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1
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Nakamura K, Kitahashi T, Kogawa R, Yoshino Y, Ogura I. Definition of Synovial Mesenchymal Stem Cells for Meniscus Regeneration by the Mechanism of Action and General Amp1200 Gene Expression. Int J Mol Sci 2024; 25:10510. [PMID: 39408838 PMCID: PMC11476826 DOI: 10.3390/ijms251910510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/22/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
The quality control (QC) of pharmaceutical-grade cell-therapy products, such as mesenchymal stem cells (MSCs), is challenging. Attempts to develop such products have been hampered by difficulties defining cell-type-specific characteristics and therapeutic mechanisms of action (MoAs). Although we have developed a cell therapy product, FF-31501, consisting of human synovial MSCs (SyMSCs), it was difficult to find specific markers for SyMSCs and to define the cells separately from other MSCs. The purpose of this study was to create a method for identifying and defining SyMSCs from other tissue-derived MSCs and to delve deeper into the mechanism of action of SyMSC-induced meniscus regeneration. Specifically, as a cell-type-dependent approach, we constructed a set of 1143 genes (Amp1200) reported to be associated with MSCs and established a method to evaluate them by correlating gene expression patterns. As a result, it was possible to define SyMSCs separately from other tissue-derived MSCs and non-MSCs. In addition, the gene expression analysis also highlighted TNSF-15. The in vivo rat model of meniscus injury found TNSF-15 to be an essential molecule for meniscus regeneration via SyMSC administration. This molecule and previously reported MoA molecules allowed an MoA-dependent approach to define the mechanism of action for SyMSCs. Therefore, SyMSCs for meniscus regeneration were defined by means of two approaches: the method to separate them from other MSCs and the identification of the MoA molecules. These approaches would be useful for the QC of cell therapy products.
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Affiliation(s)
- Kentaro Nakamura
- Bioscience & Engineering Laboratory, FUJIFILM Corporation, Ashigarakamigun 258-8577, Kanagawa, Japan; (T.K.); (R.K.); (Y.Y.); (I.O.)
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2
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Wu J, Huang S, Yu Y, Lian Q, Liu Y, Dai W, Liu Q, Pan Y, Liu GA, Li K, Liu C, Li G. Human adipose and synovial-derived MSCs synergistically attenuate osteoarthritis by promoting chondrocyte autophagy through FoxO1 signaling. Stem Cell Res Ther 2024; 15:261. [PMID: 39148121 PMCID: PMC11328463 DOI: 10.1186/s13287-024-03870-6] [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: 02/19/2024] [Accepted: 07/30/2024] [Indexed: 08/17/2024] Open
Abstract
BACKGROUND Human adipose-derived stem cells (ADSCs) exert a strong anti-inflammatory effect, and synovium-derived stem cells (SDSCs) have high chondrogenic potential. Thus, this study aims to investigate whether a combination of human ADSCs and SDSCs will have a synergistic effect that will increase the chondrogenic potential of osteoarthritis (OA) chondrocytes in vitro and attenuate the cartilage degeneration of early and advanced OA in vitro. METHODS ADSCs, SDSCs, and chondrocytes were isolated from OA patients who underwent total knee arthroplasty. The ADSCs-SDSCs mixed cell ratios were 1:0 (ADSCs only), 8:2, 5:5 (5A5S), 2:8, and 0:1 (SDSCs only). The chondrogenic potential of the OA chondrocytes was evaluated in vitro with a transwell assay or pellet culture with various mixed cell groups. The mixed cell group with the highest chondrogenic potential was then selected and injected into the knee joints of nude rats of early and advanced OA stages in vivo. The animals were then evaluated 12 and 20 weeks after surgery through gait analysis, von frey test, microcomputed tomography, MRI, and immunohistochemical and histological analyses. Finally, the mechanisms underlying these findings were investigated through the RNA sequencing of tissue samples in vivo and Western blot of the OA chondrocyte autophagy pathway. RESULTS Among the MSCs treatment groups, 5A5S had the greatest synergistic effect that increased the chondrogenic potential of OA chondrocytes in vitro and inhibited early and advanced OA in vivo. The 5A5S group significantly reduced cartilage degeneration, synovial inflammation, pain sensation, and nerve invasion in subchondral nude rat OA, outperforming both single-cell treatments. The underlying mechanism was the activation of chondrocyte autophagy via the FoxO1 signaling pathway. CONCLUSION A combination of human ADSCs and SDSCs demonstrated higher potential than a single type of stem cell, demonstrating potential as a novel treatment for OA.
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Affiliation(s)
- Jianqun Wu
- Division of Adult Joint Reconstruction and Sports Medicine, Department of Orthopedic Surgery, The First Affiliated Hospital (Shenzhen People's Hospital),, School of Medicine, Southern University of Science and Technology, 1017 Dongmen North Road, Luohu District, Shenzhen, 518055, China
- Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen People's Hospital, Guangdong, China
| | - Songqiang Huang
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan, China
| | - Yangyi Yu
- Division of Adult Joint Reconstruction and Sports Medicine, Department of Orthopedic Surgery, The First Affiliated Hospital (Shenzhen People's Hospital),, School of Medicine, Southern University of Science and Technology, 1017 Dongmen North Road, Luohu District, Shenzhen, 518055, China
- Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen People's Hospital, Guangdong, China
| | - Qiang Lian
- Division of Adult Joint Reconstruction and Sports Medicine, Department of Orthopedic Surgery, The First Affiliated Hospital (Shenzhen People's Hospital),, School of Medicine, Southern University of Science and Technology, 1017 Dongmen North Road, Luohu District, Shenzhen, 518055, China
- Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen People's Hospital, Guangdong, China
| | - Yang Liu
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Nanshan District, Shenzhen, 518055, Guangdong, China
- Guangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Wenfeng Dai
- Division of Adult Joint Reconstruction and Sports Medicine, Department of Orthopedic Surgery, The First Affiliated Hospital (Shenzhen People's Hospital),, School of Medicine, Southern University of Science and Technology, 1017 Dongmen North Road, Luohu District, Shenzhen, 518055, China
- Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen People's Hospital, Guangdong, China
| | - Qisong Liu
- Division of Adult Joint Reconstruction and Sports Medicine, Department of Orthopedic Surgery, The First Affiliated Hospital (Shenzhen People's Hospital),, School of Medicine, Southern University of Science and Technology, 1017 Dongmen North Road, Luohu District, Shenzhen, 518055, China
- Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen People's Hospital, Guangdong, China
| | - Yonghao Pan
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Nanshan District, Shenzhen, 518055, Guangdong, China
- Guangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Gui-Ang Liu
- Division of Adult Joint Reconstruction and Sports Medicine, Department of Orthopedic Surgery, The First Affiliated Hospital (Shenzhen People's Hospital),, School of Medicine, Southern University of Science and Technology, 1017 Dongmen North Road, Luohu District, Shenzhen, 518055, China
- Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen People's Hospital, Guangdong, China
| | - Kai Li
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Nanshan District, Shenzhen, 518055, Guangdong, China
- Guangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Chao Liu
- Department of Biomedical Engineering, College of Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Nanshan District, Shenzhen, 518055, Guangdong, China.
- Guangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Guangheng Li
- Division of Adult Joint Reconstruction and Sports Medicine, Department of Orthopedic Surgery, The First Affiliated Hospital (Shenzhen People's Hospital),, School of Medicine, Southern University of Science and Technology, 1017 Dongmen North Road, Luohu District, Shenzhen, 518055, China.
- Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration, Shenzhen People's Hospital, Guangdong, China.
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Zupan J, Stražar K. Synovium-Derived and Bone-Derived Mesenchymal Stem/Stromal Cells from Early OA Patients Show Comparable In Vitro Properties to Those of Non-OA Patients. Cells 2024; 13:1238. [PMID: 39120270 PMCID: PMC11311703 DOI: 10.3390/cells13151238] [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: 06/15/2024] [Revised: 07/15/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
Degenerative disorders like osteoarthritis (OA) might impair the ability of tissue-resident mesenchymal stem/stromal cells (MSCs) for tissue regeneration. As primary cells with MSC-like properties are exploited for patient-derived stem cell therapies, a detailed evaluation of their in vitro properties is needed. Here, we aimed to compare synovium-derived and bone-derived MSCs in early hip OA with those of patients without OA (non-OA). Tissues from three synovial sites of the hip (paralabral synovium, cotyloid fossa, inner surface of peripheral capsule) were collected along with peripheral trabecular bone from 16 patients undergoing hip arthroscopy (8 early OA and 8 non-OA patients). Primary cells isolated from tissues were compared using detailed in vitro analyses. Gene expression profiling was performed for the skeletal stem cell markers podoplanin (PDPN), CD73, CD164 and CD146 as well as for immune-related molecules to assess their immunomodulatory potential. Synovium-derived and bone-derived MSCs from early OA patients showed comparable clonogenicity, cumulative population doublings, osteogenic, adipogenic and chondrogenic potential, and immunophenotype to those of non-OA patients. High PDPN/low CD146 profile (reminiscent of skeletal stem cells) was identified mainly for non-OA MSCs, while low PDPN/high CD146 mainly defined early OA MSCs. These data suggest that MSCs from early OA patients are not affected by degenerative changes in the hip. Moreover, the synovium represents an alternative source of MSCs for patient-derived stem cell therapies, which is comparable to bone. The expression profile reminiscent of skeletal stem cells suggests the combination of low PDPN and high CD146 as potential biomarkers in early OA.
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Affiliation(s)
- Janja Zupan
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia;
| | - Klemen Stražar
- Department of Orthopaedic Surgery, University Medical Centre Ljubljana, Zaloska 9, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
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Tang X, Huang H, Hao L. Decadal analysis of efficacy and safety profiles of mesenchymal stem cells from varied sources in knee osteoarthritis patients: A systematic review and network meta-analysis. Exp Gerontol 2024; 192:112460. [PMID: 38772192 DOI: 10.1016/j.exger.2024.112460] [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: 11/10/2023] [Revised: 05/01/2024] [Accepted: 05/14/2024] [Indexed: 05/23/2024]
Abstract
OBJECTIVE Knee Osteoarthritis (KOA) is a debilitating degenerative joint ailment afflicting millions of patients. Numerous studies have assessed the efficacy of mesenchymal stem cells (MSCs) derived from various sources for KOA treatment, yet direct comparisons are scarce and inconsistent. Furthermore, network meta-analysis (NMA) conclusions require updating, while the safety of MSCs therapy remains contentious. This study evaluates therapeutic approaches involving MSCs from different sources in patients with KOA through randomized controlled trials (RCTs) and cohort studies. The objective is to compare the effectiveness and safety of MSCs strategies from various sources for KOA treatment. METHODS A systematic literature review was conducted to identify RCTs and cohort studies comparing different sources of MSCs in KOA patients. A randomized effects network meta-analysis was used to concurrently evaluate both direct and indirect comparisons across all protocols. RESULTS The NMA included 16 RCTS and reported 1005 participants. Adipose-derived mesenchymal stem cells (AD-MSCs) were the most effective treatment, showing significant improvements in the Visual Analogue Scale (VAS), the Short Form 36 (SF-36 scale), the International Knee Literature Committee Knee Evaluation Scale (IKDC subjective scores), and the Knee Injury and OA Outcome Score (KOOS). The probabilities are P = 85.3, P = 70.5, P = 88 and P = 87, respectively. Compared with placebo, AD-MSCs resulted in a VAS Score (SMD 0.97; 95%CI 0.37, 1.57), IKDC subjective scores (SMD -0.71; 95%CI -1.20, -0.21) was significantly reduced. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) showed significant improvements in the University of Western Ontario and McMaster University OA (WOMAC) (P = 91.4). Compared with placebo, UC-MSCs had a higher WOMAC Score (SMD 1.65; 95%CI 0.27, 3.03) and ranked first. Compared with MSCs, placebo emerged as the safer option (P = 74.9), with a notable reduction in AEs associated with HA treatment (RR 0.77; 95%CI 0.61, 0.97). AD-MSCs were found to have the least favorable impact on AEs with a probability of P = 13.3. CONCLUSIONS This network meta-analysis established that MSCs offer pain relief and enhance various knee scores in KOA patients compared to conventional treatment. It also identifies other therapeutic avenues warranting further exploration through high-quality studies. Nonetheless, it underscores the necessity to emphasize the potential complications and safety concerns associated with MSCs.
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Affiliation(s)
- Xiaofu Tang
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330008, China
| | - Haiqiang Huang
- The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330008, China
| | - Liang Hao
- Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
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Thacher RR, Pascual-Leone N, Rodeo SA. Treatment of Knee Chondral Defects in Athletes. Sports Med Arthrosc Rev 2024; 32:75-86. [PMID: 38978201 DOI: 10.1097/jsa.0000000000000405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Cartilage lesions of the knee are a challenging problem, especially for active individuals and athletes who desire a return to high-load activities. They occur both through chronic repetitive loading of the knee joint or through acute traumatic injury and represent a major cause of pain and time lost from sport. They can arise as isolated lesions or in association with concomitant knee pathology. Management of these defects ultimately requires a sound understanding of their pathophysiologic underpinnings to help guide treatment. Team physicians should maintain a high index of suspicion for underlying cartilage lesions in any patient presenting with a knee effusion, whether painful or not. A thorough workup should include a complete history and physical examination. MRI is the most sensitive and specific imaging modality to assess these lesions and can provide intricate detail not only of the structure and composition of cartilage, but also of the surrounding physiological environment in the joint. Treatment of these lesions consists of both conservative or supportive measures, as well as surgical interventions designed to restore or regenerate healthy cartilage. Because of the poor inherent capacity for healing associated with hyaline cartilage, the vast majority of symptomatic lesions will ultimately require surgery. Surgical treatment options range from simple arthroscopic debridement to large osteochondral reconstructions. Operative decision-making is based on numerous patient- and defect-related factors and requires open lines of communication between the athlete, the surgeon, and the rest of the treatment team. Ultimately, a positive outcome is based on the creation of a durable, resistant repair that allows the athlete to return to pain-free sporting activities.
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Affiliation(s)
- Ryan R Thacher
- Department of Orthopaedic Surgery, Sports Medicine Institute, Hospital for Special Surgery, New York, NY
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Tjandra KC, Novriansyah R, Sudiasa INS, Ar A, Rahmawati NAD, Dilogo IH. Modified Mesenchymal stem cell, platelet-rich plasma, and hyaluronic acid intervention in early stage osteoarthritis: A systematic review, meta-analysis, and meta-regression of arthroscopic-guided intra-articular approaches. PLoS One 2024; 19:e0295876. [PMID: 38457479 PMCID: PMC10923406 DOI: 10.1371/journal.pone.0295876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/25/2024] [Indexed: 03/10/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) hold promise for osteoarthritis (OA) treatment, potentially enhanced by combining them with platelet-rich plasma (PRP) and hyaluronic acid (HA). This study aimed to assess the synergy of MSCs, PRP, and varying HA doses, and determine optimal MSC sources to treat early-stage OA in the perspective of Lysholm score, VAS Score, KSS score, and WOMAC score. METHOD Original articles from 2013 to 2023 were screened from four databases, focusing on clinical trials and randomized controlled trials. The Risk of Bias in Non-randomized Studies-of Interventions (ROB-2) tool evaluated bias, and a PICOS criteria table guided result construction. Revman 5.4 analyzed outcomes such as Lysholm score, VAS score, KSS, WOMAC score, cartilage volume, and defect size using MRI. This systematic review adhered to PRISMA guidelines. RESULT Nine studies met the final inclusion criteria. Meta-analysis revealed a significant improvement in Lysholm score (MD: 17.89; 95% CI: 16.01, 19.77; I2 = 0%, P = 0.56), a notable reduction in VAS score (MD: -2.62; 95% CI: -2.83, -2.41; I2 = 99%, P < 0.00001), elevated KSS (MD: 29.59; 95% CI: 27.66, 31.52; I2 = 95%, P < 0.0001), and reduced WOMAC score (MD: -12.38; 95% CI: -13.75, -11.01; I2 = 99%, P < 0.0001). CONCLUSIONS Arthroscopic guided high-dose subchondral application of primary cultured synovial MSCs in popliteal PRP media with HA effectively regenerates cartilage defects and improves clinical outcomes in early-stage osteoarthritis. Clarification of MSC sources and quantities enhances the understanding of this promising treatment modality.
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Affiliation(s)
- Kevin Christian Tjandra
- Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Robin Novriansyah
- Kariadi General Hospital, Semarang, Indonesia
- Department of Surgery, Faculty of Medicine, Universitas Diopnegoro, Semarang, Indonesia
| | - I. Nyoman Sebastian Sudiasa
- Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Ardiyana Ar
- Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Nurul Azizah Dian Rahmawati
- Department of Medicine, Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
- Kariadi General Hospital, Semarang, Indonesia
| | - Ismail Hadisoebroto Dilogo
- Stem Cell Medical Technology Integrated Service Unit, Cipto Mangunkusumo Central Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
- Stem Cell and Tissue Engineering Research Cluster Indonesian Medical Education and Research Institute (IMERI) Universitas Indonesia, Jakarta, Indonesia
- Department of Orthopaedic and Traumatology, Cipto Mangunkusumo General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
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Cognetti DJ, Defoor MT, Yuan TT, Sheean AJ. Knee Joint Preservation in Tactical Athletes: A Comprehensive Approach Based upon Lesion Location and Restoration of the Osteochondral Unit. Bioengineering (Basel) 2024; 11:246. [PMID: 38534520 DOI: 10.3390/bioengineering11030246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/18/2024] [Accepted: 02/28/2024] [Indexed: 03/28/2024] Open
Abstract
The unique physical demands of tactical athletes put immense stress on the knee joint, making these individuals susceptible to injury. In order to ensure operational readiness, management options must restore and preserve the native architecture and minimize downtime, while optimizing functionality. Osteochondral lesions (OCL) of the knee have long been acknowledged as significant sources of knee pain and functional deficits. The management of OCL is predicated on certain injury characteristics, including lesion location and the extent of subchondral disease. Techniques such as marrow stimulation, allograft and autologous chondrocyte implantation are examined in detail, with a focus on their application and suitability in tactical athlete populations. Moreover, the restoration of the osteochondral unit (OCU) is highlighted as a central aspect of knee joint preservation. The discussion encompasses the biomechanical considerations and outcomes associated with various cartilage restoration techniques. Factors influencing procedure selection, including lesion size, location, and patient-specific variables, are thoroughly examined. Additionally, the review underscores the critical role of post-operative rehabilitation and conditioning programs in optimizing outcomes. Strengthening the surrounding musculature, enhancing joint stability, and refining movement patterns are paramount in facilitating the successful integration of preservation procedures. This narrative review aims to provide a comprehensive resource for surgeons, engineers, and sports medicine practitioners engaged in the care of tactical athletes and the field of cartilage restoration. The integration of advanced preservation techniques and tailored rehabilitation protocols offers a promising avenue for sustaining knee joint health and function in this demanding population.
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Affiliation(s)
- Daniel J Cognetti
- Department of Orthopedic Surgery, Brooke Army Medical Center, 3551 Roger Brooke Drive, San Antonio, TX 78234, USA
| | - Mikalyn T Defoor
- Department of Orthopedic Surgery, Brooke Army Medical Center, 3551 Roger Brooke Drive, San Antonio, TX 78234, USA
| | - Tony T Yuan
- Advanced Exposures Diagnostics, Interventions and Biosecurity Group, 59 Medical Wing, Lackland Air Force Base, San Antonio, TX 78236, USA
- Center for Biotechnology (4D Bio3), Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Andrew J Sheean
- Department of Orthopedic Surgery, Brooke Army Medical Center, 3551 Roger Brooke Drive, San Antonio, TX 78234, USA
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Jarecki J, Waśko MK, Widuchowski W, Tomczyk-Warunek A, Wójciak M, Sowa I, Blicharski T. Knee Cartilage Lesion Management-Current Trends in Clinical Practice. J Clin Med 2023; 12:6434. [PMID: 37892577 PMCID: PMC10607427 DOI: 10.3390/jcm12206434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/26/2023] [Accepted: 10/07/2023] [Indexed: 10/29/2023] Open
Abstract
Many patients, particularly those aged above 40, experience knee joint pain, which hampers both sports activities and daily living. Treating isolated chondral and osteochondral defects in the knee poses a significant clinical challenge, particularly in younger patients who are not typically recommended partial or total knee arthroplasty as alternatives. Several surgical approaches have been developed to address focal cartilage defects. The treatment strategies are characterized as palliation (e.g., chondroplasty and debridement), repair (e.g., drilling and microfracture), or restoration (e.g., autologous chondrocyte implantation, osteochondral autograft, and osteochondral allograft). This review offers an overview of the commonly employed clinical methods for treating articular cartilage defects, with a specific focus on the clinical trials conducted in the last decade. Our study reveals that, currently, no single technology fully meets the essential requirements for effective cartilage healing while remaining easily applicable during surgical procedures. Nevertheless, numerous methods are available, and the choice of treatment should consider factors such as the location and size of the cartilage lesion, patient preferences, and whether it is chondral or osteochondral in nature. Promising directions for the future include tissue engineering, stem cell therapies, and the development of pre-formed scaffolds from hyaline cartilage, offering hope for improved outcomes.
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Affiliation(s)
- Jaromir Jarecki
- Department of Orthopaedics and Rehabilitation, Medical University of Lublin, 20-059 Lublin, Poland;
| | - Marcin Krzysztof Waśko
- Department of Radiology and Imaging, The Medical Centre of Postgraduate Education, 01-813 Warsaw, Poland;
| | - Wojciech Widuchowski
- Department of Physiotherapy, The College of Physiotherapy, 50-038 Wrocław, Poland;
| | - Agnieszka Tomczyk-Warunek
- Laboratory of Locomotor Systems Research, Department of Rehabilitation and Physiotherapy, Medical University of Lublin, 20-059 Lublin, Poland;
| | - Magdalena Wójciak
- Department of Analytical Chemistry, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland; (M.W.); (I.S.)
| | - Ireneusz Sowa
- Department of Analytical Chemistry, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland; (M.W.); (I.S.)
| | - Tomasz Blicharski
- Department of Orthopaedics and Rehabilitation, Medical University of Lublin, 20-059 Lublin, Poland;
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Zou Z, Li H, Yu K, Ma K, Wang Q, Tang J, Liu G, Lim K, Hooper G, Woodfield T, Cui X, Zhang W, Tian K. The potential role of synovial cells in the progression and treatment of osteoarthritis. EXPLORATION (BEIJING, CHINA) 2023; 3:20220132. [PMID: 37933282 PMCID: PMC10582617 DOI: 10.1002/exp.20220132] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 06/15/2023] [Indexed: 11/08/2023]
Abstract
Osteoarthritis (OA), the commonest arthritis, is characterized by the progressive destruction of cartilage, leading to disability. The Current early clinical treatment strategy for OA often centers on anti-inflammatory or analgesia medication, weight loss, improved muscular function and articular cartilage repair. Although these treatments can relieve symptoms, OA tends to be progressive, and most patients require arthroplasty at the terminal stages of OA. Recent studies have shown a close correlation between joint pain, inflammation, cartilage destruction and synovial cells. Consequently, understanding the potential mechanisms associated with the action of synovial cells in OA could be beneficial for the clinical management of OA. Therefore, this review comprehensively describes the biological functions of synovial cells, the synovium, together with the pathological changes of synovial cells in OA, and the interaction between the cartilage and synovium, which is lacking in the present literature. Additionally, therapeutic approaches based on synovial cells for OA treatment are further discussed from a clinical perspective, highlighting a new direction in the treatment of OA.
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Affiliation(s)
- Zaijun Zou
- Department of Sports MedicineThe First Affiliated Hospital of Dalian Medical UniversityDalianLiaoningChina
| | - Han Li
- Department of Sports MedicineThe First Affiliated Hospital of Dalian Medical UniversityDalianLiaoningChina
| | - Kai Yu
- Department of Bone and JointCentral Hospital of Zhuang He CityDalianLiaoningChina
| | - Ke Ma
- Department of Clinical MedicineChina Medical UniversityShenyangLiaoningChina
| | - Qiguang Wang
- National Engineering Research Center for BiomaterialsSichuan UniversityChengduSichuanChina
| | - Junnan Tang
- Department of CardiologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Guozhen Liu
- School of MedicineThe Chinese University of Hong Kong (Shenzhen)ShenzhenGuangdongChina
| | - Khoon Lim
- Christchurch Regenerative Medicine and Tissue Engineering Group (CReaTE)Department of Orthopaedic Surgery and Musculoskeletal MedicineUniversity of OtagoChristchurchNew Zealand
| | - Gary Hooper
- Christchurch Regenerative Medicine and Tissue Engineering Group (CReaTE)Department of Orthopaedic Surgery and Musculoskeletal MedicineUniversity of OtagoChristchurchNew Zealand
| | - Tim Woodfield
- Christchurch Regenerative Medicine and Tissue Engineering Group (CReaTE)Department of Orthopaedic Surgery and Musculoskeletal MedicineUniversity of OtagoChristchurchNew Zealand
| | - Xiaolin Cui
- Department of Sports MedicineThe First Affiliated Hospital of Dalian Medical UniversityDalianLiaoningChina
- School of MedicineThe Chinese University of Hong Kong (Shenzhen)ShenzhenGuangdongChina
- Christchurch Regenerative Medicine and Tissue Engineering Group (CReaTE)Department of Orthopaedic Surgery and Musculoskeletal MedicineUniversity of OtagoChristchurchNew Zealand
| | - Weiguo Zhang
- Department of Sports MedicineThe First Affiliated Hospital of Dalian Medical UniversityDalianLiaoningChina
- Key Laboratory of Molecular Mechanisms for Repair and Remodeling of Orthopaedic DiseasesLiaoning ProvinceDalianLiaoningChina
| | - Kang Tian
- Department of Sports MedicineThe First Affiliated Hospital of Dalian Medical UniversityDalianLiaoningChina
- Key Laboratory of Molecular Mechanisms for Repair and Remodeling of Orthopaedic DiseasesLiaoning ProvinceDalianLiaoningChina
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Furuoka H, Endo K, Sekiya I. Mesenchymal stem cells in synovial fluid increase in number in response to synovitis and display more tissue-reparative phenotypes in osteoarthritis. Stem Cell Res Ther 2023; 14:244. [PMID: 37679780 PMCID: PMC10485949 DOI: 10.1186/s13287-023-03487-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 08/31/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND Synovial fluid mesenchymal stem cells (SF-MSCs) originate in the synovium and contribute to the endogenous repair of damaged intra-articular tissues. Here, we clarified the relationship between their numbers and joint structural changes during osteoarthritis (OA) progression and investigated whether SF-MSCs had phenotypes favorable for tissue repair, even in an OA environment. METHODS Partial medial meniscectomy (pMx) and sham surgery were performed on both knees of rats. SF and knee joints were collected from intact rats and from rats at 2, 4, and 6 weeks after surgery. SF was cultured for 1 week to calculate the numbers of colony-forming cells and colony areas. Joint structural changes were evaluated histologically to investigate their correlation with the numbers and areas of colonies. RNA sequencing was performed for SF-MSCs from intact knees and knees 4 weeks after the pMx and sham surgery. RESULTS Colony-forming cell numbers and colony areas were greater in the pMx group than in the intact and sham groups and peaked at 2 and 4 weeks, respectively. Synovitis scores showed the strongest correlation with colony numbers (R = 0.583) and areas (R = 0.456). RNA sequencing revealed higher expression of genes related to extracellular matrix binding, TGF-β signaling, and superoxide dismutase activity in SF-MSCs in the pMx group than in the sham group. CONCLUSION The number of SF-MSCs was most closely correlated with the severity of synovitis in this rat OA model. Tissue-reparative gene expression patterns were observed in SF-MSCs from OA knees, but not from knees without intra-articular tissue damage.
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Affiliation(s)
- Hideto Furuoka
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8510, Japan
| | - Kentaro Endo
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8510, Japan.
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8510, Japan
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11
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Onodera T, Momma D, Matsuoka M, Kondo E, Suzuki K, Inoue M, Higano M, Iwasaki N. Single-step ultra-purified alginate gel implantation in patients with knee chondral defects. Bone Joint J 2023; 105-B:880-887. [PMID: 37524343 DOI: 10.1302/0301-620x.105b8.bjj-2022-1071.r2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
Aims Implantation of ultra-purified alginate (UPAL) gel is safe and effective in animal osteochondral defect models. This study aimed to examine the applicability of UPAL gel implantation to acellular therapy in humans with cartilage injury. Methods A total of 12 patients (12 knees) with symptomatic, post-traumatic, full-thickness cartilage lesions (1.0 to 4.0 cm2) were included in this study. UPAL gel was implanted into chondral defects after performing bone marrow stimulation technique, and assessed for up to three years postoperatively. The primary outcomes were the feasibility and safety of the procedure. The secondary outcomes were self-assessed clinical scores, arthroscopic scores, tissue biopsies, and MRI-based estimations. Results No obvious adverse events related to UPAL gel implantation were observed. Self-assessed clinical scores, including pain, symptoms, activities of daily living, sports activity, and quality of life, were improved significantly at three years after surgery. Defect filling was confirmed using second-look arthroscopy at 72 weeks. Significantly improved MRI scores were observed from 12 to 144 weeks postoperatively. Histological examination of biopsy specimens obtained at 72 weeks after implantation revealed an extracellular matrix rich in glycosaminoglycan and type II collagen in the reparative tissue. Histological assessment yielded a mean overall International Cartilage Regeneration & Joint Preservation Society II score of 69.1 points (SD 10.4; 50 to 80). Conclusion This study provides evidence supporting the safety of acellular UPAL gel implantation in facilitating cartilage repair. Despite being a single-arm study, it demonstrated the efficacy of UPAL gel implantation, suggesting it is an easy-to-use, one-step method of cartilage tissue repair circumventing the need to harvest donor cells.
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Affiliation(s)
- Tomohiro Onodera
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Global Station of Soft Matter, Global Institution for Collaborative Research and Education, Sapporo, Japan
| | - Daisuke Momma
- Center for Sports Medicine, Hokkaido University Hospital, Sapporo, Japan
| | - Masatake Matsuoka
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Eiji Kondo
- Center for Sports Medicine, Hokkaido University Hospital, Sapporo, Japan
- Hokkaido Orthopaedic Memorial Hospital, Sapporo, Japan
| | - Koji Suzuki
- Hokkaido Orthopaedic Memorial Hospital, Sapporo, Japan
| | | | | | - Norimasa Iwasaki
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Global Station of Soft Matter, Global Institution for Collaborative Research and Education, Sapporo, Japan
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12
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Liu Z, Luo Z, Yu H, Zhao E, Guo J, Mou P, Chen A, Chen J, Zhou Z, Zeng W. Near-infrared light-controlled kartogenin delivery of multifunctional Prussian blue nanocomposites for cartilage defect repair. NANOSCALE 2023; 15:9076-9093. [PMID: 37129436 DOI: 10.1039/d3nr00205e] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Articular cartilage injury repair remains a challenge for clinicians and researchers. Mesenchymal stem cells (MSCs) have multiple differentiation potentials and can be induced to differentiate into the chondrogenic lineage for cartilage defect repair; however, the insufficient capacity of chondrogenic differentiation and excess reactive oxygen species (ROS)-mediated oxidative stress, which always lead to differentiation into hypertrophic chondrocytes, still need to be resolved. Accordingly, kartogenin (KGN), which can promote chondrogenic differentiation of MSCs, has shown promise in promoting infected cartilage repair. However, realizing controllable release to prolong its action time and avoid hypertrophic differentiation is critical. We herein developed a mesoporous Prussian blue nanoparticle (mPB)-based near-infrared (NIR) light-responsive controlled nanosystem. KGN was encapsulated in temperature-stimulated responsive phase change materials (PCMs), which were used as excellent gating materials (KGN-PCM@mPBs). In addition, the mPBs could efficiently scavenge ROS by their enzyme-like antioxidative activities. Our study demonstrates that the nanocomposites could efficiently promote chondrogenic differentiation and successfully inhibit the hypertrophic differentiation of MSCs. By intra-articular injection of KGN-PCM@mPBs and NIR-triggered precisely controlled release, satisfactory cartilage repair effects can be achieved in a rat chondral defect model. Thus, this constructed NIR-mediated KGN-PCM@mPB nanoplatform may represent an effective cartilage repair strategy with satisfactory biosafety in clinical applications.
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Affiliation(s)
- Zunhan Liu
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, 610041, China.
- Department of Sports Medicine Center, State Key Laboratory of Trauma, Burn and Combined Injury, the First Affiliated Hospital of the Army Military Medical University, Chongqing, 400038, China
| | - Zhenyu Luo
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Haoda Yu
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Enze Zhao
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Junfeng Guo
- Department of Sports Medicine Center, State Key Laboratory of Trauma, Burn and Combined Injury, the First Affiliated Hospital of the Army Military Medical University, Chongqing, 400038, China
| | - Ping Mou
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Anjing Chen
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Jiali Chen
- West China School of Nursing, Sichuan University/Department of Orthopedics, West China Hospital, Sichuan University Chengdu, 610041, P.R. China
| | - Zongke Zhou
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Weinan Zeng
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, 610041, China.
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Intra-Articular Injection of Autologous Micro-Fragmented Adipose Tissue for the Treatment of Knee Osteoarthritis: A Prospective Interventional Study. J Pers Med 2023; 13:jpm13030504. [PMID: 36983686 PMCID: PMC10059754 DOI: 10.3390/jpm13030504] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/03/2023] [Accepted: 03/04/2023] [Indexed: 03/14/2023] Open
Abstract
Background: To investigate the efficacy and safety of autologous micro-fragmented adipose tissue (MF-AT) for improving joint function and cartilage repair in patients with knee osteoarthritis. Methods: From March 2019 to December 2020, 20 subjects (40 knees) between 50 and 65 years old suffering from knee osteoarthritis were enrolled in the study and administered a single injection of autologous MF-A. The data of all patients were prospectively collected. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), knee society score (KSS), hospital for special surgery (HSS) score, visual analogue score (VAS) pain score, changes in cartilage Recht grade on magnetic resonance imaging (MRI) and adverse events were analyzed before and 3, 6, 9, 12 and 18 months after injection. Results: The WOMAC, VAS, KSS and HSS scores at 3, 6, 9, 12 and 18 months after injection were improved compared with those before injection (p < 0.05). There was no significant difference in WOMAC scores between 9 and 12 months after injection (p > 0.05), but the WOMAC score 18 months after injection was worse than that at the last follow-up (p < 0.05). The VAS, KSS and HSS scores 9, 12 and 18 months after injection were worse than those at the last follow-up (p < 0.05). The Recht score improvement rate was 25%. No adverse events occurred during the follow-up. Conclusions: Autologous MF-AT improves knee function and relieves pain with no adverse events. However, the improved knee function was not sustained, with the best results occurring 9–12 months after injection and the cartilage regeneration remaining to be investigated.
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14
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Ozeki N, Mizuno M, Yanada S, Okada T, Kubota R, Kushida Y, Furuoka H, Endo K, Katano H, Nakamura K, Ohya S, Koga H, Sekiya I. Autologous Synovial Mesenchymal Stem Cell Transplantation Suppresses Inflammation Caused by Synovial Harvesting and Promotes Healing in a Micro Minipig Repaired Meniscus Model. Transplant Proc 2023; 55:470-480. [PMID: 36906438 DOI: 10.1016/j.transproceed.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 01/05/2023] [Indexed: 03/12/2023]
Abstract
PURPOSE Allogeneic synovial mesenchymal stem cells (MSCs) effectively promote meniscus healing in micro minipigs. We investigated the effect of autologous synovial MSC transplantation on meniscus healing in a micro minipig model of meniscus repair showing synovitis after synovial harvesting. MATERIALS AND METHODS Synovium was harvested from the left knee of the micro minipigs after arthrotomy and used to prepare synovial MSCs. The left medial meniscus in the avascular region was injured, repaired, and transplanted with synovial MSCs. First, synovitis was compared after 6 weeks in knees with and without synovial harvesting. Second, the repaired meniscus was compared for the autologous MSC group and the control group (in which synovium was harvested but MSCs were not transplanted) 4 weeks after transplantation. RESULTS Synovitis was more severe in knees subjected to synovium harvesting than in knees not subjected to harvesting. Menisci treated with autologous MSCs showed no red granulation at the tear of the meniscus, but menisci not treated with MSCS showed red granulation. Macroscopic scores, inflammatory cell infiltration scores, and matrix scores assessed by toluidine blue staining were all significantly better in the autologous MSC group than in the control group without MSCs (n = 6). CONCLUSION Autologous synovial MSC transplantation suppressed the inflammation caused by synovial harvesting in micro minipigs and promoted healing of the repaired meniscus.
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Affiliation(s)
- Nobutake Ozeki
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mitsuru Mizuno
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | | | - Takuya Okada
- Japan Tissue Engineering Co., Ltd., Aichi, Japan
| | - Rei Kubota
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshihisa Kushida
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hideto Furuoka
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kentaro Endo
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hisako Katano
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | | | | | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
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15
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Mizuno M, Ozeki N, Sekiya I. Safety of using cultured cells with trisomy 7 in cell therapy for treating osteoarthritis. Regen Ther 2022; 21:81-86. [PMID: 35785042 PMCID: PMC9234008 DOI: 10.1016/j.reth.2022.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/25/2022] [Accepted: 06/01/2022] [Indexed: 12/27/2022] Open
Abstract
Cell therapy is a promising alternative treatment approach currently under study for osteoarthritis (OA), the most common chronic musculoskeletal disease. However, the mesenchymal stem cells (MSCs) used in cell therapy to treat OA are usually expanded in vitro to obtain sufficient numbers for transplantation, and their safety has not been fully assessed from multiple perspectives. Analysis of karyotypic abnormalities, in particular, is important to ensure the safety of cells; however, chromosomal mutations may also occur during the cell-expansion process. In addition, there have been many reports showing chromosome abnormalities, mainly trisomy 7, in the cartilage and synovium of patients with OA as well as in normal tissues. The suitability of cells with these karyotypic abnormalities as cells for cell therapy has not been evaluated. Recently, we assessed the safety of using cells with trisomy 7 from the osteoarthritic joint of a patient for transplantation, and we followed up with the patient for 5 years. This study showed analysis for copy number variant and whole-genome sequencing, compared with blood DNA from the same patient. We did not find any abnormalities in the genes regardless of trisomy 7. No side effects were observed for at least 5 years in the human clinical study. This suggests that the transplantation of cultured cells with trisomy 7 isolated from an osteoarthritic joint and transplanted into the osteoarthritic joints of the same person is not expected to cause serious adverse events. However, it is unclear what problems may arise in the case of allogeneic transplantation. Different types of risks will also exist depending on other transplantation routes, such as localization to the knee-joint only or circulation inflow and lung entrapment. In addition, since the cause of trisomy 7 occurrence remains unclear, it is necessary to clarify the mechanism of trisomy 7 in OA to perform cell therapy for OA patients in a safe manner.
Trisomy 7 is frequently observed in the cartilage and synovium of patients with OA. MSCs with trisomy 7 did not form tumor after transplantation into mice. No side effects were observed 5 years after transplantation of MSCs with trisomy 7.
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Affiliation(s)
- Mitsuru Mizuno
- Corresponding author. Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University,1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Fax: +81 3 5803-0192.
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Zelinka A, Roelofs AJ, Kandel RA, De Bari C. Cellular therapy and tissue engineering for cartilage repair. Osteoarthritis Cartilage 2022; 30:1547-1560. [PMID: 36150678 DOI: 10.1016/j.joca.2022.07.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 02/02/2023]
Abstract
Articular cartilage (AC) has limited capacity for repair. The first attempt to repair cartilage using tissue engineering was reported in 1977. Since then, cell-based interventions have entered clinical practice in orthopaedics, and several tissue engineering approaches to repair cartilage are in the translational pipeline towards clinical application. Classically, these involve a scaffold, substrate or matrix to provide structure, and cells such as chondrocytes or mesenchymal stromal cells to generate the tissue. We discuss the advantages and drawbacks of the use of various cell types, natural and synthetic scaffolds, multiphasic or gradient-based scaffolds, and self-organizing or self-assembling scaffold-free systems, for the engineering of cartilage constructs. Several challenges persist including achieving zonal tissue organization and integration with the surrounding tissue upon implantation. Approaches to improve cartilage thickness, organization and mechanical properties include mechanical stimulation, culture under hypoxic conditions, and stimulation with growth factors or other macromolecules. In addition, advanced technologies such as bioreactors, biosensors and 3D bioprinting are actively being explored. Understanding the underlying mechanisms of action of cell therapy and tissue engineering approaches will help improve and refine therapy development. Finally, we discuss recent studies of the intrinsic cellular and molecular mechanisms of cartilage repair that have identified novel signals and targets and are inspiring the development of molecular therapies to enhance the recruitment and cartilage reparative activity of joint-resident stem and progenitor cells. A one-fits-all solution is unrealistic, and identifying patients who will respond to a specific targeted treatment will be critical.
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Affiliation(s)
- A Zelinka
- Lunenfeld Tanenbaum Research Institute, Sinai Health, Dept. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - A J Roelofs
- Arthritis and Regenerative Medicine Laboratory, Aberdeen Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, Aberdeen, UK
| | - R A Kandel
- Lunenfeld Tanenbaum Research Institute, Sinai Health, Dept. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
| | - C De Bari
- Arthritis and Regenerative Medicine Laboratory, Aberdeen Centre for Arthritis and Musculoskeletal Health, University of Aberdeen, Aberdeen, UK.
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17
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Huang J, Liu Q, Xia J, Chen X, Xiong J, Yang L, Liang Y. Modification of mesenchymal stem cells for cartilage-targeted therapy. J Transl Med 2022; 20:515. [PMID: 36348497 PMCID: PMC9644530 DOI: 10.1186/s12967-022-03726-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/24/2022] [Indexed: 11/10/2022] Open
Abstract
Osteoarthritis (OA) is a chronic degenerative joint disease characterized by the destruction of the articular cartilage, sclerosis of the subchondral bone, and joint dysfunction. Its pathogenesis is attributed to direct damage and mechanical destruction of joint tissues. Mesenchymal stem cells (MSCs), suggested as a potential strategy for the treatment of OA, have shown therapeutic effects on OA. However, the specific fate of MSCs after intraarticular injection, including cell attachment, proliferation, differentiation, and death, is still unclear, and there is no guarantee that stem cells can be retained in the cartilage tissue to enact repair. Direct homing of MSCs is an important determinant of the efficacy of MSC-based cartilage repair. Recent studies have revealed that the unique homing capacity of MSCs and targeted modification can improve their ability to promote tissue regeneration. Here, we comprehensively review the homing effect of stem cells in joints and highlight progress toward the targeted modification of MSCs. In the future, developments of this targeting system that accelerate tissue regeneration will benefit targeted tissue repair.
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18
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Human synovial mesenchymal stem cells show time-dependent morphological changes and increased adhesion to degenerated porcine cartilage. Sci Rep 2022; 12:16619. [PMID: 36198727 PMCID: PMC9534877 DOI: 10.1038/s41598-022-20386-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
The possibility that mesenchymal stem cells (MSCs) can adhere to partial defects or degenerative areas in cartilage remains to be established. The purposes of the present study were to verify the adhesion of synovial MSCs to degenerated cartilage, the time course of that adhesion, and the morphological changes that MSCs might undergo during the adhesion process. The surface of pig cartilage was abraded, and a human synovial MSC suspension was placed on the abraded surface. The proportion/number of MSCs that adhered to the cartilage was quantified by counting non-adhered MSCs, measuring the fluorescence intensity of DiI-labeled MSCs, and scanning electron microscopy (SEM) observations. The presence of microspikes or pseudopodia on the MSCs that adhered to the cartilage was also evaluated. SEM confirmed the adhesion of synovial MSCs to degenerated cartilage. The three independent quantification methods confirmed increases in the proportion/number of adhered MSCs within 10 s of placement and over time up to 24 h. The MSCs that adhered at 10 s had a high proportion of microspikes, whereas those that adhered after 1 h had that of pseudopodia. MSCs showed time-dependent morphological changes and increased adhesion to degenerated cartilage after placement of the human synovial MSC suspension.
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Kurenkova AD, Romanova IA, Kibirskiy PD, Timashev P, Medvedeva EV. Strategies to Convert Cells into Hyaline Cartilage: Magic Spells for Adult Stem Cells. Int J Mol Sci 2022; 23:11169. [PMID: 36232468 PMCID: PMC9570095 DOI: 10.3390/ijms231911169] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/17/2022] [Accepted: 09/19/2022] [Indexed: 11/30/2022] Open
Abstract
Damaged hyaline cartilage gradually decreases joint function and growing pain significantly reduces the quality of a patient's life. The clinically approved procedure of autologous chondrocyte implantation (ACI) for treating knee cartilage lesions has several limits, including the absence of healthy articular cartilage tissues for cell isolation and difficulties related to the chondrocyte expansion in vitro. Today, various ACI modifications are being developed using autologous chondrocytes from alternative sources, such as the auricles, nose and ribs. Adult stem cells from different tissues are also of great interest due to their less traumatic material extraction and their innate abilities of active proliferation and chondrogenic differentiation. According to the different adult stem cell types and their origin, various strategies have been proposed for stem cell expansion and initiation of their chondrogenic differentiation. The current review presents the diversity in developing applied techniques based on autologous adult stem cell differentiation to hyaline cartilage tissue and targeted to articular cartilage damage therapy.
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Affiliation(s)
- Anastasiia D. Kurenkova
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia or
| | - Irina A. Romanova
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
| | - Pavel D. Kibirskiy
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia or
| | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia or
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
| | - Ekaterina V. Medvedeva
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia or
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Effect of CD44 signal axis in the gain of mesenchymal stem cell surface antigens from synovial fibroblasts in vitro. Heliyon 2022; 8:e10739. [PMID: 36247177 PMCID: PMC9557910 DOI: 10.1016/j.heliyon.2022.e10739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 05/24/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
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21
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Autologous Stem Cells for the Treatment of Chondral Injury and Disease. OPER TECHN SPORT MED 2022. [DOI: 10.1016/j.otsm.2022.150963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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22
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Orthobiologics for the Management of Early Arthritis in the Middle-Aged Athlete. Sports Med Arthrosc Rev 2022; 30:e9-e16. [PMID: 35533063 DOI: 10.1097/jsa.0000000000000337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
This article is dedicated to the use of orthobiologic therapies in the management of early osteoarthritis in middle-aged athletes. Understanding a patient's presenting symptoms, physical examination, imaging results, and goals is of critical importance in applying orthobiologic therapies. The field of orthobiologics is expanding at a rapid pace, and the clinical studies examining the utility of each treatment lag behind the direct-to-consumer marketing that leads to these products being used. Here we provide a review of the available treatments, emerging treatments, and the current literature supporting or refuting their use. Currently studied orthobiologics include autologous and allogenic cell therapies, autologous blood products, hyaluronic acid, gene therapies, Wnt inhibitors, and a variety of systemic treatments.
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Nakashima H, Uchida S, Hatakeyama A, Murata Y, Yamanaka Y, Tsukamoto M, Sekiya I, Sakai A. Isolation and Characterization of Synovial Mesenchymal Stem Cells Derived From Patients With Chronic Lateral Ankle Instability: A Comparative Analysis of Synovial Fluid, Adipose Synovium, and Fibrous Synovium of the Ankle Joint. Orthop J Sports Med 2022; 10:23259671221094615. [PMID: 35601732 PMCID: PMC9118449 DOI: 10.1177/23259671221094615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/17/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Synovial mesenchymal stem cells (MSCs) have high proliferative potential and are considered an excellent source for stem cell therapy. Purposes: To isolate MSCs from the synovium of ankle joints in patients with chronic lateral ankle instability (CLAI) and to compare the characteristics of MSCs derived from the synovium anterior to the talus with those from the surrounding anterior talofibular ligament (ATFL) synovium. Study Design: Controlled laboratory study. Methods: The synovium was harvested from 2 locations in the ankle, the synovium anterior to the talus and the surrounding ATFL synovium, of 14 patients who underwent arthroscopic ATFL repair for CLAI without osteochondral lesions of the talus (OLTs). Synovial fluid was also harvested. MSCs were isolated from both types of synovial tissue, as well as synovial fluid. The number of MSCs in the synovium and their viability, proliferation, colony-forming units, and potential to differentiate into adipose, bone, and cartilage tissues were determined and compared between groups. Additionally, real-time polymerase chain reaction was used to assess the differentiation capacity of adipose, bone, and cartilage tissues from both samples. The Wilcoxon signed rank test was used to compare the sample weight, number of colonies, number of nucleated cells per colony, yield obtained, and phenotypic characteristics of MSCs derived from different locations of the synovium. Results: No significant differences were observed in the sample weight ( P = .051), number of nucleated cells per milligram ( P = .272), number of colonies ( P = .722), and yield obtained ( P = .099) between the 2 groups. MSCs could not be isolated from synovial fluid. The frequency of oil red O–positive adipogenic colonies ( P = .028) and the expression of the adipsin gene ( P < .05) were significantly increased in the cells from the synovium anterior to the talus compared to those in the cells from the surrounding ATFL synovium. However, chondrogenic and osteogenic potentials were not significantly different between the 2 groups. Conclusion: Synovial MSCs obtained from the ankle joint had self-renewal and multilineage differentiation potential, although the adipogenesis potential of MSCs from the synovium anterior to the talus was superior to that from the surrounding ATFL synovium. Clinical Relevance: Both the adipose synovium and fibrous synovium in the ankle joints of patients with CLAI may be a good source of MSCs for stem cell therapy applications, whereas synovial fluid appeared unsuitable.
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Affiliation(s)
- Hirotaka Nakashima
- Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Soshi Uchida
- Department of Orthopaedic Surgery, Wakamatsu Hospital, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Akihisa Hatakeyama
- Department of Orthopaedic Surgery, Wakamatsu Hospital, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yoichi Murata
- Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yoshiaki Yamanaka
- Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Manabu Tsukamoto
- Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akinori Sakai
- Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan
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Tang G, Asou Y, Matsumura E, Nakagawa Y, Miyatake K, Katagiri H, Nakamura T, Koga H, Komori K, Sekiya I, Ezura Y, Tsuji K. Short cytoplasmic isoform of IL1R1/CD121a mediates IL1β induced proliferation of synovium-derived mesenchymal stem/stromal cells through ERK1/2 pathway. Heliyon 2022; 8:e09476. [PMID: 35647352 PMCID: PMC9133583 DOI: 10.1016/j.heliyon.2022.e09476] [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: 01/11/2022] [Revised: 02/17/2022] [Accepted: 05/13/2022] [Indexed: 11/03/2022] Open
Abstract
Objectives IL1β enhances proliferation of synovial mesenchymal stem/stromal cells (synMSCs) although they don't express its receptor, IL1R1/CD121a, on the cell surface. This study was aimed to elucidate the underlying mechanisms of IL1β-mediated growth promotion. Methods Human synMSCs were isolated from the suprapatellar synovial membrane. Cell proliferation was measured by MTT. Flowcytometric analyses were performed for surface antigen expression. Intracellular signaling pathway was analyzed by western blotting, immunocytochemistry and Q-PCR. Results IL1β enhanced proliferation through IL1R1/CD121a because IL1 receptor antagonist (IL1Ra) completely inhibited it. Expression analyses indicated that a short isoform of IL1R1/CD121a is expressed in synMSCs. Immunocytochemistry indicated that IL1R1/CD121a was majorly localized to the cytoplasm. Western blotting indicated that IL1β induced delayed timing of the ERK1/2 phosphorylation and IκBα degradation in synMSCs. Q-PCR analyses for IL1β-target genes indicated that cyclin D was specifically downregulated by a MAPK/ERK inhibitor, U0126, but not by a NFκB inhibitor, TPCA-1. In contrast, the expression of inflammatory cytokines such as IL1α and IL6 are significantly decreased by TPCA-1 but less effectively decreased by U0126. Conclusion Our data indicated that the cytoplasmic IL1R1/CD121a transduced IL1β signal in synMSCs. And the growth-promoting effect of IL1β can be separated from its inflammatory cytokine-inducing function in synMSCs.
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Affiliation(s)
- Guo Tang
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshinori Asou
- Department of Nano-Bioscience, Tokyo Medical and Dental University, Tokyo, Japan
| | - Etsuko Matsumura
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Nakagawa
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazumasa Miyatake
- Department of Cartilage Regeneration, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroki Katagiri
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomomasa Nakamura
- Department of Cartilage Regeneration, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiichiro Komori
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ichiro Sekiya
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoich Ezura
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kunikazu Tsuji
- Department of Nano-Bioscience, Tokyo Medical and Dental University, Tokyo, Japan
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25
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Kohno Y, Mizuno M, Endo K, Ozeki N, Katano H, Matsumoto M, Kaneko H, Takazawa Y, Koga H, Sekiya I. Yields of mesenchymal stromal cells from synovial fluid reflect those from synovium in patients with rheumatoid arthritis. Tissue Cell 2022; 75:101727. [PMID: 34998163 DOI: 10.1016/j.tice.2021.101727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 01/02/2023]
Abstract
The yield of primary synovial mesenchymal stromal cells (MSCs) from synovium of patients with rheumatoid arthritis (RA) is highly variable, but cell transplantation therapy with autologous synovial MSCs requires accurate prediction of the synovial MSC yield per synovium weight. Here, we determined whether the yield of synovial fluid MSCs might predict the ultimate yield of primary MSCs from the synovium of RA knees. Synovial fluid and synovium were harvested during total knee arthroplasty from the knee joints of 10 patients with RA. Synovial fluid (1.5 mL) was diluted fourfold and plated equally into six 60 cm2 dishes. Nucleated cells from digested synovium were similarly plated at 1 × 104 cells in 6 dishes. All dishes were cultured for 14 days and analyzed for MSC yields and properties, including in vitro chondrogenesis. The cultured synovial cell number was correlated with the cultured synovial fluid cell number (n = 10, R2 = 0.64, p < 0.01). Synovial fluid cells formed cell colonies and showed MSC-like surface epitopes and multi-differentiation potential. However, the cartilage pellet weight indicated a greater chondrogenic potential of the synovial MSCs (n = 8). The primary MSC yields from synovial fluid and synovium were correlated, indicating that the synovial fluid MSC yield can predict the ultimate synovial MSC yield.
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Affiliation(s)
- Yuji Kohno
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Mitsuru Mizuno
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Kentaro Endo
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Nobutake Ozeki
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Hisako Katano
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Mikio Matsumoto
- Department of Orthopaedics, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan
| | - Haruka Kaneko
- Department of Orthopaedics, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan
| | - Yuji Takazawa
- Department of Orthopaedics, Juntendo University School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8431, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Ichiro Sekiya
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
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Zhu J, Yang S, Qi Y, Gong Z, Zhang H, Liang K, Shen P, Huang YY, Zhang Z, Ye W, Yue L, Fan S, Shen S, Mikos AG, Wang X, Fang X. Stem cell-homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model. SCIENCE ADVANCES 2022; 8:eabk0011. [PMID: 35353555 PMCID: PMC8967232 DOI: 10.1126/sciadv.abk0011] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Osteoarthritis (OA) is a common joint disease characterized by progressive loss of cartilage and reduction in lubricating synovial fluid, which lacks effective treatments currently. Here, we propose a hydrogel-based miRNA delivery strategy to rejuvenate impaired cartilage by creating a regenerative microenvironment to mitigate chondrocyte senescence that mainly contributes to cartilage breakdown during OA development. An aging-related miRNA, miR-29b-5p, was first found to be markedly down-regulated in OA cartilage, and their up-regulation suppressed the expression of matrix metalloproteinases and senescence-associated genes (P16INK4a/P21) via ten-eleven-translocation enzyme 1 (TET1). An injectable bioactive self-assembling peptide nanofiber hydrogel was applied to deliver agomir-29b-5p, which was functionalized by conjugating a stem cell-homing peptide SKPPGTSS for endogenous synovial stem cell recruitment simultaneously. Sustained miR-29b-5p delivery and recruitment of synovial stem cells and their subsequent differentiation into chondrocytes led to successful cartilage repair and chondrocyte rejuvenation. This strategy enables miRNA-based therapeutic modality to become a viable alternative for surgery in OA treatment.
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Affiliation(s)
- Jinjin Zhu
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang, Hangzhou 310016, China
- State Key Laboratory of New Ceramics and Fine Processing, Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
| | - Shuhui Yang
- State Key Laboratory of New Ceramics and Fine Processing, Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
| | - Yadong Qi
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Zhe Gong
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang, Hangzhou 310016, China
| | - Haitao Zhang
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang, Hangzhou 310016, China
| | - Kaiyu Liang
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang, Hangzhou 310016, China
| | - Panyang Shen
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang, Hangzhou 310016, China
| | - Yin-Yuan Huang
- State Key Laboratory of New Ceramics and Fine Processing, Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
| | - Zhe Zhang
- State Key Laboratory of New Ceramics and Fine Processing, Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
| | - Weilong Ye
- State Key Laboratory of New Ceramics and Fine Processing, Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
| | - Lei Yue
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Shunwu Fan
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang, Hangzhou 310016, China
| | - Shuying Shen
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang, Hangzhou 310016, China
| | - Antonios G. Mikos
- Department of Bioengineering, Rice University, 6100 Main Street, Houston, TX 77005, USA
| | - Xiumei Wang
- State Key Laboratory of New Ceramics and Fine Processing, Key Laboratory of Advanced Materials of Ministry of Education, School of Materials Science and Engineering, Tsinghua University, Beijing 100084, China
- Corresponding author. (X.F.); (X.W.)
| | - Xiangqian Fang
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine and Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang, Hangzhou 310016, China
- Corresponding author. (X.F.); (X.W.)
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Liu X, Liu Y, He H, Xiang W, He C. Human adipose and synovial mesenchymal stem cells improve osteoarthritis in rats by reducing chondrocyte reactive oxygen species and inhibiting inflammatory response. J Clin Lab Anal 2022; 36:e24353. [PMID: 35312120 PMCID: PMC9102617 DOI: 10.1002/jcla.24353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 03/02/2022] [Accepted: 03/08/2022] [Indexed: 12/01/2022] Open
Abstract
Background We explored the therapeutic effects of Adipose‐derived mesenchymal stem cells (ADMSCs) and Synovial‐derived mesenchymal stem cells (SDMSCs) on osteoarthritis (OA). Methods SDMSCs and ADMSCs were co‐cultured with chondrocytes and stimulated with interleukin (IL)‐1β. An OA model was established on rats by intra‐articular injection with ADMSCs and SDMSCs. After 8 weeks, the joint diameter difference was detected, and histological staining was used to observe the pathological changes in cartilage tissue. Enzyme‐linked immunosorbent assay (ELISA) was used to detect the expressions of IL‐6, tumor necrosis factor (TNF)‐α and IL‐1β in joint fluid. The expressions of COL2A1, Aggrecan, Matrix metalloproteinase (MMP)‐13, SOX9, IL‐6, TNF‐α and IL‐1β were detected by qRT‐PCR and Western blotting in cartilage tissue. Reactive oxygen species (ROS) content in cells and cartilage tissues was detected by ROS kit. Results SDMSCs and ADMSCs co‐cultured with chondrocytes could reduce MMP‐13 expression, increase the expressions of COL2A1, Aggrecan and SOX9, as well as reverse the effects of IL‐1β on promoting ROS content and inflammatory factors levels. After the OA model was established, the injection of ADMSCs and SDMSCs reduced the differences in joint diameter and tissue lesions in OA rats. The OA model led to increased levels of IL‐6, TNF‐α and IL‐1β in joint fluid and cartilage tissue, while the injection of ADMSCs and SDMSCs inhibited the inflammatory factor levels in OA rats, and increased the expressions of COL2A1, Aggrecan and SOX9 in OA rats. Conclusion ADMSCs and SDMSCs improve osteoarthritis in rats by reducing chondrocyte ROS and inhibiting inflammatory response.
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Affiliation(s)
- Xunzhi Liu
- Orthopedics Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
| | - Yaqing Liu
- Pediatric Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
| | - Huabin He
- Orthopedics Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
| | - Weiwei Xiang
- Orthopedics Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
| | - Cheng He
- Orthopedics Department First Affiliated Hospital of Gannan Medical University Ganzhou City China
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Haring G, Zupan J. Knee and Peri-Knee Tissues of Post Mortem Donors Are Strategic Sources of Mesenchymal Stem/Stromal Cells for Regenerative Procedures. Int J Mol Sci 2022; 23:ijms23063170. [PMID: 35328593 PMCID: PMC8956054 DOI: 10.3390/ijms23063170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/09/2022] [Accepted: 03/14/2022] [Indexed: 12/14/2022] Open
Abstract
Tissues of post mortem donors represent valuable alternative sources for the isolation of primary cells with mesenchymal stem/stromal cell (MSC)-like properties. However, the properties of primary cells derived from different tissues and at different post mortem times are poorly recognized. Here, we aim to identify the optimal tissue source between three knee and peri-knee tissues for the isolation of primary cells with MSC-like properties, and to define the influence of the time post mortem on the properties of these cells. We harvested tissues from subchondral bone marrow, synovium and periosteum from 32 donors at various post mortem times. Primary cells were evaluated using detailed in vitro analyses, including colony formation, trilineage differentiation, immunophenotyping and skeletal stem cell marker-gene expression profiling. These data show that the primary cells with MSC-like properties isolated from these three tissues show no differences in their properties, except for higher expression of CD146 in bone-marrow cells. The success rate of the primary cell isolation is dependent on the post mortem time. However, synovium and periosteum cells isolated more than 48 h post mortem show improved osteogenic and chondrogenic potential. This study suggests that knee and peri-knee tissues from donors even 3 days post mortem are strategic sources of MSCs for regenerative procedures.
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Affiliation(s)
- Gregor Haring
- Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
| | - Janja Zupan
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia
- Correspondence: ; Tel.: +386-1-4769626
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Kwon DG, Kim MK, Jeon YS, Nam YC, Park JS, Ryu DJ. State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis. Int J Mol Sci 2022; 23:1618. [PMID: 35163541 PMCID: PMC8835711 DOI: 10.3390/ijms23031618] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 01/15/2023] Open
Abstract
Osteoarthritis (OA) has generally been introduced as a degenerative disease; however, it has recently been understood as a low-grade chronic inflammatory process that could promote symptoms and accelerate the progression of OA. Current treatment strategies, including corticosteroid injections, have no impact on the OA disease progression. Mesenchymal stem cells (MSCs) based therapy seem to be in the spotlight as a disease-modifying treatment because this strategy provides enlarged anti-inflammatory and chondroprotective effects. Currently, bone marrow, adipose derived, synovium-derived, and Wharton's jelly-derived MSCs are the most widely used types of MSCs in the cartilage engineering. MSCs exert immunomodulatory, immunosuppressive, antiapoptotic, and chondrogenic effects mainly by paracrine effect. Because MSCs disappear from the tissue quickly after administration, recently, MSCs-derived exosomes received the focus for the next-generation treatment strategy for OA. MSCs-derived exosomes contain a variety of miRNAs. Exosomal miRNAs have a critical role in cartilage regeneration by immunomodulatory function such as promoting chondrocyte proliferation, matrix secretion, and subsiding inflammation. In the future, a personalized exosome can be packaged with ideal miRNA and proteins for chondrogenesis by enriching techniques. In addition, the target specific exosomes could be a gamechanger for OA. However, we should consider the off-target side effects due to multiple gene targets of miRNA.
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Affiliation(s)
| | | | | | | | | | - Dong Jin Ryu
- Orthopedic Surgery, Inha University Hospital, 22332 Inhang-ro 27, Jung-gu, Incheon 22332, Korea; (D.G.K.); (M.K.K.); (Y.S.J.); (Y.C.N.); (J.S.P.)
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Zamudio-Cuevas Y, Plata-Rodríguez R, Fernández-Torres J, Flores KM, Cárdenas-Soria VH, Olivos-Meza A, Hernández-Rangel A, Landa-Solís C. Synovial membrane mesenchymal stem cells for cartilaginous tissues repair. Mol Biol Rep 2022; 49:2503-2517. [PMID: 35013859 DOI: 10.1007/s11033-021-07051-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/02/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND The present review is focused on general aspects of the synovial membrane as well as specialized aspects of its cellular constituents, particularly the composition and location of synovial membrane mesenchymal stem cells (S-MSCs). S-MSC multipotency properties are currently at the center of translational medicine for the repair of multiple joint tissues, such as articular cartilage and meniscus lesions. METHODS AND RESULTS We reviewed the results of in vitro and in vivo research on the current clinical applications of S-MSCs, surface markers, cell culture techniques, regenerative properties, and immunomodulatory mechanisms of S-MSCs as well as the practical limitations of the last twenty-five years (1996 to 2021). CONCLUSIONS Despite the poor interest in the development of new clinical trials for the application of S-MSCs in joint tissue repair, we found evidence to support the clinical use of S-MSCs for cartilage repair. S-MSCs can be considered a valuable therapy for the treatment of repairing joint lesions.
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Affiliation(s)
- Yessica Zamudio-Cuevas
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Calzada México-Xochimilco #289 Col. Arenal de Guadalupe, Delegación Tlalpan, 14389, Mexico City, Mexico
| | - Ricardo Plata-Rodríguez
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Calzada México-Xochimilco #289 Col. Arenal de Guadalupe, Delegación Tlalpan, 14389, Mexico City, Mexico
| | - Javier Fernández-Torres
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Calzada México-Xochimilco #289 Col. Arenal de Guadalupe, Delegación Tlalpan, 14389, Mexico City, Mexico
| | - Karina Martínez Flores
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Calzada México-Xochimilco #289 Col. Arenal de Guadalupe, Delegación Tlalpan, 14389, Mexico City, Mexico
| | - Víctor Hugo Cárdenas-Soria
- Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Calzada México-Xochimilco #289. Col. Arenal de Guadalupe, Delegación Tlalpan, 14389, Mexico City, Mexico
| | - Anell Olivos-Meza
- Ortopedia del Deporte y Artroscopía, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Calzada México-Xochimilco #289 Col. Arenal de Guadalupe, Delegación Tlalpan, 14389, Mexico City, Mexico
| | - Adriana Hernández-Rangel
- Instituto Politécnico Nacional-ESIQIE, Av. Luis Enrique Erro S/N, Nueva Industrial Vallejo, Gustavo A. Madero, 07738, Mexico City, CDMX, Mexico
| | - Carlos Landa-Solís
- Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Calzada México-Xochimilco #289. Col. Arenal de Guadalupe, Delegación Tlalpan, 14389, Mexico City, Mexico.
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Angele P, Docheva D, Pattappa G, Zellner J. Cell-based treatment options facilitate regeneration of cartilage, ligaments and meniscus in demanding conditions of the knee by a whole joint approach. Knee Surg Sports Traumatol Arthrosc 2022; 30:1138-1150. [PMID: 33666685 PMCID: PMC9007795 DOI: 10.1007/s00167-021-06497-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/08/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE This article provides an update on the current therapeutic options for cell-based regenerative treatment of the knee with a critical review of the present literature including a future perspective on the use of regenerative cell-based approaches. Special emphasis has been given on the requirement of a whole joint approach with treatment of comorbidities with aim of knee cartilage restoration, particularly in demanding conditions like early osteoarthritis. METHODS This narrative review evaluates recent clinical data and published research articles on cell-based regenerative treatment options for cartilage and other structures around the knee RESULTS: Cell-based regenerative therapies for cartilage repair have become standard practice for the treatment of focal, traumatic chondral defects of the knee. Specifically, matrix-assisted autologous chondrocyte transplantation (MACT) shows satisfactory long-term results regarding radiological, histological and clinical outcome for treatment of large cartilage defects. Data show that regenerative treatment of the knee requires a whole joint approach by addressing all comorbidities including axis deviation, instability or meniscus pathologies. Further development of novel biomaterials and the discovery of alternative cell sources may facilitate the process of cell-based regenerative therapies for all knee structures becoming the gold standard in the future. CONCLUSION Overall, cell-based regenerative cartilage therapy of the knee has shown tremendous development over the last years and has become the standard of care for large and isolated chondral defects. It has shown success in the treatment of traumatic, osteochondral defects but also for degenerative cartilage lesions in the demanding condition of early OA. Future developments and alternative cell sources may help to facilitate cell-based regenerative treatment for all different structures around the knee by a whole joint approach. LEVEL OF EVIDENCE IV.
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Affiliation(s)
- Peter Angele
- Sporthopaedicum Regensburg, Hildegard von Bingen Strasse 1, 93053, Regensburg, Germany.
- Department of Trauma Surgery, University Medical Center of Regensburg, Franz Josef Strauss Allee 11, 93042, Regensburg, Germany.
| | - Denitsa Docheva
- Department of Trauma Surgery, University Medical Center of Regensburg, Franz Josef Strauss Allee 11, 93042, Regensburg, Germany
| | - Girish Pattappa
- Department of Trauma Surgery, University Medical Center of Regensburg, Franz Josef Strauss Allee 11, 93042, Regensburg, Germany
| | - Johannes Zellner
- Department of Trauma Surgery, University Medical Center of Regensburg, Franz Josef Strauss Allee 11, 93042, Regensburg, Germany
- Department of Trauma Surgery, Caritas Hospital St. Josef Regensburg, Landshuter Strasse 65, 93053, Regensburg, Germany
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Jeyaraman M, Muthu S, Jeyaraman N, Ranjan R, Jha SK, Mishra P. Synovium Derived Mesenchymal Stromal Cells (Sy-MSCs): A Promising Therapeutic Paradigm in the Management of Knee Osteoarthritis. Indian J Orthop 2022; 56:1-15. [PMID: 35070137 PMCID: PMC8748553 DOI: 10.1007/s43465-021-00439-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 06/03/2021] [Indexed: 02/05/2023]
Abstract
Synovium-derived mesenchymal stromal cell (Sy-MSC) is a newer member of the mesenchymal stromal cell families. The first successful demonstration of the mesenchymal stromal cell from the human synovial membrane was done in 2001 and since then its potential role for musculoskeletal regeneration has been keenly documented. The regenerative effects of Sy-MSCs are through paracrine signaling, direct cell-cell interactions, and extracellular vehicles. Sy-MSCs possess superior chondrogenicity than other sources of mesenchymal stromal cells. This article aims to outline the advancement of synovium-derived mesenchymal stromal cells along with a specific insight into the application for managing osteoarthritis knee.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
- Department of Orthopaedics, Government Medical College & Hospital, Dindigul, Tamil Nadu India
| | - Naveen Jeyaraman
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
- Department of Orthopaedics, Kasturba Medical College, MAHE University, Manipal, Karnataka India
| | - Rajni Ranjan
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
| | - Prabhu Mishra
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
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Altaie A, Baboolal TG, Wall O, Pandit H, Jones E, McGonagle D. Device-Based Enrichment of Knee Joint Synovial Cells to Drive MSC Chondrogenesis Without Prior Culture Expansion In Vitro: A Step Closer to 1-Stage Orthopaedic Procedures. Am J Sports Med 2022; 50:152-161. [PMID: 34779670 PMCID: PMC8739599 DOI: 10.1177/03635465211055164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 07/27/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND Synovial fluid (SF) mesenchymal stem cells (MSCs) are derived from the synovial membrane and have cartilage repair potential. Their current use in clinical practice is largely exploratory. As their numbers tend to be small, therapeutic procedures using MSCs typically require culture expansion. Previous reports indicate that the stem cell-mobilizing device (STEM device) intraoperatively increases SF-MSCs. PURPOSE This study evaluated the chondrogenic potential of non-culture expanded synovium-mobilized MSCs and SF-microfragments obtained after enrichment using the STEM device and ascertained if device-mediated synovial membrane manipulation facilitated ongoing MSC release. STUDY DESIGN Controlled laboratory study. METHODS Two samples of aspiration fluid were collected intraoperatively before and after STEM device utilization from patients (n = 16) undergoing diagnostic or therapeutic knee arthroscopy. Human knee synovium (n = 5) was collected during total knee replacement, and a suspended culture was performed to assess the effect of the STEM device on ongoing MSC release. Colony forming unit-fibroblastic assays were used to determine the number of MSCs. Additionally, cytometric characterization of stromal and immune cells and chondrogenesis differentiation assay were performed without culture expansion. Filtered platelet concentrates were prepared using the HemaTrate system. RESULTS After STEM device use, a significant increase was evident in SF-MSCs (P = .03) and synovial fluid-resident synovial tissue microfragments (P = .03). In vitro-suspended synovium released significantly more MSCs following STEM device use than nonstimulated synovium (P = .01). The STEM device-released total cellular fraction produced greater in vitro chondrogenesis with significantly more glycosaminoglycans (GAGs; P < .0001) when compared with non-STEM device synovial fluid material. Nonexpanded SF-MSCs and SF-microfragments combined with autologous filtered platelet concentrate produced significantly more GAGs than the complete chondrogenic media (P < .0001). The STEM device-mobilized cells contained more M2 macrophage cells and fewer M1 cells. CONCLUSION Non-culture expanded SF-MSCs and SF-microfragments had the potential to undergo chondrogenesis without culture expansion, which can be augmented using the STEM device with increased MSC release from manipulated synovium for several days. Although preliminary, these findings offer proof of concept toward manipulation of the knee joint environment to facilitate endogenous repair responses. CLINICAL RELEVANCE Although numbers were small, this study highlights 3 factors relevant to 1-stage joint repair using the STEM device: increased SF-MSCs and SF-microfragments and prolonged synovial release of MSCs. Joint repair strategies involving endogenous MSCs for cartilage repair without the need for culture expansion in a 1-stage procedure may be possible.
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Affiliation(s)
- Ala Altaie
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Thomas G. Baboolal
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Owen Wall
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- Leeds Biomedical Research Centre, National Institute for Health Research, Leeds, UK
| | - Hemant Pandit
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- Leeds Biomedical Research Centre, National Institute for Health Research, Leeds, UK
| | - Elena Jones
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
- Leeds Biomedical Research Centre, National Institute for Health Research, Leeds, UK
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Lee JS, Shim DW, Kang KY, Chae DS, Lee WS. Method Categorization of Stem Cell Therapy for Degenerative Osteoarthritis of the Knee: A Review. Int J Mol Sci 2021; 22:ijms222413323. [PMID: 34948119 PMCID: PMC8704290 DOI: 10.3390/ijms222413323] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/05/2021] [Accepted: 12/08/2021] [Indexed: 01/02/2023] Open
Abstract
Current clinical applications of mesenchymal stem cell therapy for osteoarthritis lack consistency because there are no established criteria for clinical processes. We aimed to systematically organize stem cell treatment methods by reviewing the literature. The treatment methods used in 27 clinical trials were examined and reviewed. The clinical processes were separated into seven categories: cell donor, cell source, cell preparation, delivery methods, lesion preparation, concomitant procedures, and evaluation. Stem cell donors were sub-classified as autologous and allogeneic, and stem cell sources included bone marrow, adipose tissue, peripheral blood, synovium, placenta, and umbilical cord. Mesenchymal stem cells can be prepared by the expansion or isolation process and attached directly to cartilage defects using matrices or injected into joints under arthroscopic observation. The lesion preparation category can be divided into three subcategories: chondroplasty, microfracture, and subchondral drilling. The concomitant procedure category describes adjuvant surgery, such as high tibial osteotomy. Classification codes were assigned for each subcategory to provide a useful and convenient method for organizing documents associated with stem cell treatment. This classification system will help researchers choose more unified treatment methods, which will facilitate the efficient comparison and verification of future clinical outcomes of stem cell therapy for osteoarthritis.
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Affiliation(s)
- Jae Sun Lee
- Stem Cell Therapy Center, International St. Mary’s Hospital, College of Medicine, Catholic Kwandong University, Incheon 22711, Korea;
| | - Dong Woo Shim
- Department of Orthopedic Surgery, International St. Mary’s Hospital, College of Medicine, Catholic Kwandong University, Incheon 22711, Korea;
| | - Kyung-Yil Kang
- Department of Medicine, Catholic Kwandong Graduate School, Gangneung-si 25601, Korea;
| | - Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary’s Hospital, College of Medicine, Catholic Kwandong University, Incheon 22711, Korea;
- Correspondence: (D.-S.C.); (W.-S.L.); Tel.: +82-32-290-3878 (D.-S.C.); +82-2-2019-3410 (W.-S.L.); Fax: +82-32-290-3879 (D.-S.C.); +82-2-573-5393 (W.-S.L.)
| | - Woo-Suk Lee
- Department of Orthopedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06276, Korea
- Correspondence: (D.-S.C.); (W.-S.L.); Tel.: +82-32-290-3878 (D.-S.C.); +82-2-2019-3410 (W.-S.L.); Fax: +82-32-290-3879 (D.-S.C.); +82-2-573-5393 (W.-S.L.)
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Jaibaji M, Jaibaji R, Volpin A. Mesenchymal Stem Cells in the Treatment of Cartilage Defects of the Knee: A Systematic Review of the Clinical Outcomes. Am J Sports Med 2021; 49:3716-3727. [PMID: 33555942 DOI: 10.1177/0363546520986812] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Osteochondral lesions are a common clinical problem and their management has been historically challenging. Mesenchymal stem cells have the potential to differentiate into chondrocytes and thus restore hyaline cartilage to the defect, theoretically improving clincal outcomes in these patients. They can also be harvested with minimal donor site morbidity. PURPOSE To assess the clinical and functional outcomes of mesenchymal stem cell implantation to treat isolated osteochondral defects of the knee. A secondary purpose is to assess the quality of the current available evidence as well as the radiological and histological outcomes. We also reviewed the cellular preparation and operative techniques for implantation. STUDY DESIGN Systematic review. METHODS A comprehensive literature search of 4 databases was carried out: CINAHL, Embase, MEDLINE, and PubMed. We searched for clinical studies reporting the outcomes on a minimum of 5 patients with at least 12 months of follow-up. Clinical, radiological, and histological outcomes were recorded. We also recorded demographics, stem cell source, culture technique, and operative technique. Methodological quality of each study was assessed using the modified Coleman methodology score, and risk of bias for the randomized controlled studies was assessed using the Cochrane Collaboration tool. RESULTS Seventeen studies were found, encompassing 367 patients. The mean patient age was 35.1 years. Bone marrow was the most common source of stem cells utilized. Mesenchymal stem cell therapy consistently demonstrated good short- to medium-term outcomes in the studies reviewed with no serious adverse events being recorded. There was significant heterogeneity in cell harvesting and preparation as well as in the reporting of outcomes. CONCLUSION Mesenchymal stem cells demonstrated a clinically relevant improvement in outcomes in patients with osteochondral defects of the knee. More research is needed to establish an optimal treatment protocol, long-term outcomes, and superiority over other therapies. REGISTRATION CRD42020179391 (PROSPERO).
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Affiliation(s)
- Monketh Jaibaji
- Division of Interventional Sciences, University College London, London, UK
| | - Rawan Jaibaji
- Division of Interventional Sciences, University College London, London, UK
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Solanki K, Shanmugasundaram S, Shetty N, Kim SJ. Articular cartilage repair & joint preservation: A review of the current status of biological approach. J Clin Orthop Trauma 2021; 22:101602. [PMID: 34631411 PMCID: PMC8488240 DOI: 10.1016/j.jcot.2021.101602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/12/2021] [Accepted: 09/12/2021] [Indexed: 01/03/2023] Open
Abstract
The articular cartilage of the joint is the thin viscoelastic layer of the connective tissue. It has a unique anatomy and physiology, which makes the repair of the articular cartilage damage more difficult and challenging due to its limited healing capacity. Increasing knowledge regarding the importance of articular cartilage for joint preservation has led to increased attention on early identification of cartilage damage as well as degeneration in order to delay osteoarthritis. There are various treatment modalities ranging from preventive management, physical therapy, pharmacological, non-pharmacological and surgical treatments exist in current literature. However most of the studies have limited long term follow up and mainly consists of small case series and case reports. This is an up to date concise review discussing the available management options for articular cartilage damage starting to lifestyle modification to pharmacotherapy, physiotherapy, and osteobiologics till various joint preservation techniques that have been in use currently.
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Affiliation(s)
- Ketansinh Solanki
- Department of Arthroscopy and Trauma, Soundarapandian Bone and Joint Hospital, Chennai, India
| | - Saseendar Shanmugasundaram
- Department of Arthroscopy and Cartilage Reconstruction, Apollo Hospital, Muscat, Oman
- Corresponding author.
| | - Neha Shetty
- Kent Knee Unit, Spire Alexandra Hospital, Chatham, Kent, ME5 9PG, UK
| | - Seok-Jung Kim
- Department of Orthopaedic Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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Urlić I, Ivković A. Cell Sources for Cartilage Repair-Biological and Clinical Perspective. Cells 2021; 10:cells10092496. [PMID: 34572145 PMCID: PMC8468484 DOI: 10.3390/cells10092496] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 01/04/2023] Open
Abstract
Cell-based therapy represents a promising treatment strategy for cartilage defects. Alone or in combination with scaffolds/biological signals, these strategies open many new avenues for cartilage tissue engineering. However, the choice of the optimal cell source is not that straightforward. Currently, various types of differentiated cells (articular and nasal chondrocytes) and stem cells (mesenchymal stem cells, induced pluripotent stem cells) are being researched to objectively assess their merits and disadvantages with respect to the ability to repair damaged articular cartilage. In this paper, we focus on the different cell types used in cartilage treatment, first from a biological scientist’s perspective and then from a clinician’s standpoint. We compare and analyze the advantages and disadvantages of these cell types and offer a potential outlook for future research and clinical application.
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Affiliation(s)
- Inga Urlić
- Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Correspondence: (I.U.); (A.I.)
| | - Alan Ivković
- Department of Orthopaedic Surgery, University Hospital Sveti Duh, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department of Clinical Medicine, University of Applied Health Sciences, 10000 Zagreb, Croatia
- Correspondence: (I.U.); (A.I.)
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Liu YL, Yen CC, Liu TST, Chang CH, Shih TTF, Wang JH, Yang MC, Lin FH, Liu HC. Safety and Efficacy of Kartigen ® in Treating Cartilage Defects: A Randomized, Controlled, Phase I Trial. Polymers (Basel) 2021; 13:polym13183029. [PMID: 34577930 PMCID: PMC8466236 DOI: 10.3390/polym13183029] [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: 07/30/2021] [Revised: 08/31/2021] [Accepted: 08/31/2021] [Indexed: 01/18/2023] Open
Abstract
Here, we aimed to investigate the safety and preliminary efficacy of Kartigen®, a matrix with autologous bone marrow mesenchymal stem cell-derived chondrocyte precursors embedded in atelocollagen. As a surgical graft, Kartigen® was implanted onto the cartilage defects at the weight-bearing site of the medial femoral condyle of the knee. Fifteen patients were enrolled and stratified into two groups, undergoing either Kartigen® implantation (n = 10) or microfracture (control group, n = 5). The primary endpoint was to evaluate the safety of Kartigen® by monitoring the occurrence of adverse events through physician queries, physical examinations, laboratory tests, and radiological analyses for 2 years. There were no infections, inflammations, adhesions, loose body, or tumor formations in the Kartigen®-implanted knees. The preliminary efficacy was assessed using the International Knee Documentation Committee (IKDC) score, visual analog scale, and second-look arthroscopy. The postoperative IKDC scores of the Kartigen® group significantly improved in the 16th week (IKDC = 62.1 ± 12.8, p = 0.025), kept increasing in the first year (IKDC = 78.2 ± 15.4, p < 0.005), and remained satisfactory in the second year (IKDC = 73.6 ± 13.8, p < 0.005), compared to the preoperative condition (IKDC = 47.1 ± 17.0), while the postoperative IKDC scores of the control group also achieved significant improvement in the 28th week (IKDC = 68.5 ± 6.1, p = 0.032) versus preoperative state (IKDC = 54.0 ± 9.1). However, the IKDC scores decreased in the first year (IKDC = 63.5 ± 11.6) as well as in the second year (IKDC = 52.6 ± 16.4). Thirteen patients underwent second-look arthroscopy and biopsy one year after the operation. The Kartigen® group exhibited integration between Kartigen® and host tissue with a smooth appearance at the recipient site, whereas the microfracture group showed fibrillated surfaces. The histological and immunohistochemical analyses of biopsy specimens demonstrated the columnar structure of articular cartilage and existence of collagen type II and glycosaminoglycan mimic hyaline cartilage. This study indicates that Kartigen® is safe and effective in treating cartilage defects.
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Affiliation(s)
- Yen-Liang Liu
- Master Program for Biomedical Engineering, College of Biomedical Engineering, China Medical University, Taichung 406040, Taiwan;
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 406040, Taiwan
| | - Chun-Che Yen
- Kartigen Biomedical Inc., Taipei 100047, Taiwan;
| | | | - Chih-Hung Chang
- Department of Orthopaedic Surgery, Far Eastern Memorial Hospital, New Taipei 220216, Taiwan;
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan
| | - Tiffany Ting-Fang Shih
- Department of Medical Imaging and Radiology, National Taiwan University Hospital, Taipei 100225, Taiwan;
| | - Jyh-Horng Wang
- Department of Orthopaedic Surgery, National Taiwan University Hospital, Taipei 100225, Taiwan;
| | - Ming-Chia Yang
- Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 310401, Taiwan;
| | - Feng-Huei Lin
- Department of Biomedical Engineering, College of Engineering, National Taiwan University, Taipei 106319, Taiwan;
| | - Hwa-Chang Liu
- Department of Orthopaedic Surgery, National Taiwan University Hospital, Taipei 100225, Taiwan;
- Department of Orthopaedic Surgery, Taiwan Adventist Hospital, Taipei 105404, Taiwan
- Correspondence:
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Mizuno M, Endo K, Katano H, Amano N, Nomura M, Hasegawa Y, Ozeki N, Koga H, Takasu N, Ohara O, Morio T, Sekiya I. Transplantation of human autologous synovial mesenchymal stem cells with trisomy 7 into the knee joint and 5 years of follow-up. Stem Cells Transl Med 2021; 10:1530-1543. [PMID: 34342383 PMCID: PMC8550709 DOI: 10.1002/sctm.20-0491] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 05/20/2021] [Accepted: 06/16/2021] [Indexed: 01/16/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can show trisomy 7; however, the safety of these cells has not been fully investigated. The purposes of this study were to determine the ratio of patients whose synovial MSCs were transplanted clinically, to intensively investigate MSCs with trisomy 7 from a safety perspective, and to follow up the patients for 5 years after transplantation. Synovial MSCs at passage 0 were transplanted into a knee for degenerative meniscus tears in 10 patients, and the patients were checked at 5 years. The synovial MSCs were evaluated at passages 0 to 15 by G‐bands and digital karyotyping, and trisomy 7 was found in 3 of 10 patients. In those three patients, 5% to 10% of the synovial MSCs showed trisomy 7. The mRNA expressions of representative oncogenes and genes on chromosome 7 did not differ between MSCs with and without trisomy 7. Whole‐genome sequencing and DNA methylation analysis showed similar results for MSCs with and without trisomy 7. Transplantation of human synovial MSCs with trisomy 7 into eight mouse knees did not result in tumor formation under the skin or in the knees after 8 weeks in any mouse, whereas transplanted HT1080 cells formed tumors. In vitro chondrogenic potentials were similar between MSCs with and without trisomy 7. Five‐year follow‐ups revealed no serious adverse events in all 10 human patients, including 3 who had received MSCs with trisomy 7. Overall, our findings indicated that synovial MSCs with trisomy 7 were comparable with MSCs without trisomy 7 from a safety perspective.
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Affiliation(s)
- Mitsuru Mizuno
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental University (TMDU)TokyoJapan
| | - Kentaro Endo
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental University (TMDU)TokyoJapan
| | - Hisako Katano
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental University (TMDU)TokyoJapan
| | - Naoki Amano
- Department of Fundamental Cell TechnologyCenter for iPS Cell Research and Application, Kyoto UniversityKyotoJapan
| | - Masaki Nomura
- Department of Fundamental Cell TechnologyCenter for iPS Cell Research and Application, Kyoto UniversityKyotoJapan
| | | | - Nobutake Ozeki
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental University (TMDU)TokyoJapan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports MedicineGraduate School, Tokyo Medical and Dental University (TMDU)TokyoJapan
| | - Naoko Takasu
- Department of Fundamental Cell TechnologyCenter for iPS Cell Research and Application, Kyoto UniversityKyotoJapan
| | - Osamu Ohara
- Department of Applied GenomicsKazusa DNA Research InstituteChibaJapan
| | - Tomohiro Morio
- Department of Pediatrics and Developmental BiologyGraduate School, Tokyo Medical and Dental University (TMDU)TokyoJapan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental University (TMDU)TokyoJapan
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Chijimatsu R, Miwa S, Okamura G, Miyahara J, Tachibana N, Ishikura H, Higuchi J, Maenohara Y, Tsuji S, Sameshima S, Takagi K, Nakazato K, Kawaguchi K, Yamagami R, Inui H, Taketomi S, Tanaka S, Saito T. Divergence in chondrogenic potential between in vitro and in vivo of adipose- and synovial-stem cells from mouse and human. Stem Cell Res Ther 2021; 12:405. [PMID: 34266496 PMCID: PMC8281654 DOI: 10.1186/s13287-021-02485-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Somatic stem cell transplantation has been performed for cartilage injury, but the reparative mechanisms are still conflicting. The chondrogenic potential of stem cells are thought as promising features for cartilage therapy; however, the correlation between their potential for chondrogenesis in vitro and in vivo remains undefined. The purpose of this study was to investigate the intrinsic chondrogenic condition depends on cell types and explore an indicator to select useful stem cells for cartilage regeneration. METHODS The chondrogenic potential of two different stem cell types derived from adipose tissue (ASCs) and synovium (SSCs) of mice and humans was assessed using bone morphogenic protein-2 (BMP2) and transforming growth factor-β1 (TGFβ1). Their in vivo chondrogenic potential was validated through transplantation into a mouse osteochondral defect model. RESULTS All cell types showed apparent chondrogenesis under the combination of BMP2 and TGFβ1 in vitro, as assessed by the formation of proteoglycan- and type 2 collagen (COL2)-rich tissues. However, our results vastly differed with those observed following single stimulation among species and cell types; apparent chondrogenesis of mouse SSCs was observed with supplementation of BMP2 or TGFβ1, whereas chondrogenesis of mouse ASCs and human SSCs was observed with supplementation of BMP2 not TGFβ1. Human ASCs showed no obvious chondrogenesis following single stimulation. Mouse SSCs showed the formation of hyaline-like cartilage which had less fibrous components (COL1/3) with supplementation of TGFβ1. However, human cells developed COL1/3+ tissues with all treatments. Transcriptomic analysis for TGFβ receptors and ligands of cells prior to chondrogenic induction did not indicate their distinct reactivity to the TGFβ1 or BMP2. In the transplanted site in vivo, mouse SSCs formed hyaline-like cartilage (proteoglycan+/COL2+/COL1-/COL3-) but other cell types mainly formed COL1/3-positive fibrous tissues in line with in vitro reactivity to TGFβ1. CONCLUSION Optimal chondrogenic factors driving chondrogenesis from somatic stem cells are intrinsically distinct among cell types and species. Among them, the response to TGFβ1 may possibly represent the fate of stem cells when locally transplanted into cartilage defects.
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Affiliation(s)
- Ryota Chijimatsu
- Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Satoshi Miwa
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Junya Miyahara
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naohiro Tachibana
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hisatoshi Ishikura
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junya Higuchi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuji Maenohara
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Shin Sameshima
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kentaro Takagi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keiu Nakazato
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kohei Kawaguchi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Yamagami
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Inui
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shuji Taketomi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Sakae Tanaka
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Taku Saito
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Sheppard WL, Hinckel BB, Arshi A, Sherman SL, Jones KJ. Accurate Reporting of Concomitant Procedures Is Highly Variable in Studies Investigating Knee Cartilage Restoration. Cartilage 2021; 12:333-343. [PMID: 30971096 PMCID: PMC8236649 DOI: 10.1177/1947603519841673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Successful clinical outcomes following cartilage restoration procedures are highly dependent on addressing concomitant pathology. The purpose of this study was to document methods for evaluating concomitant procedures of the knee when performed with articular cartilage restoration techniques, and to review their reported findings in high-impact clinical orthopedic studies. We hypothesized that there are substantial inconsistencies in reporting clinical outcomes associated with concomitant procedures relative to outcomes related to isolated cartilage repair. DESIGN A total of 133 clinical studies on articular cartilage repair of the knee were identified from 6 high-impact orthopedic journals between 2011 and 2017. Studies were included if they were primary research articles reporting clinical outcomes data following surgical treatment of articular cartilage lesions with a minimum sample size of 5 patients. Studies were excluded if they were review articles, meta-analyses, and articles reporting only nonclinical outcomes (e.g., imaging, histology). A full-text review was then used to evaluate details regarding study methodology and reporting on the following variables: primary cartilage repair procedure, and the utilization of concomitant procedures to address additional patient comorbidities, including malalignment, meniscus pathology, and ligamentous instability. Each study was additionally reviewed to document variation in clinical outcomes reporting in patients that had these comorbidities addressed at the time of surgery. RESULTS All studies reported on the type of primary cartilage repair procedure, with autologous chondrocyte implantation (ACI) noted in 43% of studies, microfracture (MF) reported in 16.5%, osteochondral allograft (OCA) in 15%, and osteochondral autograft transplant (OAT) in 8.2%. Regarding concomitant pathology, anterior cruciate ligament (ACL) reconstruction (24.8%) and meniscus repair (23.3%) were the most commonly addressed patient comorbidities. A total of 56 studies (42.1%) excluded patients with malalignment, meniscus injury, and ligamentous instability. For studies that addressed concomitant pathology, 72.7% reported clinical outcomes separately from the cohort treated with only cartilage repair. A total of 16.5% of studies neither excluded nor addressed concomitant pathologies. There was a significant amount of variation in the patient reported outcome scores used among the studies, with the majority of studies reporting International Knee Documentation Committee (IKDC) and Knee Injury and Osteoarthritis Outcomes Score (KOOS) in 47.2% and 43.6% of articles, respectively. CONCLUSIONS In this study on knee cartilage restoration, recognition and management of concomitant pathology is inadequately reported in approximately 28% of studies. Only 30% of articles reported adequate treatment of concomitant ailments while scoring their outcomes using one of a potential 18 different scoring systems. These findings highlight the need for more standardized methods to be applied in future research with regard to inclusion, exclusion, and scoring concomitant pathologies with regard to treatment of cartilage defects in the knee.
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Affiliation(s)
- William L. Sheppard
- Department of Orthopaedic Surgery, University of California, Los Angeles, Santa Monica, CA, USA,David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Betina B. Hinckel
- Department of Orthopedic Surgery, University of Missouri Health, Columbia, MO, USA
| | - Armin Arshi
- Department of Orthopaedic Surgery, University of California, Los Angeles, Santa Monica, CA, USA,David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Seth L. Sherman
- Department of Orthopedic Surgery, University of Missouri Health, Columbia, MO, USA
| | - Kristofer J. Jones
- Department of Orthopaedic Surgery, University of California, Los Angeles, Santa Monica, CA, USA,David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA,Kristofer J. Jones, Department of Orthopaedic Surgery, Division of Sports Medicine and Shoulder Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 76-143 CHS, Los Angeles, CA 90095-6902, USA. Emails:
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Ueki H, Katagiri H, Tsuji K, Miyatake K, Watanabe T, Sekiya I, Muneta T, Koga H. Effect of transplanted mesenchymal stem cell number on the prevention of cartilage degeneration and pain reduction in a posttraumatic osteoarthritis rat model. J Orthop Sci 2021; 26:690-697. [PMID: 32859470 DOI: 10.1016/j.jos.2020.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/02/2020] [Accepted: 06/30/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) transplantation therapy is considered an alternative therapy to prevent posttraumatic osteoarthritis (PTOA). However, consensus as to the sufficient number of MSCs for the prevention of PTOA is lacking. The purpose of this study was to determine the sufficient number of MSCs to achieve PTOA prevention and the reduction in pain after anterior cruciate ligament transection (ACLT). METHODS Eight-week-old male Wistar rats were used. ACLT was conducted in the knee joint as a PTOA model. According to the species-specific knee joint volume, 104 MSCs in rats are equivalent to 3 × 107 MSCs in humans, which was clinically prepared. MSCs (104, 105, or 106 cells) or phosphate-buffered saline were injected into the knee joint at 1, 2, and 3 weeks after ACLT. Histological examinations were performed at 12 weeks after ACLT. The weight-bearing distribution improvement ratio was calculated as an assessment of pain until 12 weeks after ACLT. RESULTS Histological evaluations showed that all the MSCs groups except for 104 MSCs group in femur were significantly improved compared to the control group at 12 weeks after ACLT. The weight-bearing distribution in the 104 and 105 MSCs groups at 12 weeks after ACLT and in the 106 MSCs group at 6, 8, 10, and 12 weeks after ACLT were significantly higher than those of the control group. CONCLUSION A clinically feasible number of MSCs was found to reduce the articular cartilage degeneration and to decrease pain in the PTOA model. Increasing numbers of the cells further protected the articular cartilage against degeneration.
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Affiliation(s)
- Hiroko Ueki
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Hiroki Katagiri
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan; Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
| | - Kunikazu Tsuji
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Kazumasa Miyatake
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan; Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Toshifumi Watanabe
- Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Takeshi Muneta
- Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan; Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
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Proteomic Analysis Reveals Commonly Secreted Proteins of Mesenchymal Stem Cells Derived from Bone Marrow, Adipose Tissue, and Synovial Membrane to Show Potential for Cartilage Regeneration in Knee Osteoarthritis. Stem Cells Int 2021; 2021:6694299. [PMID: 34306096 PMCID: PMC8264516 DOI: 10.1155/2021/6694299] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/28/2021] [Accepted: 06/08/2021] [Indexed: 12/24/2022] Open
Abstract
Paracrine factors secreted by mesenchymal stem cells (MSCs) reportedly modulate inflammation and reparative processes in damaged tissues and have been explored for knee osteoarthritis (OA) therapy. Although various studies have reported the effects of paracrine factors in knee OA, it is not yet clear which paracrine factors directly affect the regeneration of damaged cartilage and which are secreted under various knee OA conditions. In this study, we cultured MSCs derived from three types of tissues and treated each type with IL-1β and TNF-α or not to obtain conditioned medium. Each conditioned medium was used to analyse the paracrine factors related to cartilage regeneration using liquid chromatography-tandem mass spectrometry. Bone marrow-, adipose tissue-, and synovial membrane-MSCs (all-MSCs) exhibited expression of 93 proteins under normal conditions and 105 proteins under inflammatory conditions. It was confirmed that the types of secreted proteins differed depending on the environmental conditions, and the proteins were validated using ELISA. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis using a list of proteins secreted by all-MSCs under each condition confirmed that the secreted proteins were closely related to cartilage repair under inflammatory conditions. Protein-protein interaction networks were confirmed to change depending on environmental differences and were found to enhance the secretion of paracrine factors related to cartilage regeneration under inflammatory conditions. In conclusion, our results demonstrated that compared with knee OA conditions, the differential expression proteins may contribute to the regeneration of damaged cartilage. In addition, the detailed information on commonly secreted proteins by all-MSCs provides a comprehensive basis for understanding the potential of paracrine factors to influence tissue repair and regeneration in knee OA.
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Atelocollagen-Embedded Chondrocyte Precursors as a Treatment for Grade-4 Cartilage Defects of the Femoral Condyle: A Case Series with up to 9-Year Follow-Up. Biomolecules 2021; 11:biom11070942. [PMID: 34202002 PMCID: PMC8301975 DOI: 10.3390/biom11070942] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/17/2021] [Accepted: 06/22/2021] [Indexed: 12/22/2022] Open
Abstract
We demonstrated the safety and efficacy of autologous chondrocyte precursor (CP) cell therapy in repairing Grade 4 cartilage defects of medial femoral condyles. The autologous bone marrow mesenchymal stem cells of each participant were isolated, amplified, and then differentiated into CPs in atelocollagen. Neotissues made of CPs were implanted into cartilage defects with an average cell density of 4.9 ± 2.1 × 106 cells/cm2 through arthrotomy. The knee function was evaluated with the International Knee Documentation Committee (IKDC) subjective knee form. Patients' knee functions significantly improved by the 28th week (IKDC score = 68.3 ± 12.1), relative to the initial functionality before the CP therapy (IKDC score = 46.1 ± 16.4, p-value = 0.0014). Nine of these twelve patients maintained good knee functions for 9 years post-implantation (IKDC score = 69.8 ± 12.3) at levels higher than the pre-implantation values (p-value = 0.0018). Patients were evaluated with MRI and arthroscopy, and the defective sites exhibited a smooth surface without a gap between the implant and host tissue. This study demonstrates that autologous CPs successfully engraft into the host tissue and result in the re-formation of hyaline-like cartilage, thereby improving the impaired knee functions. Most importantly, no adverse event was reported during this long-term follow-up period.
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Ozeki N, Nakagawa Y, Mizuno M, Kohno Y, Katano H, Koga H, Sekiya I. Ultrasound-Guided Harvesting of Synovium for Regenerative Medicine of Cartilage and Meniscus Using Synovial Mesenchymal Stem Cells. Arthrosc Tech 2021; 10:e1723-e1727. [PMID: 34336570 PMCID: PMC8322568 DOI: 10.1016/j.eats.2021.03.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/09/2021] [Indexed: 02/03/2023] Open
Abstract
Mesenchymal stem cell (MSC) therapy for cartilage or meniscus pathologies, including osteoarthritis, requires the easy and safe collection of MSC source materials. Synovial MSCs are attractive cell sources for joint pathology because of their high proliferative and chondrogenic potential in vitro and in vivo. We developed an ultrasound-guided harvesting procedure for synovium for the regenerative medicine of cartilage and meniscus. A ∼1-cm skin incision is made at the proximal side of the patellae, and a forceps is inserted under ultrasound guidance of the suprapatellar pouch to grasp the synovium. Here, several synovium samples were retrieved and transported sterilely for culture at the cell-processing facility. After a 14-day culture of the nucleated cells, crystal violet confirmed colony formation. Cell growth was enough for MSC therapy of joint pathology (0.89 ± 0.06 × 106 cells/dish). No adverse events occurred during synovium harvesting. A key advantage of this procedure is its minimal invasiveness, as synovium is harvested from a 1-cm skin incision in the knee joint. A disadvantage is the possible risk of hemostasis, as arresting bleeding at the synovial harvest site is difficult, even though the suprapatellar pouch contains no major vessels.
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Affiliation(s)
- Nobutake Ozeki
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Yusuke Nakagawa
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Mitsuru Mizuno
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan
| | - Yuji Kohno
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Hisako Katano
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan,Address correspondence to Ichiro Sekiya, M.D., Ph.D., Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510 Japan.
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Zha K, Li X, Yang Z, Tian G, Sun Z, Sui X, Dai Y, Liu S, Guo Q. Heterogeneity of mesenchymal stem cells in cartilage regeneration: from characterization to application. NPJ Regen Med 2021; 6:14. [PMID: 33741999 PMCID: PMC7979687 DOI: 10.1038/s41536-021-00122-6] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 02/01/2021] [Indexed: 01/31/2023] Open
Abstract
Articular cartilage is susceptible to damage but hard to self-repair due to its avascular nature. Traditional treatment methods are not able to produce satisfactory effects. Mesenchymal stem cells (MSCs) have shown great promise in cartilage repair. However, the therapeutic effect of MSCs is often unstable partly due to their heterogeneity. Understanding the heterogeneity of MSCs and the potential of different types of MSCs for cartilage regeneration will facilitate the selection of superior MSCs for treating cartilage damage. This review provides an overview of the heterogeneity of MSCs at the donor, tissue source and cell immunophenotype levels, including their cytological properties, such as their ability for proliferation, chondrogenic differentiation and immunoregulation, as well as their current applications in cartilage regeneration. This information will improve the precision of MSC-based therapeutic strategies, thus maximizing the efficiency of articular cartilage repair.
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Affiliation(s)
- Kangkang Zha
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Xu Li
- Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhen Yang
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Guangzhao Tian
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Zhiqiang Sun
- Medical School of Chinese PLA, Beijing, China
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Xiang Sui
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, China
| | - Yongjing Dai
- Institute of Orthopaedics, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma & War Injuries, PLA, Beijing, 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, 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, China.
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Characteristics of MSCs in Synovial Fluid and Mode of Action of Intra-Articular Injections of Synovial MSCs in Knee Osteoarthritis. Int J Mol Sci 2021; 22:ijms22062838. [PMID: 33799588 PMCID: PMC8001624 DOI: 10.3390/ijms22062838] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/01/2021] [Accepted: 03/01/2021] [Indexed: 11/17/2022] Open
Abstract
We have been studying mesenchymal stem cells (MSCs) in synovial fluid and the intra-articular injection of synovial MSCs in osteoarthritis (OA) knees. Here, mainly based on our own findings, we overview the characteristics of endogenous MSCs in the synovial fluid of OA knees and their mode of action when injected exogenously into OA knees. Many MSCs similar to synovial MSCs were detected in the synovial fluid of human OA knees, and their number correlated with the radiological OA grade. Our suspended synovium culture model demonstrated the release of MSCs from the synovium through a medium into a non-contacting culture dish. In OA knees, endogenous MSCs possibly mobilize in a similar manner from the synovium through the synovial fluid and act protectively. However, the number of mobilized MSCs is limited; therefore, OA progresses in its natural course. Synovial MSC injections inhibited the progression of cartilage degeneration in a rat OA model. Injected synovial MSCs migrated into the synovium, maintained their MSC properties, and increased the gene expressions of TSG-6, PRG-4, and BMP-2. Exogenous synovial MSCs can promote anti-inflammation, lubrication, and cartilage matrix synthesis in OA knees. Based on our findings, we have initiated a human clinical study of synovial MSC injections in OA knees.
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Zhu X, Chan YT, Yung PSH, Tuan RS, Jiang Y. Subchondral Bone Remodeling: A Therapeutic Target for Osteoarthritis. Front Cell Dev Biol 2021; 8:607764. [PMID: 33553146 PMCID: PMC7859330 DOI: 10.3389/fcell.2020.607764] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/28/2020] [Indexed: 12/21/2022] Open
Abstract
There is emerging awareness that subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). This review presents recent investigations on the cellular and molecular mechanism of subchondral bone remodeling, and summarizes the current interventions and potential therapeutic targets related to OA subchondral bone remodeling. The first part of this review covers key cells and molecular mediators involved in subchondral bone remodeling (osteoclasts, osteoblasts, osteocytes, bone extracellular matrix, vascularization, nerve innervation, and related signaling pathways). The second part of this review describes candidate treatments for OA subchondral bone remodeling, including the use of bone-acting reagents and the application of regenerative therapies. Currently available clinical OA therapies and known responses in subchondral bone remodeling are summarized as a basis for the investigation of potential therapeutic mediators.
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Affiliation(s)
- Xiaobo Zhu
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yau Tsz Chan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Patrick S H Yung
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Rocky S Tuan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Yangzi Jiang
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
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Al-Masawa ME, Wan Kamarul Zaman WS, Chua KH. Biosafety evaluation of culture-expanded human chondrocytes with growth factor cocktail: a preclinical study. Sci Rep 2020; 10:21583. [PMID: 33299022 PMCID: PMC7725787 DOI: 10.1038/s41598-020-78395-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 10/27/2020] [Indexed: 01/03/2023] Open
Abstract
The scarcity of chondrocytes is a major challenge for cartilage tissue engineering. Monolayer expansion is necessary to amplify the limited number of chondrocytes needed for clinical application. Growth factors are often added to improve monolayer culture conditions, promoting proliferation, and enhancing chondrogenesis. Limited knowledge on the biosafety of the cell products manipulated with growth factors in culture has driven this study to evaluate the impact of growth factor cocktail supplements in chondrocyte culture medium on chondrocyte genetic stability and tumorigenicity. The growth factors were basic fibroblast growth factor (b-FGF), transforming growth factor β2 (TGF β2), insulin-like growth factor 1 (IGF-1), insulin-transferrin-selenium (ITS), and platelet-derived growth factor (PD-GF). Nasal septal chondrocytes cultured in growth factor cocktail exhibited a significantly high proliferative capacity. Comet assay revealed no significant DNA damage. Flow cytometry showed chondrocytes were mostly at G0-G1 phase, exhibiting normal cell cycle profile with no aneuploidy. We observed a decreased tumour suppressor genes’ expression (p53, p21, pRB) and no TP53 mutations or tumour formation after 6 months of implantation in nude mice. Our data suggest growth factor cocktail has a low risk of inducing genotoxic and tumorigenic effects on chondrocytes up to passage 6 with 16.6 population doublings. This preclinical tumorigenicity and genetic instability evaluation is crucial for further clinical works.
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Affiliation(s)
- Maimonah-Eissa Al-Masawa
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia.
| | | | - Kien-Hui Chua
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia.
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Li N, Gao J, Mi L, Zhang G, Zhang L, Zhang N, Huo R, Hu J, Xu K. Synovial membrane mesenchymal stem cells: past life, current situation, and application in bone and joint diseases. Stem Cell Res Ther 2020; 11:381. [PMID: 32894205 PMCID: PMC7487958 DOI: 10.1186/s13287-020-01885-3] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/31/2020] [Accepted: 08/14/2020] [Indexed: 01/04/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can be isolated from not only bone marrow, but also various adult mesenchymal tissues such as periosteum, skeletal muscle, and adipose tissue. MSCs from different tissue sources have different molecular phenotypes and differentiation potential. Synovial membrane (SM) is an important and highly specific component of synovial joints. Previous studies have suggested that the synovium is a structure with a few cell layers thick and consists mainly of fibroblast-like synoviocytes (FLS), which forms a layer that lining the synovial membrane on the joint cavity and synovial fluid through cell-cell contact. In recent years, studies have found that there are also mesenchymal stem cells in the synovium, and as an important part of the mesenchymal stem cell family, it has strong capabilities of cartilage forming and tissue repairing. This article reviews the sources, surface markers, subtypes, influencing factors, and applications in inflammatory joints of synovial membrane mesenchymal stem cells (SM-MSCs) in recent years, aiming to clarify the research status and existing problems of SM-MSCs.
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Affiliation(s)
- Na Li
- Department of Rheumatology, Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Jinfang Gao
- Department of Rheumatology, Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Liangyu Mi
- Department of Rheumatology, Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Gailian Zhang
- Department of Rheumatology, Shanxi Bethune Hospital, Taiyuan, 030032, Shanxi, China
| | - Liyun Zhang
- Department of Rheumatology, Shanxi Bethune Hospital, Taiyuan, 030032, Shanxi, China
| | - Na Zhang
- Department of Rheumatology, Shanxi Bethune Hospital, Taiyuan, 030032, Shanxi, China
| | - Rongxiu Huo
- Department of Rheumatology, Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Junping Hu
- Department of Rheumatology, Bethune Hospital Affiliated to Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Ke Xu
- Department of Rheumatology, Shanxi Bethune Hospital, Taiyuan, 030032, Shanxi, China.
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