo, OH, USA
| | - Halim Ayan
- Department of Bioengineering, University of Toledo, Toledo, OH, USA
| | - Eda Yildirim-Ayan
- Department of Bioengineering, University of Toledo, Toledo, OH, USA.
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19
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Efficacy of Platelet-Rich Plasma in Retarding Intervertebral Disc Degeneration: A Meta-Analysis of Animal Studies. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7919201. [PMID: 28752097 PMCID: PMC5511641 DOI: 10.1155/2017/7919201] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Revised: 03/24/2017] [Accepted: 04/11/2017] [Indexed: 01/04/2023]
Abstract
Objectives Several animal studies have demonstrated the positive effects of platelet-rich plasma (PRP) on disc degeneration retardation. The present meta-analysis was to verify the efficacy of PRP in retarding disc degeneration in animal. Methods Relevant studies were identified and evaluated according to our inclusion and exclusion criteria. The standardized mean difference (SMD) and related 95% confidence interval (95% CI) were estimated to assess PRP efficiency. Results In total, eleven studies were included in this meta-analysis. Significant differences were found in the PRP treatment group, which showed increased disc height (SMD = 2.66, 95% CI: 1.86, 3.47, p = 0.000), increased MRI T2 signal intensity (SMD = −3.29, 95% CI: −4.44, −2.13, p = 0.000), and decreased histological degeneration grade (SMD = −4.28, 95% CI: −5.26, −3.30, p = 0.000). However, no significant increase in collagen II expression was found (SMD = 25389.74, 95% CI: −27585.72, 78365.21, p = 0.348). Apart from the subgroup analysis of the disc height based on animal species (pig) and disc degeneration model (chymopapain induction), other subgroup analysis based on animal species (rabbit and rat), study design, disc degeneration model, and follow-up period demonstrated that PRP treatment can significantly restore disc height and increase MRI T2 signal intensity. Conclusions PRP treatment is potentially effective in restoring disc height of rodent rabbit and rat, reducing histological degeneration grade, and increasing MRI T2 image signal. PRP injection may be promising therapy for retarding disc degeneration.
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20
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Kraus P, Lufkin T. Implications for a Stem Cell Regenerative Medicine Based Approach to Human Intervertebral Disk Degeneration. Front Cell Dev Biol 2017; 5:17. [PMID: 28326305 PMCID: PMC5339228 DOI: 10.3389/fcell.2017.00017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 02/20/2017] [Indexed: 12/11/2022] Open
Abstract
The human body develops from a single cell, the zygote, the product of the maternal oocyte and the paternal spermatozoon. That 1-cell zygote embryo will divide and eventually grow into an adult human which is comprised of ~3.7 × 1013 cells. The tens of trillions of cells in the adult human can be classified into approximately 200 different highly specialized cell types that make up all of the different tissues and organs of the human body. Regenerative medicine aims to replace or restore dysfunctional cells, tissues and organs with fully functional ones. One area receiving attention is regeneration of the intervertebral discs (IVDs), which are located between the vertebrae and function to give flexibility and support load to the spine. Degenerated discs are a major cause of lower back pain. Different stem cell based regenerative medicine approaches to cure disc degeneration are now available, including using autologous mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs) and even attempts at direct transdifferentiation of somatic cells. Here we discuss some of the recent advances, successes, drawbacks, and the failures of the above-mentioned approaches.
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Affiliation(s)
- Petra Kraus
- Department of Biology, Clarkson University Potsdam, NY, USA
| | - Thomas Lufkin
- Department of Biology, Clarkson University Potsdam, NY, USA
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21
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van den Akker GGH, Surtel DAM, Cremers A, Richardson SM, Hoyland JA, van Rhijn LW, Voncken JW, Welting TJM. Novel Immortal Cell Lines Support Cellular Heterogeneity in the Human Annulus Fibrosus. PLoS One 2016; 11:e0144497. [PMID: 26794306 PMCID: PMC4721917 DOI: 10.1371/journal.pone.0144497] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 11/19/2015] [Indexed: 12/11/2022] Open
Abstract
Introduction Loss of annulus fibrosus (AF) integrity predisposes to disc herniation and is associated with IVD degeneration. Successful implementation of biomedical intervention therapy requires in-depth knowledge of IVD cell biology. We recently generated unique clonal human nucleus pulposus (NP) cell lines. Recurring functional cellular phenotypes from independent donors provided pivotal evidence for cell heterogeneity in the mature human NP. In this study we aimed to generate and characterize immortal cell lines for the human AF from matched donors. Methods Non-degenerate healthy disc material was obtained as surplus surgical material. AF cells were immortalized by simian virus Large T antigen (SV40LTAg) and human telomerase (hTERT) expression. Early passage cells and immortalized cell clones were characterized based on marker gene expression under standardized culturing and in the presence of Transforming Growth factor β (TGFβ). Results The AF-specific expression signature included COL1A1, COL5A1, COL12A1, SFRP2 and was largely maintained in immortal AF cell lines. Remarkably, TGFβ induced rapid 3D sheet formation in a subgroup of AF clones. This phenotype was associated with inherent differences in Procollagen type I processing and maturation, and correlated with differential mRNA expression of Prolyl 4-hydroxylase alpha polypeptide 1 and 3 (P4HA1,3) and Lysyl oxidase (LOX) between clones and differential P4HA3 protein expression between AF cells in histological sections. Conclusion We report for the first time the generation of representative human AF cell lines. Gene expression profile analysis and functional comparison of AF clones revealed variation between immortalized cells and suggests phenotypic heterogeneity in the human AF. Future characterization of AF cellular (sub-)populations aims to combine identification of additional specific AF marker genes and their biological relevance. Ultimately this knowledge will contribute to clinical application of cell-based technology in IVD repair.
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Affiliation(s)
- Guus G. H. van den Akker
- Department of Orthopaedic Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands
- Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Don A. M. Surtel
- Department of Orthopaedic Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Andy Cremers
- Department of Orthopaedic Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Stephen M. Richardson
- Centre for Tissue Injury and Repair, Institute of Inflammation and Repair, The University of Manchester, Manchester, United Kingdom
| | - Judith A. Hoyland
- Centre for Tissue Injury and Repair, Institute of Inflammation and Repair, The University of Manchester, Manchester, United Kingdom
| | - Lodewijk W. van Rhijn
- Department of Orthopaedic Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Jan Willem Voncken
- Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands
- * E-mail: (JWV); (TJMW)
| | - Tim J. M. Welting
- Department of Orthopaedic Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands
- * E-mail: (JWV); (TJMW)
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22
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Knezevic NN, Candido KD, Desai R, Kaye AD. Is Platelet-Rich Plasma a Future Therapy in Pain Management? Med Clin North Am 2016; 100:199-217. [PMID: 26614728 DOI: 10.1016/j.mcna.2015.08.014] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Platelet-rich plasma (PRP) has the potential to regenerate tissues and decrease pain through the effects of bioactive molecules and growth factors present in alpha granules. Several PRP preparation systems are available with varying end products, doses of growth factors, and bioactive molecules. This article presents the biology of PRP, the preparation of PRP, and the effects PRP-related growth factors have on tissue healing and repair. Based on available evidence-based literature, the success of PRP therapy depends on the method of preparation and composition of PRP, the patient's medical condition, anatomic location of the injection, and the type of tissue injected.
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Affiliation(s)
- Nebojsa Nick Knezevic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 West Wellington Avenue, Suite 4815, Chicago, IL 60657, USA; Department of Anesthesiology, University of Illinois, 1740 W. Taylor St, Chicago, IL 60612, USA
| | - Kenneth D Candido
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 West Wellington Avenue, Suite 4815, Chicago, IL 60657, USA; Department of Anesthesiology, University of Illinois, 1740 W. Taylor St, Chicago, IL 60612, USA
| | - Ravi Desai
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, 836 West Wellington Avenue, Suite 4815, Chicago, IL 60657, USA
| | - Alan David Kaye
- Department of Anesthesiology, Louisiana State University School of Medicine, LSU Health Science Center, 1542 Tulane Avenue, Room 659, New Orleans, LA 70112, USA; Department of Pharmacology, Louisiana State University School of Medicine, 1901 Perdido St, New Orleans, LA 70112, USA.
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23
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Bechtold TE, Saunders C, Mundy C, Um H, Decker RS, Salhab I, Kurio N, Billings PC, Pacifici M, Nah HD, Koyama E. Excess BMP Signaling in Heterotopic Cartilage Forming in Prg4-null TMJ Discs. J Dent Res 2015; 95:292-301. [PMID: 26534931 DOI: 10.1177/0022034515613508] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Heterotopic cartilage develops in certain pathologic conditions, including those affecting the human temporomandibular joint (TMJ), but the underlying molecular mechanisms remain obscure. This is in part due to the fact that a reliable animal model of such TMJ diseases is not available. Here, we show that aberrant chondrocyte differentiation and ectopic cartilage formation occur spontaneously in proteoglycan 4 (Prg4) mutant TMJ discs without further invasive procedure. By 2 mo of age, mutant disc cells displayed chondrocyte transdifferentiation, accompanied by strong expression of cartilage master gene Sox9 and matrix genes aggrecan and type II collagen. By 6 mo, heterotopic cartilage had formed in the discs and expressed cartilage hypertrophic markers Runx2 and ColX. The ectopic tissue grew in size over time and exhibited regional mineralization by 12 mo. Bone morphogenetic protein (BMP) signaling was activated with the ectopic chondrogenic cells and chondrocytes, as indicated by phosphorylated Smad 1/5/8 nuclear staining and by elevated expression of Bmp2, Bmpr1b, Bmpr2, and BMP signaling target genes. Likewise, we found that upon treatment with recombinant human BMP 2 in high-density micromass culture, mutant disc cells differentiated into chondrocytes and synthesized cartilage matrix more robustly than control cells. Importantly, a specific kinase inhibitor of BMP receptors drastically attenuated chondrogenesis in recombinant human BMP 2-treated mutant disc cultures. Unexpectedly, we found that Prg4 was expressed at joint-associated sites, including disc/muscle insertion and muscle/bone interface, and all these structures were abnormal in Prg4 mutants. Our data indicate that Prg4 is needed for TMJ disc integrity and function and that its absence leads to ectopic chondrogenesis and cartilage formation in conjunction with abnormal BMP signaling. Our findings imply that the BMP signaling pathway could be a potential therapeutic target for prevention or inhibition of ectopic cartilage formation in TMJ disease.
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Affiliation(s)
- T E Bechtold
- Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA Department of Orthodontics and Orofacial Orthopaedics, Center of Dentistry, Oral Medicine and Maxillofacial Surgery, University Hospital Tuebingen, Tuebingen, Germany
| | - C Saunders
- Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - C Mundy
- Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - H Um
- Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - R S Decker
- Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - I Salhab
- Division of Plastic and Reconstructive Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - N Kurio
- Division of Plastic and Reconstructive Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - P C Billings
- Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - M Pacifici
- Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - H D Nah
- Division of Plastic and Reconstructive Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - E Koyama
- Division of Orthopaedic Surgery, Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
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Thrombocytopenia in Dengue: Interrelationship between Virus and the Imbalance between Coagulation and Fibrinolysis and Inflammatory Mediators. Mediators Inflamm 2015; 2015:313842. [PMID: 25999666 PMCID: PMC4427128 DOI: 10.1155/2015/313842] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Accepted: 01/22/2015] [Indexed: 01/15/2023] Open
Abstract
Dengue is an infectious disease caused by dengue virus (DENV). In general, dengue is a self-limiting acute febrile illness followed by a phase of critical defervescence, in which patients may improve or progress to a severe form. Severe illness is characterized by hemodynamic disturbances, increased vascular permeability, hypovolemia, hypotension, and shock. Thrombocytopenia and platelet dysfunction are common in both cases and are related to the clinical outcome. Different mechanisms have been hypothesized to explain DENV-associated thrombocytopenia, including the suppression of bone marrow and the peripheral destruction of platelets. Studies have shown DENV-infected hematopoietic progenitors or bone marrow stromal cells. Moreover, anti-platelet antibodies would be involved in peripheral platelet destruction as platelets interact with endothelial cells, immune cells, and/or DENV. It is not yet clear whether platelets play a role in the viral spread. Here, we focus on the mechanisms of thrombocytopenia and platelet dysfunction in DENV infection. Because platelets participate in the inflammatory and immune response by promoting cytokine, chemokine, and inflammatory mediator secretion, their relevance as "immune-like effector cells" will be discussed. Finally, an implication for platelets in plasma leakage will be also regarded, as thrombocytopenia is associated with clinical outcome and higher mortality.
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Wang SZ, Chang Q, Lu J, Wang C. Growth factors and platelet-rich plasma: promising biological strategies for early intervertebral disc degeneration. INTERNATIONAL ORTHOPAEDICS 2015; 39:927-34. [PMID: 25653173 DOI: 10.1007/s00264-014-2664-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 12/28/2014] [Indexed: 12/20/2022]
Abstract
Intervertebral disc degeneration (IDD) is a complex process with the mechanism not fully elucidated. The current clinical treatments for IDD are mainly focused on providing symptomatic relief without addressing the underlying cause of the IDD. Biological therapeutic strategies to repair and regenerate the degenerated discs are drawing more attention. Growth factor therapy is one of the biological strategies and holds promising prospects. As a promising bioactive substance, platelet-rich plasma (PRP) is considered to be an ideal growth factor "cocktail" for intervertebral disc (IVD) restoration. Results from many in vitro and in vivo studies have confirmed the efficacy of growth factors and PRP in IVD repair and regeneration. It is essential to advance the research on growth factor therapy and associated mechanism for IDD. This article reviews the background of IDD, current concepts in growth factor and PRP-related therapy for IDD. Future research perspectives and clinical directions are also discussed.
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Affiliation(s)
- Shan-zheng Wang
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, 87 Ding Jia Qiao Road, Nanjing, Jiangsu, 210009, People's Republic of China
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Chuah YJ, Lee WC, Wong HK, Kang Y, Hee HT. Three-dimensional development of tensile pre-strained annulus fibrosus cells for tissue regeneration: An in-vitro study. Exp Cell Res 2015; 331:176-182. [DOI: 10.1016/j.yexcr.2014.09.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 09/16/2014] [Accepted: 09/17/2014] [Indexed: 01/13/2023]
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Andia I, Abate M. Platelet-rich plasma: underlying biology and clinical correlates. Regen Med 2014; 8:645-58. [PMID: 23998756 DOI: 10.2217/rme.13.59] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Platelet-rich plasma (PRP) has recently become the focus of intensive interest and discussion, in part because of the expanding understanding of platelet function. Anucleate platelets within PRP release a myriad of growth factors and cytokines while contributing to plasma coagulation and fibrin development; the latter acts as vehicle for the local delivery. The biological effects of PRP are largely attributed to the platelet secretome and plasma signaling proteins. Clinical data suggest that PRPs may exploit different regenerative mechanisms under diverse disease conditions, including hemostasis, inflammation, angiogenesis and the synthesis of extracellular matrix. The success of PRP therapies depends on current tissue healing research and the translation of this knowledge into clinical developments.
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Affiliation(s)
- Isabel Andia
- BioCruces Health Research Institute, Cruces University Hospital, 48903 Barakaldo, Bizkaia, Spain.
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Maerz T, Herkowitz H, Baker K. Molecular and genetic advances in the regeneration of the intervertebral disc. Surg Neurol Int 2013; 4:S94-S105. [PMID: 23646279 PMCID: PMC3642750 DOI: 10.4103/2152-7806.109449] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 01/30/2013] [Indexed: 02/06/2023] Open
Abstract
Background: Owing to the debilitating nature of degenerative disc disease (DDD) and other spine pathologies, significant research has been performed with the goal of healing or regenerating the intervertebral disc (IVD). Structural complexity, coupled with low vascularity and cellularity, make IVD regeneration an extremely challenging task. Methods: Tissue engineering-based strategies utilize three components to enhance tissue regeneration; scaffold materials to guide cell growth, biomolecules to enhance cell migration and differentiation, and cells (autologous, or allogeneic) to initiate the process of tissue formation. Significant advances in IVD regeneration have been made utilizing these tissue engineering strategies. Results: The current literature demonstrates that members of the transforming growth factor beta (TGF-β) superfamily are efficacious in the regeneration of an anabolic response in the IVD and to facilitate chondrogenic differentiation. Gene therapy, though thwarted by safety concerns and the risk of ectopic transfection, has significant potential for a targeted and sustained regenerative response. Stem cells in combination with injectable, biocompatible, and biodegradable scaffolds in the form of hydrogels can differentiate into de novo IVD tissue and facilitate regeneration of the existing matrix. Therapies that address both anabolism and the inherent catabolic state of the IVD using either direct inhibitors or broad-spectrum inhibitors show extensive promise. Conclusion: This review article summarizes the genetic and molecular advances that promise to play an integral role in the development of new strategies to combat DDD and promote healing of injured discs.
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Affiliation(s)
- Tristan Maerz
- Department of Orthopaedic Research, Beaumont Health System, Royal Oak, MI, USA
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Sivakamasundari V, Lufkin T. Stemming the Degeneration: IVD Stem Cells and Stem Cell Regenerative Therapy for Degenerative Disc Disease. ACTA ACUST UNITED AC 2013; 2013. [PMID: 23951558 DOI: 10.5171/2013.724547] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The intervertebral disc (IVD) is immensely important for the integrity of vertebral column function. The highly specialized IVD functions to confer flexibility and tensile strength to the spine and endures various types of biomechanical force. Degenerative disc disease (DDD) is a prevalent musculoskeletal disorder and is the major cause of low back pain and includes the more severe degenerative lumbar scoliosis, disc herniation and spinal stenosis. DDD is a multifactorial disorder whereby an imbalance of anabolic and catabolic factors, or alterations to cellular composition, or biophysical stimuli and genetic background can all play a role in its genesis. However, our comprehension of IVD formation and theetiology of disc degeneration (DD) are far from being complete, hampering efforts to formulate appropriate therapies to tackle DD. Knowledge of the stem cells and various techniques to manipulate and direct them to particular fates have been promising in adopting a stem-cell based regenerative approach to DD. Moreover, new evidence on the residence of stem/progenitor cells within particular IVD niches has emerged holding promise for future therapeutic applications. Existing issues pertaining to current therapeutic approaches are also covered in this review.
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The challenge and advancement of annulus fibrosus tissue engineering. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2013; 22:1090-100. [PMID: 23361531 DOI: 10.1007/s00586-013-2663-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Revised: 12/26/2012] [Accepted: 01/07/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Intervertebral disc degeneration, a main cause of back pain, is an endemic problem and a big economic burden for the health care system. Current treatments are symptom relieving but do not address underlying problems-biological and structural deterioration of the disc. Tissue engineering is an emerging approach for the treatment of intervertebral disc degeneration since it restores the functionality of native tissues. Although numerous studies have focused on the nucleus pulposus tissue engineering and achieved successes in laboratory settings, disc tissue engineering without annulus fibrosus for the end stage of disc degeneration is deemed to fail. The purpose of this article is to review the advancement of annulus fibrosus tissue engineering. MATERIAL AND METHODS Relevant articles regarding annulus fibrosus tissue engineering were identified in PubMed and Medline databases. RESULTS The ideal strategy for disc regeneration is to restore the function and integrity of the disc by using biomaterials, native matrices, growth factors, and cells that producing matrices. In the past decades there are tremendous advancement in annulus fibrosus tissue engineering including cell biology, biomaterials, and whole disc replacement. The recent promising results on whole disc tissue engineering-a composite of annulus fibrosus and nucleus pulposus-make the tissue engineering approach more appealing. CONCLUSION Despite the promising results in disc tissue engineering, there is still much work to be done regarding the clinical application.
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Wang SZ, Rui YF, Tan Q, Wang C. Enhancing intervertebral disc repair and regeneration through biology: platelet-rich plasma as an alternative strategy. Arthritis Res Ther 2013; 15:220. [PMID: 24165687 PMCID: PMC3978730 DOI: 10.1186/ar4353] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Intervertebral disc degeneration (IDD) is a common orthopedic disease associated with mechanical changes that may result in significant pain. Current treatments for IDD mainly depend on conservative therapies and spinal surgeries that are only able to relieve the symptoms but do not address the cause of the degeneration and even accelerate the degeneration of adjacent segments. This has prompted research to improve our understanding of the biology of intervertebral disc healing and into methods to enhance the regenerative process. Recently, biological therapies, including active substances, gene therapy and tissue engineering based on certain cells, have been attracting more attention in the field of intervertebral disc repair and regeneration. Early selection of suitable biological treatment is an ideal way to prevent or even reverse the progressive trend of IDD. Growth factors have been enjoying more popularity in the field of regeneration of IDD and many have been proved to be effective in reversing the degenerative trend of the intervertebral disc. Identification of these growth factors has led to strategies to deliver platelet-derived factors to the intervertebral disc for regeneration. Platelet-rich plasma (PRP) is the latest technique to be evaluated for promoting intervertebral disc healing. Activation of the PRP leads to the release of growth factors from the α-granules in the platelet cytoplasm. These growth factors have been associated with the initiation of a healing cascade that leads to cellular chemotaxis, angiogenesis, synthesis of collagen matrix, and cell proliferation. This review describes the current understanding of IDD and related biological therapeutic strategies, especially the promising prospects of PRP treatment. Future limitations and perspectives of PRP therapy for IDD are also discussed.
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Affiliation(s)
- Shan-Zheng Wang
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, 87 Ding Jia Qiao Road, Nanjing, Jiangsu 210009, China
| | - Yun-Feng Rui
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, 87 Ding Jia Qiao Road, Nanjing, Jiangsu 210009, China
| | - Qi Tan
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, Hongkong, China
| | - Chen Wang
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, 87 Ding Jia Qiao Road, Nanjing, Jiangsu 210009, China
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Pattappa G, Li Z, Peroglio M, Wismer N, Alini M, Grad S. Diversity of intervertebral disc cells: phenotype and function. J Anat 2012; 221:480-96. [PMID: 22686699 DOI: 10.1111/j.1469-7580.2012.01521.x] [Citation(s) in RCA: 215] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The intervertebral disc (IVD) is a moderately moving joint that is located between the bony vertebrae and provides flexibility and load transmission throughout the spinal column. The disc is composed of different but interrelated tissues, including the central highly hydrated nucleus pulposus (NP), the surrounding elastic and fibrous annulus fibrosus (AF), and the cartilaginous endplate (CEP), which provides the connection to the vertebral bodies. Each of these tissues has a different function and consists of a specific matrix structure that is maintained by a cell population with distinct phenotype. Although the healthy IVD is able to balance the slow matrix turnover of synthesis and degradation, this balance is often disturbed, leading to degenerative disorders. Successful therapeutic management of IVD degeneration requires a profound understanding of the cellular and molecular characteristics of the functional IVD. Hence, the phenotype of IVD cells has been of significant interest from multiple perspectives, including development, growth, remodelling, degeneration and repair. One major challenge that complicates our understanding of the disc cells is that both the cellular phenotype and the extracellular matrix strongly depend on disc maturity and health and as a consequence are continuously evolving. This review delineates the diversity of the cell types found in the intervertebral disc, with emphasis on human, but with reference to other species. The cells of the NP appear rounded and express a proteoglycan-rich matrix, whereas the more elongated AF cells are embedded in a collagen fibre matrix and the CEPs represent a layer of cartilage. Even though all disc cells have often been referred to as 'intervertebral disc chondrocytes', distinct phenotypical differences in comparison with articular chondrocytes exist and have been reported recently. The availability of more specific markers has also improved our understanding of progenitor cell differentiation towards an IVD cell phenotype. Ultimately, new cell- and tissue-engineering approaches to regenerative therapies will only be successful if the specific characteristics of the individual tissues and their context in the function of the whole organ, are taken into consideration.
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Liang C, Li H, Li C, Yang Z, Zhou X, Tao Y, Xiao Y, Li F, Chen Q. Fabrication of a Layered Microstructured Polymeric Microspheres as a Cell Carrier for Nucleus Pulposus Regeneration. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2012; 23:2287-302. [PMID: 22243931 DOI: 10.1163/156856211x614789] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
This study aimed to investigate the feasibility of nanostructured 3D poly(lactide-co-glycolide) (PLGA) constructs, which are loaded with dexamethasone (DEX) and growth factor embedded hepaiin/poly(L-lysine) nanoparticles by a layer-by-layer system, to serve as an effective scaffold for nucleus pulposus (NP) tissue engineering. Our results demonstrated that the microsphere constructs were capable of simultaneously releasing basic fibroblast growth factor and DEX with approximately zero-order kinetics. The dual bead microspheres showed no cytotoxicity, and promoted the proliferation of the rat mesenchymal stem cells (rMSCs) by lactate dehydrogenase assay and CCK-8 assay. After 4 weeks of culture in vitro, the rMSCs- scaffold hybrids contained significantly higher levels of sulfated GAG/DNA and type-II collagen than the control samples. Moreover, quantity real-time PCR analysis revealed that the expression of disc-matrix proteins, including type-II collagen, aggrecan and versican, in the rMSCs-scaffold hybrids was significantly higher than the control group, whereas the expression of osteogenic differentiation marker type-I collagen was decreased. Taken together, these data indicate that the heparin bound bFGF-coated and DEX-loaded PLGA microsphere constructs is an effective bioactive scaffold for the regeneration of NP tissue.
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Affiliation(s)
- Chengzhen Liang
- a Department of Orthopedic Surgery , 2nd Affiliated Hospital, School of Medicine, Zhejiang University , 88 Jie Fang Road , Hangzhou , 310009 , Zhejiang , P. R. China
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Hübner S, Efthymiadis A. Recent progress in histochemistry and cell biology. Histochem Cell Biol 2012; 137:403-57. [PMID: 22366957 DOI: 10.1007/s00418-012-0933-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2012] [Indexed: 01/06/2023]
Abstract
Studies published in Histochemistry and Cell Biology in the year 2011 represent once more a manifest of established and newly sophisticated techniques being exploited to put tissue- and cell type-specific molecules into a functional context. The review is therefore the Histochemistry and Cell Biology's yearly intention to provide interested readers appropriate summaries of investigations touching the areas of tissue biology, developmental biology, the biology of the immune system, stem cell research, the biology of subcellular compartments, in order to put the message of such studies into natural scientific-/human- and also pathological-relevant correlations.
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Affiliation(s)
- Stefan Hübner
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.
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Caterson B. Fell-Muir Lecture: chondroitin sulphate glycosaminoglycans: fun for some and confusion for others. Int J Exp Pathol 2012; 93:1-10. [PMID: 22264297 PMCID: PMC3311016 DOI: 10.1111/j.1365-2613.2011.00807.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 12/13/2011] [Indexed: 12/12/2022] Open
Abstract
This review emphasizes the importance of glycobiology in nature and aims to highlight, simplify and summarize the multiple functions and structural complexities of the different oligosaccharide combinatorial domains that are found in chondroitin sulphate/dermatan sulphate (CS/DS) glycosaminoglycan (GAG) chains. For example, there are 1008 different pentasaccharide sequences possible within CS, DS or CS/DS hybrid GAG chains. These combinatorial possibilities provide numerous potential ligand-binding domains that are important for cell and extracellular matrix interactions as well as specific associations with cytokines, chemokines, morphogens and growth factors that regulate cellular differentiation and proliferation during tissue development, for example, morphogen gradient establishment. The review provides some details of the large and diverse number of different enzymes that are involved in CS/DS biosynthesis and attempts to explain how differences in their expression patterns in different cell types can lead to subtle but important differences in the GAG metabolism that influence cellular proliferation and differentiation in development as well as regeneration and repair in disease. Our laboratory was the first to generate and characterize monoclonal antibodies (mAb) that very specifically recognize different ‘native’ sulphation motif/epitopes in CS/DS GAG chains. These monoclonal antibodies have been used to identify very specific spatio-temporal expression patterns of CS/DS sulphation motifs that occur during tissue and organ development (in particular their association with stem/progenitor cell niches) and also their recapitulated expression in adult tissues with the onset of degenerative joint diseases. In summary, diversity in CS/DS sulphation motif expression is a very important necessity for animal life as we know it.
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Affiliation(s)
- Bruce Caterson
- School of Biosciences, Cardiff University, Cardiff, Wales, UK.
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