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1
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Chen Q, Su Y, Yang Z, Lin Q, Ke Y, Xing D, Li H. Bibliometric mapping of mesenchymal stem cell therapy for bone regeneration from 2013 to 2023. Front Med (Lausanne) 2025; 11:1484097. [PMID: 39835103 PMCID: PMC11743382 DOI: 10.3389/fmed.2024.1484097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/05/2024] [Indexed: 01/22/2025] Open
Abstract
Mesenchymal stem cells (MSCs) have shown significant potential in bone regeneration and regenerative medicine in recent years. With the advancement of tissue engineering, MSCs have been increasingly applied in bone repair and regeneration, and their clinical application potential has grown through interdisciplinary approaches involving biomaterials and genetic engineering. However, there is a lack of systematic reviews summarizing their applications in bone regeneration. To address this gap, we analyzed the latest research on MSCs for bone regeneration published from 2013 to 2023. Using the Web of Science Core Collection, we conducted a literature search in December 2024 and employed bibliometric tools like CiteSpace and VOSviewer for a comprehensive analysis of the key research trends. Our findings focus on the development of cell engineering, highlighting the advantages, limitations, and future prospects of MSC applications in bone regeneration. These insights aim to enhance understanding of MSC-based bone regeneration, inspire new research directions, and facilitate the clinical translation of MSC research.
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Affiliation(s)
- Qianqian Chen
- Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
- Arthritis Clinic & Research Center, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yiqi Su
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing, China
| | - Zhen Yang
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing, China
| | - Qiyuan Lin
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing, China
| | - Yan Ke
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing, China
- Arthritis Institute, Peking University, Beijing, China
| | - Dan Xing
- Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
- Arthritis Clinic & Research Center, Zhejiang Chinese Medical University, Hangzhou, China
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing, China
- Arthritis Institute, Peking University, Beijing, China
| | - Hui Li
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing, China
- Arthritis Institute, Peking University, Beijing, China
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2
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Transcriptomic response of bioengineered human cartilage to parabolic flight microgravity is sex-dependent. NPJ Microgravity 2023; 9:5. [PMID: 36658138 PMCID: PMC9852254 DOI: 10.1038/s41526-023-00255-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 01/10/2023] [Indexed: 01/20/2023] Open
Abstract
Spaceflight and simulated spaceflight microgravity induced osteoarthritic-like alterations at the transcriptomic and proteomic levels in the articular and meniscal cartilages of rodents. But little is known about the effect of spaceflight or simulated spaceflight microgravity on the transcriptome of tissue-engineered cartilage developed from human cells. In this study, we investigate the effect of simulated spaceflight microgravity facilitated by parabolic flights on tissue-engineered cartilage developed from in vitro chondrogenesis of human bone marrow mesenchymal stem cells obtained from age-matched female and male donors. The successful induction of cartilage-like tissue was confirmed by the expression of well-demonstrated chondrogenic markers. Our bulk transcriptome data via RNA sequencing demonstrated that parabolic flight altered mostly fundamental biological processes, and the modulation of the transcriptome profile showed sex-dependent differences. The secretome profile analysis revealed that two genes (WNT7B and WNT9A) from the Wnt-signaling pathway, which is implicated in osteoarthritis development, were only up-regulated for female donors. The results of this study showed that the engineered cartilage tissues responded to microgravity in a sex-dependent manner, and the reported data offers a strong foundation to further explore the underlying mechanisms.
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Baheti W, Lv S, Mila, Ma L, Amantai D, Sun H, He H. Graphene/hydroxyapatite coating deposit on titanium alloys for implant application. J Appl Biomater Funct Mater 2023; 21:22808000221148104. [PMID: 36633270 DOI: 10.1177/22808000221148104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Titanium (Ti) implants are widely used in medicine. Meanwhile, surface modification of Ti can strengthen the osseointegration of implants. In this study, we modified Ti implant surfaces, which was coated with GO, HA, HA-2wt%GO and HA-5wt%GO via electrophoresis deposition, to investigate their mechanisms and biological activity. Uncoated Ti was used as the control. Further, we examined the biological behavior and osteogenic performance of mouse bone marrow mesenchymal stem cells (BMSCs) cultured on coatings in vitro. We found that the HA-GO nanocomposite coating improved the roughness and hydrophilicity of the Ti surface. Compared with the uncoated Ti or Ti modified by HA or GO alone, cell adhesion and diffusion were enhanced on HA-GO-modified Ti surfaces. In addition, the proliferation and osteogenic differentiation of BMSCs in vitro were significantly improved on HA-GO-modified surfaces, whereas osteogenesis-related gene expression and alkaline phosphatase activity were slightly enhanced. Furthermore, we noted that bone regeneration was improved in the HA-2wt%GO group in vivo. Thus, the HA-2wt%GO nanocomposite coating might have potential applications in the field of dental implants.
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Affiliation(s)
- Wufanbieke Baheti
- Department of Prosthodontics, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uyghur Autonomous Region, Urumqi, P.R. China.,People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China.,Stomatological Research Institute of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - ShangYi Lv
- Department of Prosthodontics, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uyghur Autonomous Region, Urumqi, P.R. China.,Stomatological Research Institute of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - Mila
- Department of Prosthodontics, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uyghur Autonomous Region, Urumqi, P.R. China.,Stomatological Research Institute of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - Lisha Ma
- Department of Prosthodontics, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uyghur Autonomous Region, Urumqi, P.R. China.,Stomatological Research Institute of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - Dumanbieke Amantai
- Department of Prosthodontics, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uyghur Autonomous Region, Urumqi, P.R. China.,Stomatological Research Institute of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - Hao Sun
- Department of Prosthodontics, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uyghur Autonomous Region, Urumqi, P.R. China.,Stomatological Research Institute of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
| | - HuiYu He
- Department of Prosthodontics, The Affiliated Stomatology Hospital of The First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uyghur Autonomous Region, Urumqi, P.R. China.,Stomatological Research Institute of Xinjiang Uygur Autonomous Region, Urumqi, P.R. China
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4
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Ge D, O'Brien MJ, Savoie FH, Gimble JM, Wu X, Gilbert MH, Clark-Patterson GL, Schuster JD, Miller KS, Wang A, Myers L, You Z. Human adipose-derived stromal/stem cells expressing doublecortin improve cartilage repair in rabbits and monkeys. NPJ Regen Med 2021; 6:82. [PMID: 34848747 PMCID: PMC8633050 DOI: 10.1038/s41536-021-00192-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 10/29/2021] [Indexed: 11/25/2022] Open
Abstract
Localized cartilage lesions in early osteoarthritis and acute joint injuries are usually treated surgically to restore function and relieve pain. However, a persistent clinical challenge remains in how to repair the cartilage lesions. We expressed doublecortin (DCX) in human adipose-derived stromal/stem cells (hASCs) and engineered hASCs into cartilage tissues using an in vitro 96-well pellet culture system. The cartilage tissue constructs with and without DCX expression were implanted in the knee cartilage defects of rabbits (n = 42) and monkeys (n = 12). Cohorts of animals were euthanized at 6, 12, and 24 months after surgery to evaluate the cartilage repair outcomes. We found that DCX expression in hASCs increased expression of growth differentiation factor 5 (GDF5) and matrilin 2 in the engineered cartilage tissues. The cartilage tissues with DCX expression significantly enhanced cartilage repair as assessed macroscopically and histologically at 6, 12, and 24 months after implantation in the rabbits and 24 months after implantation in the monkeys, compared to the cartilage tissues without DCX expression. These findings suggest that hASCs expressing DCX may be engineered into cartilage tissues that can be used to treat localized cartilage lesions.
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Affiliation(s)
- Dongxia Ge
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA
- Department of Orthopaedic Surgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Michael J O'Brien
- Department of Orthopaedic Surgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Felix H Savoie
- Department of Orthopaedic Surgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Jeffrey M Gimble
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA
- LaCell LLC and Obatala Sciences Inc., New Orleans, LA, USA
- Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, USA
- John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
- Department of Surgery, Tulane University School of Medicine, New Orleans, LA, USA
| | - Xiying Wu
- LaCell LLC and Obatala Sciences Inc., New Orleans, LA, USA
| | - Margaret H Gilbert
- Tulane National Primate Research Center, Tulane University, New Orleans, LA, USA
| | | | - Jason D Schuster
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, USA
| | - Kristin S Miller
- Department of Biomedical Engineering, Tulane University, New Orleans, LA, USA
| | - Alun Wang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Leann Myers
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropic Medicine, New Orleans, LA, USA
| | - Zongbing You
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
- Department of Orthopaedic Surgery, Tulane University School of Medicine, New Orleans, LA, USA.
- Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
- Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University School of Medicine, New Orleans, LA, USA.
- Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA, USA.
- Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA.
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5
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Lindberg GCJ, Cui X, Durham M, Veenendaal L, Schon BS, Hooper GJ, Lim KS, Woodfield TBF. Probing Multicellular Tissue Fusion of Cocultured Spheroids-A 3D-Bioassembly Model. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2103320. [PMID: 34632729 PMCID: PMC8596109 DOI: 10.1002/advs.202103320] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Indexed: 05/02/2023]
Abstract
While decades of research have enriched the knowledge of how to grow cells into mature tissues, little is yet known about the next phase: fusing of these engineered tissues into larger functional structures. The specific effect of multicellular interfaces on tissue fusion remains largely unexplored. Here, a facile 3D-bioassembly platform is introduced to primarily study fusion of cartilage-cartilage interfaces using spheroids formed from human mesenchymal stromal cells (hMSCs) and articular chondrocytes (hACs). 3D-bioassembly of two adjacent hMSCs spheroids displays coordinated migration and noteworthy matrix deposition while the interface between two hAC tissues lacks both cells and type-II collagen. Cocultures contribute to increased phenotypic stability in the fusion region while close initial contact between hMSCs and hACs (mixed) yields superior hyaline differentiation over more distant, indirect cocultures. This reduced ability of potent hMSCs to fuse with mature hAC tissue further underlines the major clinical challenge that is integration. Together, this data offer the first proof of an in vitro 3D-model to reliably study lateral fusion mechanisms between multicellular spheroids and mature cartilage tissues. Ultimately, this high-throughput 3D-bioassembly model provides a bridge between understanding cellular differentiation and tissue fusion and offers the potential to probe fundamental biological mechanisms that underpin organogenesis.
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Affiliation(s)
- Gabriella C. J. Lindberg
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) GroupDepartment of Orthopaedic SurgeryUniversity of Otago Christchurch2 Riccarton AvenueChristchurch8011New Zealand
| | - Xiaolin Cui
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) GroupDepartment of Orthopaedic SurgeryUniversity of Otago Christchurch2 Riccarton AvenueChristchurch8011New Zealand
| | - Mitchell Durham
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) GroupDepartment of Orthopaedic SurgeryUniversity of Otago Christchurch2 Riccarton AvenueChristchurch8011New Zealand
| | - Laura Veenendaal
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) GroupDepartment of Orthopaedic SurgeryUniversity of Otago Christchurch2 Riccarton AvenueChristchurch8011New Zealand
| | - Benjamin S. Schon
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) GroupDepartment of Orthopaedic SurgeryUniversity of Otago Christchurch2 Riccarton AvenueChristchurch8011New Zealand
| | - Gary J. Hooper
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) GroupDepartment of Orthopaedic SurgeryUniversity of Otago Christchurch2 Riccarton AvenueChristchurch8011New Zealand
| | - Khoon S. Lim
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) GroupDepartment of Orthopaedic SurgeryUniversity of Otago Christchurch2 Riccarton AvenueChristchurch8011New Zealand
| | - Tim B. F. Woodfield
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) GroupDepartment of Orthopaedic SurgeryUniversity of Otago Christchurch2 Riccarton AvenueChristchurch8011New Zealand
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Kim JK, Bae HC, Ro DH, Lee S, Lee MC, Han HS. Enhancement of Cartilage Regeneration of Synovial Stem Cells/Hydrogel by Using Transglutaminase-4. Tissue Eng Part A 2020; 27:761-770. [PMID: 33107390 DOI: 10.1089/ten.tea.2020.0271] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Although mesenchymal stem cells (MSCs) transplantation is reportedly a promising strategy for repairing damaged articular cartilage, MSCs-based cartilage tissue engineering has numerous limitations, including poor implanted cell adhesion, phenotypic alteration of cells, regulation of mechanical properties, and engraftment rates after implantation. This study aimed to investigate the efficacy of transplantation of synovium-derived mesenchymal stem cells (SDSCs) encapsulated in a hyaluronic acid/collagen/fibrinogen (HA/COL/FG) composite gel by supplementing recombinant human transglutaminase 4 (rhTG-4) in treating osteochondral defects. RhTG-4 treatment induced the expression of integrin β1 and dynamic actin fiber, enhancing SDSCs adhesion to fibronectin. Supplementation of rhTG-4 significantly induced the proliferation of SDSCs encapsulated in the HA/COL/FG composite gel and increased the hardness of the extracellular matrix. Furthermore, supplementation of rhTG-4 significantly upregulated aggrecan and type II collagen mRNA. Pretreatment with integrin β1 siRNA markedly suppressed TG4-induced actin remodeling, activation mitogen-activated protein kinase (MAPK), and eventually the chondrogenesis-related genes. Moreover, transplantation of SDSCs encapsulated in HA/COL/FG/rhTG-4 composite gel in vivo yielded reconstructed tissue resembling native hyaline cartilage. These data suggest that rhTG-4 enhances cartilage regeneration of the SDSCs encapsulated in hydrogel in rabbits. Impact statement In this study, we investigated the effects of recombinant human transglutaminase 4 on the ability of synovium-derived mesenchymal stem cells encapsulated in a hyaluronic acid/collagen/fibrinogen composite gel to repair osteochondral defects. We believe that our study makes a significant contribution to the literature because it explores a method of improving an existing modality to mediate tissue repair.
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Affiliation(s)
- Jong-Keun Kim
- Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyun Cheol Bae
- Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Du Hyun Ro
- Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sahnghoon Lee
- Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Myung Chul Lee
- Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyuk-Soo Han
- Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
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7
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Osseointegration and biosafety of graphene oxide wrapped porous CF/PEEK composites as implantable materials: The role of surface structure and chemistry. Dent Mater 2020; 36:1289-1302. [DOI: 10.1016/j.dental.2020.06.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 06/16/2020] [Accepted: 06/22/2020] [Indexed: 01/05/2023]
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8
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Teimourinejad A, Hashemibeni B, Salehi H, Mostafavi FS, Kazemi M, Bahramian H. Chondrogenic activity of two herbal products; pomegranate fruit extract and avocado/soybean unsaponifiable. Res Pharm Sci 2020; 15:358-366. [PMID: 33312214 PMCID: PMC7714020 DOI: 10.4103/1735-5362.293514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 06/16/2020] [Accepted: 08/22/2020] [Indexed: 01/22/2023] Open
Abstract
Background and purpose Articular cartilage defects aren't repaired by itself. Numerous studies have been conducted in the area of cartilage tissue engineering and some of them considered herbal products. An attempt was made in this study to compare the effects of pomegranate fruit extract (PFE), avocado/soybean unsaponifiable (ASU), and their equal proportional mixture on the chondrogenesis of human adipose-derived stem cells (hADSCs). Experimental approach PFE was prepared through the percolation method. ASU powder was dissolved in ethanol at 10 μg/mL concentration and was sterilized. The hADSCs first were isolated, expanded in monolayer culture and identified, and next seeded on fibrin scaffolds. The hADSCs/fibrin scaffolds were divided into 4 groups of control, ASU, PFE, and PFE+ ASU and subjected to in vitro induction for 2 weeks. The control group received chondrogenic medium, other groups received chondrogenic medium plus ASU, PFE, or PFE + ASU, respectively. The MTT assay was performed for cell viability evaluation, real-time polymerase chain reaction for expression of cartilage genes, and the toluidine blue, safranin-O, and immunohistochemistry for staining of the constructs. Findings / Results Cell viability, cartilage genes expression, matrix staining density, and collagen II protein levels in PFE samples were significantly higher than those of the other groups (P < 0.05). Histological assessments revealed more chondrogenic centers (P < 0.05) in the PFE group compared to the other groups. Conclusion and implications In this study, it was revealed that PFE can be considered as an induction factor for future chondrogenic studies.
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Affiliation(s)
- Ahmad Teimourinejad
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Batool Hashemibeni
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Hossein Salehi
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Fatemeh Sadat Mostafavi
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Mohammad Kazemi
- Genetic and Molecular Biology Department, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Hamid Bahramian
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
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Nwankwo EC, Labaran LA, Athas V, Olson S, Adams SB. Pathogenesis of Posttraumatic Osteoarthritis of the Ankle. Orthop Clin North Am 2019; 50:529-537. [PMID: 31466668 DOI: 10.1016/j.ocl.2019.05.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Ankle osteoarthritis affects a significant portion of the global adult population. Unlike other joints, arthritis of the ankle often develops as a response to traumatic injury (intra-articular fracture) of the ankle joints. The full mechanism leading to posttraumatic osteoarthritis of the ankle (PTOAA) is poorly understood. These deficits in knowledge pose challenges in the management of the disease. Adequate surgical reduction of fractured ankle joints remains the gold standard in prevention. The purpose of this review is to thoroughly delineate the known pathogenesis of PTOAA, and provide critical updates on this pathology and new avenues to provide therapeutic management of the disease.
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Affiliation(s)
- Eugene C Nwankwo
- Department of Orthopedic Surgery, Duke University Medical Center, 4709 Creekstone Drive, Durham, NC 27703, USA; Texas Tech University School of Medicine, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, USA
| | - Lawal A Labaran
- University of Illinois College of Medicine, 1200 Harrison Street, Chicago, IL 60607, USA
| | - Vincent Athas
- Texas Tech University School of Medicine, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, USA
| | - Steve Olson
- Department of Orthopedic Surgery, Duke University Medical Center, 4709 Creekstone Drive, Durham, NC 27703, USA
| | - Samuel B Adams
- Department of Orthopedic Surgery, Duke University Medical Center, 4709 Creekstone Drive, Durham, NC 27703, USA.
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Mechanical stimulation promotes the proliferation and the cartilage phenotype of mesenchymal stem cells and chondrocytes co-cultured in vitro. Biomed Pharmacother 2019; 117:109146. [PMID: 31387186 DOI: 10.1016/j.biopha.2019.109146] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 06/17/2019] [Accepted: 06/17/2019] [Indexed: 01/29/2023] Open
Abstract
Mesenchymal stem cells and chondrocytes are an important source of the cells for cartilage tissue engineering. Therefore, the culture and expansion methods of these cells need to be improved to overcome the aging of chondrocytes and induced chondrogenic differentiation of mesenchymal stem cells. The aim of this study was to expand the cells for cartilage tissue engineering by combining the advantages of growing cells in co-culture and under a mechanically-stimulated environment. Rabbit chondrocytes and co-cultured cells (bone mesenchymal stem cells and chondrocytes) were subjected to cyclic sinusoidal dynamic tensile mechanical stimulationusing the FX-4000 tension system. Chondrocyte proliferation was assayed by flow cytometry and CFSE labeling. The cell cartilage phenotype was determined by detecting GAG, collagen II and TGF-β1 protein expression by ELISA and the Col2α1, TGF-β1 and Sox9 gene expression by RT-PCR. The results show that the co-culture improved both the proliferation ability of chondrocytes and the cartilage phenotype of co-cultured cells. A proper cyclic sinusoidal dynamic tensile mechanical stimulation improved the proliferation ability and cartilage phenotype of chondrocytes and co-cultured cells. These results suggest that the co-culture of mesenchymal stem cells with chondrocytes and proper mechanical stimulation may be an appropriate way to rapidly expand the cells that have an improved cartilage phenotype for cartilage tissue engineering.
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11
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A review of emerging bone tissue engineering via PEG conjugated biodegradable amphiphilic copolymers. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 97:1021-1035. [PMID: 30678893 DOI: 10.1016/j.msec.2019.01.057] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 12/26/2018] [Accepted: 01/12/2019] [Indexed: 01/19/2023]
Abstract
Defects in bones can be caused by a plethora of reasons, such as trauma or illness, and in many cases, it poses challenges to the current treatment approaches for bone repair. With increasing demand of bone bioengineering in tissue transplant, there is a need to source for sustainable solutions to induce bone regeneration. Polymeric biomaterials have been identified as a promising approach due to its excellent biocompatibility and controllable biodegradability. Specifically, poly(ethylene glycol) (PEG) is one of the most commonly investigated polymer for use in bio-related application due to its bioinertness and versatility. Furthermore, the hydrophilic nature enables it to be incorporated with hydrophobic but biodegradable polymers like, polylactide (PLA) and polycaprolactone (PCL), to create an amphiphilic polymer. This article reviews the recent synthetic strategies available for the construction of PEG conjugated polymeric system, analysis of PEG influence on the material properties, and provides an overview of its application in bone engineering.
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12
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Zhou H, Zhu J, Liu M, Wu Q, Dong N. Role of the protease corin in chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells. J Tissue Eng Regen Med 2017; 12:973-982. [PMID: 28714548 DOI: 10.1002/term.2514] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 05/30/2017] [Accepted: 07/11/2017] [Indexed: 01/03/2023]
Abstract
Mesenchymal stem cells (MSCs) have the potency to differentiate into chondrocytes, osteocytes and adipocytes. Corin is a cardiac protease that activates the natriuretic peptides, thereby regulating blood volume and pressure. In addition to the heart, corin gene upregulation was reported in bone marrow- and adipose tissue-derived MSCs that underwent osteogenic differentiation. To date, the biological significance of corin expression in MSC differentiation remains unknown. In this study we isolated and cultured human bone marrow-derived MSCs that were capable of undergoing chondrogenic, osteogenic and adipogenic lineage differentiation. By reverse transcription polymerase chain reaction (RT-PCR) and immunostaining, we found that corin expression was upregulated when these MSCs underwent chondrogenic, osteogenic and adipogenic differentiation. The upregulation of corin expression was most significant in the cells undergoing chondrogenic lineage differentiation. Silencing corin gene expression by small hairpin RNA in the MSCs inhibited chondrogenic, but not osteogenic and adipogenic, differentiation. These results suggest a novel function of corin in MSC differentiation and chondrocyte development.
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Affiliation(s)
- Haibin Zhou
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
- Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jinsong Zhu
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
- Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Meng Liu
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
| | - Qingyu Wu
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Ningzheng Dong
- Cyrus Tang Hematology Center, Soochow University, Suzhou, China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
- Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
- Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China
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13
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Narayanan G, Bhattacharjee M, Nair LS, Laurencin CT. Musculoskeletal Tissue Regeneration: the Role of the Stem Cells. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2017. [DOI: 10.1007/s40883-017-0036-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Mirzaei H, Sahebkar A, Sichani LS, Moridikia A, Nazari S, Sadri Nahand J, Salehi H, Stenvang J, Masoudifar A, Mirzaei HR, Jaafari MR. Therapeutic application of multipotent stem cells. J Cell Physiol 2017; 233:2815-2823. [PMID: 28475219 DOI: 10.1002/jcp.25990] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 05/04/2017] [Indexed: 12/19/2022]
Abstract
Cell therapy is an emerging fields in the treatment of various diseases such as cardiovascular, pulmonary, hepatic, and neoplastic diseases. Stem cells are an integral tool for cell therapy. Multipotent stem cells are an important class of stem cells which have the ability to self-renew through dividing and developing into multiple specific cell types in a specific tissue or organ. These cells are capable to activate or inhibit a sequence of cellular and molecular pathways leading to anti-inflammatory and anti-apoptotic effects which might contribute to the treatment of various diseases. It has been showed that multipotent stem cells exert their therapeutic effects via inhibition/activation of a sequence of cellular and molecular pathways. Although the advantages of multipotent stem cells are numerous, further investigation is still necessary to clarify the biology and safety of these cells before they could be considered as a potential treatment for different types of diseases. This review summarizes different features of multipotent stem cells including isolation, differentiation, and therapeutic applications.
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Affiliation(s)
- Hamed Mirzaei
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Laleh Shiri Sichani
- Faculty of Basic Science, Department of Genetic, University of Shahrekord, Shahrekord, Iran
| | - Abdullah Moridikia
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Sara Nazari
- Faculty of Science, Department of Biology, North Tehran Branch of Islamic Azad University, Tehran, Iran
| | - Javid Sadri Nahand
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Salehi
- Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jan Stenvang
- Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Section for Molecular Disease Biology, University of Copenhagen, Copenhagen, Denmark
| | - Aria Masoudifar
- Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECRR, Isfahan, Iran
| | - Hamid R Mirzaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud R Jaafari
- Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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16
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Meng Q, Hu X, Huang H, Liu Z, Yuan L, Shao Z, Jiang Y, Zhang J, Fu X, Duan X, Ao Y. Microfracture combined with functional pig peritoneum-derived acellular matrix for cartilage repair in rabbit models. Acta Biomater 2017; 53:279-292. [PMID: 28115294 DOI: 10.1016/j.actbio.2017.01.055] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 01/14/2017] [Accepted: 01/18/2017] [Indexed: 12/30/2022]
Abstract
Due to avascular and hypocellular nature of cartilage, repair of articular cartilage defects within synovial joints still poses a significant clinical challenge. To promote neocartilage properties, we established a functional scaffold named APM-E7 by conjugating a bone marrow-derived mesenchymal stem cell (BM-MSC) affinity peptide (E7) onto the acellular peritoneum matrix (APM). During in vitro culture, the APM-E7 scaffold can support better proliferation as well as better differentiation into chondrocytes of BM-MSCs. After implanting into cartilage defects in rabbits for 24weeks, compared with microfracture and APM groups, the APM-E7 scaffolds exhibited superior quality of neocartilage without transplant rejection, according to general observations, histological assessment, synovial fluid analysis, magnetic resonance imaging (MRI) and nanomechanical properties. This APM-E7 scaffold provided a scaffold for cell attachment, which was crucial for cartilage regeneration. Overall, the APM-E7 is a promising biomaterial with low immunogenicity for one-step cartilage repair by promoting autologous connective tissue progenitor (CTP) attachment. STATEMENT OF SIGNIFICANCE We report the one-step transplantation of functional acellular peritoneum matrix (APM-E7) with specific mesenchymal stem cell recruitment to repair rabbit cartilage injury. The experimental results illustrated that the APM-E7 scaffold was successfully fabricated, which could specifically recruit MSCs and fill the cartilage defects in the femoral trochlear of rabbits at 24weeks post-surgery. The repaired tissue was hyaline cartilage, which exhibited ideal mechanical stability. The APM-E7 biomaterial could provide scaffold for MSCs and improve cell homing, which are two key factors required for cartilage tissue engineering, thereby providing new insights into cartilage tissue engineering.
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Affiliation(s)
- Qingyang Meng
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Xiaoqing Hu
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Hongjie Huang
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Zhenlong Liu
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Lan Yuan
- Medical and Healthy Analysis Centre, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, People's Republic of China
| | - Zhenxing Shao
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Yanfang Jiang
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Jiying Zhang
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Xin Fu
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Xiaoning Duan
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China
| | - Yingfang Ao
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, People's Republic of China.
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17
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Shi Q, Qian Z, Liu D, Sun J, Xu J, Guo X. Maintaining the Phenotype Stability of Chondrocytes Derived from MSCs by C-Type Natriuretic Peptide. Front Physiol 2017; 8:143. [PMID: 28337152 PMCID: PMC5340764 DOI: 10.3389/fphys.2017.00143] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 02/23/2017] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) play a critical role in cartilage tissue engineering. However, MSCs-derived chondrocytes or cartilage tissues are not stable and easily lose the cellular and cartilage phenotype during long-term culture in vitro or implantation in vivo. As a result, chondrocytes phenotypic instability can contribute to accelerated ossification. Thus, it is a big challenge to maintain their correct phenotype for engineering hyaline cartilage. As one member of the natriuretic peptide family, C-type natriuretic peptide (CNP) is found to correlate with the development of the cartilage, affect the chondrocytes proliferation and differentiation. Besides, based on its biological effects on protection of extracellular matrix of cartilage and inhibition of mineralization, we hypothesize that CNP may contribute to the stability of chondrocyte phenotype of MSCs-derived chondrocytes.
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Affiliation(s)
- Quan Shi
- Department of Stomatology, Chinese People's Liberation Army General HospitalBeijing, China; Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical SciencesBeijing, China
| | - Zhiyong Qian
- Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical SciencesBeijing, China; School of Biological Science and Medical Engineering, Beihang UniversityBeijing, China
| | - Donghua Liu
- Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences Beijing, China
| | - Jie Sun
- Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical SciencesBeijing, China; Stomatology Center, General Hospital of Armed Police ForcesBeijing, China
| | - Juan Xu
- Department of Stomatology, Chinese People's Liberation Army General Hospital Beijing, China
| | - Ximin Guo
- Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences Beijing, China
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18
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Ng J, Wei Y, Zhou B, Burapachaisri A, Guo E, Vunjak-Novakovic G. Extracellular matrix components and culture regimen selectively regulate cartilage formation by self-assembling human mesenchymal stem cells in vitro and in vivo. Stem Cell Res Ther 2016; 7:183. [PMID: 27931263 PMCID: PMC5146812 DOI: 10.1186/s13287-016-0447-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 11/17/2016] [Accepted: 11/22/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cartilage formation from self-assembling mesenchymal stem cells (MSCs) in vitro recapitulate important cellular events during mesenchymal condensation that precedes native cartilage development. The goal of this study was to investigate the effects of cartilaginous extracellular matrix (ECM) components and culture regimen on cartilage formation by self-assembling human MSCs in vitro and in vivo. METHODS Human bone marrow-derived MSCs (hMSCs) were seeded and compacted in 6.5-mm-diameter transwell inserts with coated (type I, type II collagen) or uncoated (vehicle) membranes, at different densities (0.5 × 106, 1.0 × 106, 1.5 × 106 per insert). Pellets were formed by aggregating hMSCs (0.25 × 106) in round-bottomed wells. All tissues were cultured for up to 6 weeks for in vitro analyses. Discs (cultured for 6, 8 or 10 weeks) and pellets (cultured for 10 weeks) were implanted subcutaneously in immunocompromised mice to evaluate the cartilage stability in vivo. RESULTS Type I and type II collagen coatings enabled cartilage disc formation from self-assembling hMSCs. Without ECM coating, hMSCs formed dome-shaped tissues resembling the pellets. Type I collagen, expressed in the prechondrogenic mesenchyme, improved early chondrogenesis versus type II collagen. High seeding density improved cartilage tissue properties but resulted in a lower yield of disc formation. Discs and pellets exhibited compositional and organizational differences in vitro and in vivo. Prolonged chondrogenic induction of the discs in vitro expedited endochondral ossification in vivo. CONCLUSIONS The outcomes of cartilage tissues formed from self-assembling MSCs in vitro and in vivo can be modulated by the control of culture parameters. These insights could motivate new directions for engineering cartilage and bone via a cartilage template from self-assembling MSCs.
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Affiliation(s)
- Johnathan Ng
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY, 10032, USA
| | - Yiyong Wei
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY, 10032, USA
| | - Bin Zhou
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY, 10032, USA.,Columbia University, 345 Engineering Terrace, 1210 Amsterdam Avenue, New York, NY, 10027, USA
| | - Aonnicha Burapachaisri
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY, 10032, USA
| | - Edward Guo
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY, 10032, USA.,Columbia University, 345 Engineering Terrace, 1210 Amsterdam Avenue, New York, NY, 10027, USA
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, 622 West 168th Street, VC12-234, New York, NY, 10032, USA. .,Department of Medicine, Columbia University, New York, NY, USA.
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19
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Qi Y, Chen G, Feng G. Osteoarthritis prevention and meniscus regeneration induced by transplantation of mesenchymal stem cell sheet in a rat meniscal defect model. Exp Ther Med 2016; 12:95-100. [PMID: 27347022 PMCID: PMC4906666 DOI: 10.3892/etm.2016.3325] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 03/10/2016] [Indexed: 01/05/2023] Open
Abstract
Transplantation of mesenchymal stem cells (MSCs) is a potential therapy for meniscus regeneration. However, when using single cell suspension injection, there is frequently a significant loss of cells, with only a small percentage of cells remaining at the target site. This issue may be solved with the use of MSC sheets. In the present study, we investigated whether the use of MSC sheets were able to regenerate the meniscus effectively in a rat meniscectomized model. The anterior half of the medial meniscus in 10 rats was excised and an MSC sheet was transplanted in the MSC sheet treatment group, while untreated rats served as the control. After 4 and 8 weeks, the knee joints were examined by gross and histological observation. Histological observation revealed that the anterior portion of meniscus was similar to the native tissue, showing typical fibrochondrocytes surrounded by richer extracellular matrix in the MSC sheet group. In addition, predominant collagen-rich matrix bridging the interface was observed and the neo-meniscus integrated well with its host meniscus. Furthermore, degenerative changes of tibial plateau and femoral condyle occurred in the two groups. MSC sheet transplantation alleviated the degenerative changes efficiently. In conclusion, transplantation of MSC sheets may efficiently promote meniscus regeneration, as well as inhibit the progression of osteoarthritis in knee joints.
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Affiliation(s)
- Yiying Qi
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Guangnan Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Gang Feng
- Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
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20
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Du M, Chen B, Meng Q, Liu S, Zheng X, Zhang C, Wang H, Li H, Wang N, Dai J. 3D bioprinting of BMSC-laden methacrylamide gelatin scaffolds with CBD-BMP2-collagen microfibers. Biofabrication 2015; 7:044104. [PMID: 26684899 DOI: 10.1088/1758-5090/7/4/044104] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Three-dimensional (3D) bioprinting combines biomaterials, cells and functional components into complex living tissues. Herein, we assembled function-control modules into cell-laden scaffolds using 3D bioprinting. A customized 3D printer was able to tune the microstructure of printed bone mesenchymal stem cell (BMSC)-laden methacrylamide gelatin scaffolds at the micrometer scale. For example, the pore size was adjusted to 282 ± 32 μm and 363 ± 60 μm. To match the requirements of the printing nozzle, collagen microfibers with a length of 22 ± 13 μm were prepared with a high-speed crusher. Collagen microfibers bound bone morphogenetic protein 2 (BMP2) with a collagen binding domain (CBD) as differentiation-control module, from which BMP2 was able to be controllably released. The differentiation behaviors of BMSCs in the printed scaffolds were compared in three microenvironments: samples without CBD-BMP2-collagen microfibers in the growth medium, samples without microfibers in the osteogenic medium and samples with microfibers in the growth medium. The results indicated that BMSCs showed high cell viability (>90%) during printing; CBD-BMP2-collagen microfibers induced BMSC differentiation into osteocytes within 14 days more efficiently than the osteogenic medium. Our studies suggest that these function-control modules are attractive biomaterials and have potential applications in 3D bioprinting.
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Affiliation(s)
- Mingchun Du
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, People's Republic of China. ZonHon Biopharma Institute, Inc., Changzhou 213022, People's Republic of China
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21
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Meng Q, Man Z, Dai L, Huang H, Zhang X, Hu X, Shao Z, Zhu J, Zhang J, Fu X, Duan X, Ao Y. A composite scaffold of MSC affinity peptide-modified demineralized bone matrix particles and chitosan hydrogel for cartilage regeneration. Sci Rep 2015; 5:17802. [PMID: 26632447 PMCID: PMC4668577 DOI: 10.1038/srep17802] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 11/05/2015] [Indexed: 12/13/2022] Open
Abstract
Articular cartilage injury is still a significant challenge because of the poor intrinsic healing potential of cartilage. Stem cell-based tissue engineering is a promising technique for cartilage repair. As cartilage defects are usually irregular in clinical settings, scaffolds with moldability that can fill any shape of cartilage defects and closely integrate with the host cartilage are desirable. In this study, we constructed a composite scaffold combining mesenchymal stem cells (MSCs) E7 affinity peptide-modified demineralized bone matrix (DBM) particles and chitosan (CS) hydrogel for cartilage engineering. This solid-supported composite scaffold exhibited appropriate porosity, which provided a 3D microenvironment that supports cell adhesion and proliferation. Cell proliferation and DNA content analysis indicated that the DBM-E7/CS scaffold promoted better rat bone marrow-derived MSCs (BMMSCs) survival than the CS or DBM/CS groups. Meanwhile, the DBM-E7/CS scaffold increased matrix production and improved chondrogenic differentiation ability of BMMSCs in vitro. Furthermore, after implantation in vivo for four weeks, compared to those in control groups, the regenerated issue in the DBM-E7/CS group exhibited translucent and superior cartilage-like structures, as indicated by gross observation, histological examination, and assessment of matrix staining. Overall, the functional composite scaffold of DBM-E7/CS is a promising option for repairing irregularly shaped cartilage defects.
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Affiliation(s)
- Qingyang Meng
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Zhentao Man
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Linghui Dai
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Hongjie Huang
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Xin Zhang
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Xiaoqing Hu
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Zhenxing Shao
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Jingxian Zhu
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Jiying Zhang
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Xin Fu
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Xiaoning Duan
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Yingfang Ao
- Institute of Sports Medicine, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
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Park YB, Song M, Lee CH, Kim JA, Ha CW. Cartilage repair by human umbilical cord blood-derived mesenchymal stem cells with different hydrogels in a rat model. J Orthop Res 2015; 33:1580-6. [PMID: 26019012 DOI: 10.1002/jor.22950] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 05/25/2015] [Indexed: 02/04/2023]
Abstract
This study was carried out to assess the feasibility of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in articular cartilage repair and to further determine a suitable delivering hydrogel in a rat model. Critical sized full thickness cartilage defects were created. The hUCB-MSCs and three different hydrogel composites (hydrogel A; 4% hyaluronic acid/30% pluronic (1:1, v/v), hydrogel B; 4% hyaluronic acid, and hydrogel C; 4% hyaluronic acid/30% pluronic/chitosan (1:1:2, v/v)) were implanted into the experimental knee (right knee) and hydrogels without hUCB-MSCs were implanted into the control knee (left knee). Defects were evaluated after 8 weeks. The hUCB-MSCs with hydrogels composites resulted in a better repair as seen by gross and histological evaluation compared with hydrogels without hUCB-MSCs. Among the three different hydrogels, the 4% hyaluronic acid hydrogel composite (hydrogel B) showed the best result in cartilage repair as seen by the histological evaluation compared with the other hydrogel composites (hydrogel A and C). The results of this study suggest that hUCB-MSCs may be a promising cell source in combination with 4% hyaluronic acid hydrogels in the in vivo repair of cartilage defects.
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Affiliation(s)
- Yong-Beom Park
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Minjung Song
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Choong-Hee Lee
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jin-A Kim
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Chul-Won Ha
- Department of Orthopedic Surgery, Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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23
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Pereira RC, Costa-Pinto AR, Frias AM, Neves NM, Azevedo HS, Reis RL. In vitro chondrogenic commitment of human Wharton's jelly stem cells by co-culture with human articular chondrocytes. J Tissue Eng Regen Med 2015; 11:1876-1887. [PMID: 27035732 DOI: 10.1002/term.2085] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 07/11/2015] [Indexed: 11/09/2022]
Abstract
Wharton's jelly stem cells (WJSCs) are a potential source of transplantable stem cells in cartilage-regenerative strategies, due to their highly proliferative and multilineage differentiation capacity. We hypothesized that a non-direct co-culture system with human articular chondrocytes (hACs) could enhance the potential chondrogenic phenotype of hWJSCs during the expansion phase compared to those expanded in monoculture conditions. Primary hWJSCs were cultured in the bottom of a multiwell plate separated by a porous transwell membrane insert seeded with hACs. No statistically significant differences in hWJSCs duplication number were observed under either of the culture conditions during the expansion phase. hWJSCs under co-culture conditions show upregulations of collagen type I and II, COMP, TGFβ1 and aggrecan, as well as of the main cartilage transcription factor, SOX9, when compared to those cultured in the absence of chondrocytes. Chondrogenic differentiation of hWJSCs, previously expanded in co-culture and monoculture conditions, was evaluated for each cellular passage using the micromass culture model. Cells expanded in co-culture showed higher accumulation of glycosaminoglycans (GAGs) compared to cells in monoculture, and immunohistochemistry for localization of collagen type I revealed a strong detection signal when hWJSCs were expanded under monoculture conditions. In contrast, type II collagen was detected when cells were expanded under co-culture conditions, where numerous round-shaped cell clusters were observed. Using a micromass differentiation model, hWJSCs, previously exposed to soluble factors secreted by hACs, were able to express higher levels of chondrogenic genes with deposition of cartilage extracellular matrix components, suggesting their use as an alternative cell source for treating degenerated cartilage. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- R C Pereira
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Guimarães, Portugal.,ICVS/3Bs PT Government-associated Laboratory, Braga/Guimarães, Portugal
| | - A R Costa-Pinto
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Guimarães, Portugal.,ICVS/3Bs PT Government-associated Laboratory, Braga/Guimarães, Portugal
| | - A M Frias
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Guimarães, Portugal.,ICVS/3Bs PT Government-associated Laboratory, Braga/Guimarães, Portugal
| | - N M Neves
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Guimarães, Portugal.,ICVS/3Bs PT Government-associated Laboratory, Braga/Guimarães, Portugal
| | - H S Azevedo
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Guimarães, Portugal.,ICVS/3Bs PT Government-associated Laboratory, Braga/Guimarães, Portugal
| | - R L Reis
- 3Bs Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Guimarães, Portugal.,ICVS/3Bs PT Government-associated Laboratory, Braga/Guimarães, Portugal
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Guo P, Shi ZL, Liu A, Lin T, Bi F, Shi M, Yan SG. Effects of cartilage oligomeric matrix protein on bone morphogenetic protein-2-induced differentiation of mesenchymal stem cells. Orthop Surg 2015; 6:280-7. [PMID: 25430711 DOI: 10.1111/os.12135] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 05/27/2014] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE To investigate the effect of overexpression of cartilage oligomeric matrix protein (COMP) on bone morphogenetic protein-2 (BMP-2) induced osteogenic and chondrogenic differentiation of mesenchymal stem cells (MSCs). In this study, we used liposomes to transfect MSCs with plasmid encoding COMP and then induced the transfected MSCs to differentiate in osteogenic and chondrogenic differentiation media containing BMP-2. METHODS MSCs transfected with plasmid DNA encoding recombinant human COMP were induced to differentiate into osteocytes and chondrocytes by BMP-2. Real-time polymerase chain reaction (PCR) assays of osteogenesis-related markers (collagen type I alpha 1, runt-related transcription factor 2, osteopontin, bone gla protein) and chondrogenesis-related markers (collagen type II alpha 1, sry-related high-mobility group box 9, Aggrecan) was performed to evaluate the process of cell differentiation. Cell differentiation was evaluated by alkaline phosphatase (ALP) and Alizarin red S stains for osteogenic differentiation and alcian blue staining for chondrogenic differentiation. RESULTS Real-time PCR assay showed significantly greater COMP expression by MSCs when COMP gene had been transfected into the cells (P < 0.01). Overexpression of COMP down-regulated expression of osteogenesis-related markers and up-regulated expression of chondrogenesis-related markers. ALP staining and Alizarin red S staining were weakened, whereas alcian blue staining was enhanced. CONCLUSION Overexpression of COMP inhibits BMP-2-induced osteogenic differentiation and promotes BMP-2-induced chondrogenic differentiation. These findings may provide new insights for cartilage tissue engineering. The experiments in the present study were all in vitro, which has potential limitations. Further in vivo studies to investigate the effects of COMP in animal models are necessary, which will be the next step in our research.
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Affiliation(s)
- Peng Guo
- Department of Orthopaedic Surgery, The Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou, China
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Ghasemi-Mobarakeh L, Prabhakaran MP, Tian L, Shamirzaei-Jeshvaghani E, Dehghani L, Ramakrishna S. Structural properties of scaffolds: Crucial parameters towards stem cells differentiation. World J Stem Cells 2015; 7:728-744. [PMID: 26029344 PMCID: PMC4444613 DOI: 10.4252/wjsc.v7.i4.728] [Citation(s) in RCA: 144] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 12/18/2014] [Accepted: 03/05/2015] [Indexed: 02/06/2023] Open
Abstract
Tissue engineering is a multidisciplinary field that applies the principles of engineering and life-sciences for regeneration of damaged tissues. Stem cells have attracted much interest in tissue engineering as a cell source due to their ability to proliferate in an undifferentiated state for prolonged time and capability of differentiating to different cell types after induction. Scaffolds play an important role in tissue engineering as a substrate that can mimic the native extracellular matrix and the properties of scaffolds have been shown to affect the cell behavior such as the cell attachment, proliferation and differentiation. Here, we focus on the recent reports that investigated the various aspects of scaffolds including the materials used for scaffold fabrication, surface modification of scaffolds, topography and mechanical properties of scaffolds towards stem cells differentiation effect. We will present a more detailed overview on the effect of mechanical properties of scaffolds on stem cells fate.
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Yu Y, Brouillette MJ, Seol D, Zheng H, Buckwalter JA, Martin JA. Use of recombinant human stromal cell-derived factor 1α-loaded fibrin/hyaluronic acid hydrogel networks to achieve functional repair of full-thickness bovine articular cartilage via homing of chondrogenic progenitor cells. Arthritis Rheumatol 2015; 67:1274-85. [PMID: 25623441 PMCID: PMC11752793 DOI: 10.1002/art.39049] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 01/20/2015] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Articular cartilage damage after joint trauma seldom heals and often leads to osteoarthritis. We previously identified a migratory chondrogenic progenitor cell (CPC) population that responds chemotactically to cell death and rapidly repopulates the injured cartilage matrix, which suggests a potential approach for articular cartilage repair. This study was undertaken to determine whether recombinant human stromal cell-derived factor 1α (rhSDF-1α), a potent CPC chemoattractant, would improve the quality of cartilage regeneration, hypothesizing that increased recruitment of CPCs by rhSDF-1α would promote the formation of cartilage matrix upon chondrogenic induction. METHODS Full-thickness bovine chondral defects were filled with hydrogel, composed of fibrin and hyaluronic acid and containing rhSDF-1α. Cell migration was monitored, followed by chondrogenic induction. Regenerated tissue was evaluated by histology, immunohistochemistry, and scanning electron microscopy. Push-out tests and unconfined compression tests were performed to assess the strength of tissue integration and the mechanical properties of the regenerated cartilage. RESULTS Use of rhSDF-1α dramatically improved CPC recruitment to the chondral defects at 12 days. After 6 weeks under chondrogenic conditions, cell morphology, proteoglycan density, and the ultrastructure of the repair tissue were all similar to that found in native cartilage. Compared with empty controls, neocartilage generated in rhSDF-1α-containing defects showed significantly greater interfacial strength, and acquired mechanical properties comparable to those of native cartilage. CONCLUSION This study showed that stimulating local CPC recruitment prior to treatment with chondrogenic factors significantly improves the biochemical and mechanical properties of the cartilage tissue formed in chondral defects. This simple approach may be implemented in vivo as a one-step procedure by staging the release of chemokine and chondrogenic factors from within the hydrogel, which can be achieved using smart drug-delivery systems.
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Affiliation(s)
- Yin Yu
- Department of Orthopaedics and Rehabilitation, The University of Iowa, Iowa City, IA
- Department of Biomedical Engineering, The University of Iowa, Iowa City, IA
| | - Marc J. Brouillette
- Department of Orthopaedics and Rehabilitation, The University of Iowa, Iowa City, IA
- Department of Biomedical Engineering, The University of Iowa, Iowa City, IA
| | - Dongrim Seol
- Department of Orthopaedics and Rehabilitation, The University of Iowa, Iowa City, IA
| | - Hongjun Zheng
- Department of Orthopaedics and Rehabilitation, The University of Iowa, Iowa City, IA
| | - Joseph A. Buckwalter
- Department of Orthopaedics and Rehabilitation, The University of Iowa, Iowa City, IA
- Veterans Affairs Medical Center, Iowa City, IA
| | - James A. Martin
- Department of Orthopaedics and Rehabilitation, The University of Iowa, Iowa City, IA
- Department of Biomedical Engineering, The University of Iowa, Iowa City, IA
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Doublecortin may play a role in defining chondrocyte phenotype. Int J Mol Sci 2014; 15:6941-60. [PMID: 24758934 PMCID: PMC4013671 DOI: 10.3390/ijms15046941] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 04/03/2014] [Accepted: 04/14/2014] [Indexed: 01/01/2023] Open
Abstract
Embryonic development of articular cartilage has not been well understood and the role of doublecortin (DCX) in determination of chondrocyte phenotype is unknown. Here, we use a DCX promoter-driven eGFP reporter mouse model to study the dynamic gene expression profiles in mouse embryonic handplates at E12.5 to E13.5 when the condensed mesenchymal cells differentiate into either endochondral chondrocytes or joint interzone cells. Illumina microarray analysis identified a variety of genes that were expressed differentially in the different regions of mouse handplate. The unique expression patterns of many genes were revealed. Cytl1 and 3110032G18RIK were highly expressed in the proximal region of E12.5 handplate and the carpal region of E13.5 handplate, whereas Olfr538, Kctd15, and Cited1 were highly expressed in the distal region of E12.5 and the metacarpal region of E13.5 handplates. There was an increasing gradient of Hrc expression in the proximal to distal direction in E13.5 handplate. Furthermore, when human DCX protein was expressed in human adipose stem cells, collagen II was decreased while aggrecan, matrilin 2, and GDF5 were increased during the 14-day pellet culture. These findings suggest that DCX may play a role in defining chondrocyte phenotype.
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Singh S, Deka D, Mulinti R, Sood NK, Agrawal RK, Verma R. Isolation, Culture, In-Vitro Differentiation and Characterization of Canine Adult Mesenchymal Stem Cells. ACTA ACUST UNITED AC 2014. [DOI: 10.1007/s40011-014-0309-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Regulation of human mesenchymal stem cells differentiation into chondrocytes in extracellular matrix-based hydrogel scaffolds. Colloids Surf B Biointerfaces 2014; 114:316-23. [DOI: 10.1016/j.colsurfb.2013.10.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 09/29/2013] [Accepted: 10/02/2013] [Indexed: 11/18/2022]
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Boyette LB, Tuan RS. Adult Stem Cells and Diseases of Aging. J Clin Med 2014; 3:88-134. [PMID: 24757526 PMCID: PMC3992297 DOI: 10.3390/jcm3010088] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 12/15/2013] [Accepted: 12/17/2013] [Indexed: 02/06/2023] Open
Abstract
Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other causes contribute to tissue degeneration with age. Both progeria, an extreme example of early-onset aging, and heritable longevity have provided avenues to study regulation of the aging program and its impact on adult stem cell compartments. In this review, we discuss recent findings concerning the effects of aging on stem cells, contributions of stem cells to age-related pathologies, examples of signaling pathways at work in these processes, and lessons about cellular aging gleaned from the development and refinement of cellular reprogramming technologies. We highlight emerging therapeutic approaches to manipulation of key signaling pathways corrupting or exhausting adult stem cells, as well as other approaches targeted at maintaining robust stem cell pools to extend not only lifespan but healthspan.
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Affiliation(s)
- Lisa B Boyette
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA; ; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA; ; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA ; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Ko CY, Ku KL, Yang SR, Lin TY, Peng S, Peng YS, Cheng MH, Chu IM. In vitro and in vivo co-culture of chondrocytes and bone marrow stem cells in photocrosslinked PCL-PEG-PCL hydrogels enhances cartilage formation. J Tissue Eng Regen Med 2013; 10:E485-E496. [PMID: 24668937 DOI: 10.1002/term.1846] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Revised: 08/29/2013] [Accepted: 09/30/2013] [Indexed: 12/25/2022]
Abstract
Chondrocytes (CH) and bone marrow stem cells (BMSCs) are sources that can be used in cartilage tissue engineering. Co-culture of CHs and BMSCs is a promising strategy for promoting chondrogenic differentiation. In this study, articular CHs and BMSCs were encapsulated in PCL-PEG-PCL photocrosslinked hydrogels for 4 weeks. Various ratios of CH:BMSC co-cultures were investigated to identify the optimal ratio for cartilage formation. The results thus obtained revealed that co-culturing CHs and BMSCs in hydrogels provides an appropriate in vitro microenvironment for chondrogenic differentiation and cartilage matrix production. Co-culture with a 1:4 CH:BMSC ratio significantly increased the synthesis of GAGs and collagen. In vivo cartilage regeneration was evaluated using a co-culture system in rabbit models. The co-culture system exhibited a hyaline chondrocyte phenotype with excellent regeneration, resembling the morphology of native cartilage. This finding suggests that the co-culture of these two cell types promotes cartilage regeneration and that the system, including the hydrogel scaffold, has potential in cartilage tissue engineering. Copyright © 2013 John Wiley & Sons, Ltd.
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Affiliation(s)
- Chao-Yin Ko
- Department of Chemical Engineering, National Tsing Hua University, Taiwan, Republic of China
| | - Kuan-Lin Ku
- Department of Chemical Engineering, National Tsing Hua University, Taiwan, Republic of China
| | - Shu-Rui Yang
- Department of Chemical Engineering, National Tsing Hua University, Taiwan, Republic of China.,Division of Reconstructive Microsurgery, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taiwan, Republic of China
| | - Tsai-Yu Lin
- Department of Chemical Engineering, National Tsing Hua University, Taiwan, Republic of China.,Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Taiwan, Republic of China
| | - Sydney Peng
- Department of Chemical Engineering, National Tsing Hua University, Taiwan, Republic of China
| | - Yu-Shiang Peng
- Department of Chemical Engineering, National Tsing Hua University, Taiwan, Republic of China
| | - Ming-Huei Cheng
- Division of Reconstructive Microsurgery, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taiwan, Republic of China
| | - I-Ming Chu
- Department of Chemical Engineering, National Tsing Hua University, Taiwan, Republic of China.
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Roux C, Pisani DF, Yahia HB, Djedaini M, Beranger GE, Chambard JC, Ambrosetti D, Michiels JF, Breuil V, Ailhaud G, Euller-Ziegler L, Amri EZ. Chondrogenic potential of stem cells derived from adipose tissue: a powerful pharmacological tool. Biochem Biophys Res Commun 2013; 440:786-91. [PMID: 24134848 DOI: 10.1016/j.bbrc.2013.10.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 10/04/2013] [Indexed: 12/22/2022]
Abstract
Chondrogenesis has been widely investigated in vitro using bone marrow-derived mesenchymal stromal cells (BM-MSCs) or primary chondrocytes. However, their use raises some issues partially circumvented by the availability of Adipose tissue-derived MSCs. Herein; we characterized the chondrogenic potential of human Multipotent Adipose-Derived Stem (hMADS) cells, and their potential use as pharmacological tool. hMADS cells are able to synthesize matrix proteins including COMP, Aggrecan and type II Collagen. Furthermore, hMADS cells express BMP receptors in a similar manner to BM-MSC, and BMP6 treatment of differentiated cells prevents expression of the hypertrophic marker type X Collagen. We tested whether IL-1β and nicotine could impact chondrocyte differentiation. As expected, IL-1β induced ADAMTS-4 gene expression and modulated negatively chondrogenesis while these effects were reverted in the presence of the IL-1 receptor antagonist. Nicotine, at concentrations similar to those observed in blood of smokers, exhibited a dose dependent increase of Aggrecan expression, suggesting an unexpected protective effect of the drug under these conditions. Therefore, hMADS cells represent a valuable tool for the analysis of in vitro chondrocyte differentiation and to screen for potentially interesting pharmacological drugs.
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Affiliation(s)
- Christian Roux
- University Nice Sophia Antipolis, iBV, UMR 7277, 06100 Nice, France; CNRS, iBV, UMR 7277, 06100 Nice, France; Inserm, iBV, U1091, 06100 Nice, France; Service de Rhumatologie, Hospital l'Archet 1 CHU, 06200 Nice, France
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de Vries-van Melle ML, Narcisi R, Kops N, Koevoet WJLM, Bos PK, Murphy JM, Verhaar JAN, van der Kraan PM, van Osch GJVM. Chondrogenesis of mesenchymal stem cells in an osteochondral environment is mediated by the subchondral bone. Tissue Eng Part A 2013; 20:23-33. [PMID: 23980750 DOI: 10.1089/ten.tea.2013.0080] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
In articular cartilage repair, cells that will be responsible for the formation of repair tissue are often exposed to an osteochondral environment. To study cartilage repair mechanisms in vitro, we have recently developed a bovine osteochondral biopsy culture model in which cartilage defects can be simulated reproducibly. Using this model, we now aimed at studying the chondrogenic potential of human bone marrow-derived mesenchymal stem cells (hBMSCs) in an osteochondral environment. In contrast to standard in vitro chondrogenesis, it was found that supplementing transforming growth factor beta (TGFβ) to culture medium was not required to induce chondrogenesis of hBMSCs in an osteochondral environment. hBMSC culture in defects created in osteochondral biopsies or in bone-only biopsies resulted in comparable levels of cartilage-related gene expression, whereas culture in cartilage-only biopsies did not induce chondrogenesis. Subcutaneous implantation in nude mice of osteochondral biopsies containing hBMSCs in osteochondral defects resulted in the formation of more cartilaginous tissue than hBMSCs in chondral defects. The subchondral bone secreted TGFβ; however, the observed results could not be attributed to TGFβ, as either capturing TGFβ with an antibody or blocking the canonical TGFβ signaling pathway did not result in significant changes in cartilage-related gene expression of hBMSCs in the osteochondral culture model. Inhibition of BMP signaling did not prevent chondrogenesis. In conclusion, we demonstrate that chondrogenesis of hBMSCs is induced by factors secreted from the bone. We have strong indications that this is not solely mediated by members of the TGFβ family but other, yet unknown, factors originating from the subchondral bone appeared to play a key role.
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Madry H, Rey-Rico A, Venkatesan JK, Johnstone B, Cucchiarini M. Transforming growth factor Beta-releasing scaffolds for cartilage tissue engineering. TISSUE ENGINEERING PART B-REVIEWS 2013; 20:106-25. [PMID: 23815376 DOI: 10.1089/ten.teb.2013.0271] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The maintenance of a critical threshold concentration of transforming growth factor beta (TGF-β) for a given period of time is crucial for the onset and maintenance of chondrogenesis. Thus, the development of scaffolds that provide temporal and/or spatial control of TGF-β bioavailability has appeal as a mechanism to induce the chondrogenesis of stem cells in vitro and in vivo for articular cartilage repair. In the past decade, many types of scaffolds have been designed to advance this goal: hydrogels based on polysaccharides, hyaluronic acid, and alginate; protein-based hydrogels such as fibrin, gelatin, and collagens; biopolymeric gels and synthetic polymers; and solid and hybrid composite (hydrogel/solid) scaffolds. In this study, we review the progress in developing strategies to deliver TGF-β from scaffolds with the aim of enhancing chondrogenesis. In the future, such scaffolds could prove critical for tissue engineering cartilage, both in vitro and in vivo.
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Affiliation(s)
- Henning Madry
- 1 Center of Experimental Orthopaedics, Saarland University , Homburg, Germany
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Abstract
Cartilage damaged by trauma has a limited capacity to regenerate. Current methods of managing small chondral defects include palliative treatment with arthroscopic débridement and lavage, reparative treatment with marrow-stimulation techniques (eg, microfracture), and restorative treatment, including osteochondral grafting and autologous chondrocyte implantation. Larger defects are managed with osteochondral allograft or total joint arthroplasty. However, the future of managing cartilage defects lies in providing biologic solutions through cartilage regeneration. Laboratory and clinical studies have examined the management of larger lesions using tissue-engineered cartilage. Regenerated cartilage can be derived from various cell types, including chondrocytes, pluripotent stem cells, and mesenchymal stem cells. Common scaffolding materials include proteins, carbohydrates, synthetic materials, and composite polymers. Scaffolds may be woven, spun into nanofibers, or configured as hydrogels. Chondrogenesis may be enhanced with the application of chondroinductive growth factors. Bioreactors are being developed to enhance nutrient delivery and provide mechanical stimulation to tissue-engineered cartilage ex vivo. The multidisciplinary approaches currently being developed to produce cartilage promise to bring to fruition the desire for cartilage regeneration in clinical use.
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Shen W, Chen J, Zhu T, Yin Z, Chen X, Chen L, Fang Z, Heng BC, Ji J, Chen W, Ouyang HW. Osteoarthritis prevention through meniscal regeneration induced by intra-articular injection of meniscus stem cells. Stem Cells Dev 2013; 22:2071-82. [PMID: 23461527 DOI: 10.1089/scd.2012.0563] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Meniscus injury is frequently encountered in clinical practice. Current surgical therapy involving partial or complete meniscectomy relieves pain in the short-term but often leads to osteoarthritis (OA) in the long-term. Here, this study aimed to identify and characterize a novel population of meniscus-derived stem cells (MeSCs) and develop a new strategy of articular cartilage protection by intra-articular injection of these cells. The "stemness" and immune properties of MeSCs were investigated in vitro, while the efficacy of intra-articular injection of MeSCs for meniscus regeneration and OA prevention were investigated in vivo at 4, 8, and 12 weeks postsurgery. MeSCs displayed typical stem cell characteristics such as low immunogenicity and even possessed immunosuppressive function. In a rabbit meniscus injury model, transplantation of allogenous MeSCs did not elicit immunological rejection, but promoted neo-tissue formation with better-defined shape and more matured extracellular matrix. In a rabbit experimental OA model, transplantation of MeSCs further protected joint surface cartilage and maintained joint space at 12 weeks postsurgery, whereas extensive joint surface irregularities and joint space stenosis were observed in the control group. This study thus evoked a new strategy for articular cartilage protection and meniscus regeneration by intra-articular injection of MeSCs for patients undergoing meniscectomy.
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Affiliation(s)
- Weiliang Shen
- Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China
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Ma A, Jiang L, Song L, Hu Y, Dun H, Daloze P, Yu Y, Jiang J, Zafarullah M, Chen H. Reconstruction of cartilage with clonal mesenchymal stem cell-acellular dermal matrix in cartilage defect model in nonhuman primates. Int Immunopharmacol 2013; 16:399-408. [PMID: 23499511 DOI: 10.1016/j.intimp.2013.02.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Accepted: 02/01/2013] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Articular cartilage defects are commonly associated with trauma, inflammation and osteoarthritis. Mesenchymal stem cell (MSC)-based therapy is a promising novel approach for repairing articular cartilage. Direct intra-articular injection of uncommitted MSCs does not regenerate high-quality cartilage. This study explored utilization of a new three-dimensional, selected chondrogenic clonal MSC-loaded monkey acellular dermal matrix (MSC-ADM) scaffold to repair damaged cartilage in an experimental model of knee joint cartilage defect in Cynomolgus monkeys. METHODS MSCs were characterized for cell size, cell yield, phenotypes, proliferation and chondrogenic differentiation capacity. Chondrogenic differentiation assays were performed at different MSC passages by sulfated glycosaminoglycans (sGAG), collagen, and fluorescence activated cell sorter (FACS) analysis. Selected chondrogenic clonal MSCs were seeded onto ADM scaffold with the sandwich model and MSC-loaded ADM grafts were analyzed by confocal microscopy and scanning electron microscopy. Cartilage defects were treated with normal saline, clonal MSCs and clonal MSC-ADM grafts, respectively. The clinical parameters, and histological and immunohistochemical examinations were evaluated at weeks 8, 16, 24 post-treatment, respectively. RESULTS Polyclonal and clonal MSCs could differentiate into the chondrogenic lineage after stimulation with suitable chondrogenic factors. They expressed mesenchymal markers and were negative for hematopoietic markers. Articular cartilage defects were considerably improved and repaired by selected chondrogenic clonal MSC-based treatment, particularly, in MSC-ADM-treated group. The histological scores in MSC-ADM-treated group were consistently higher than those of other groups. CONCLUSION Our results suggest that selected chondrogenic clonal MSC-loaded ADM grafts could improve the cartilage lesions in Cynomolgus monkey model, which may be applicable for repairing similar human cartilage defects.
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Affiliation(s)
- Anlun Ma
- Department of Surgery, Research Center, CHUM (CRCHUM), Notre-Dame Hospital, University of Montreal, Montreal, Canada
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Jiang L, Ma A, Song L, Hu Y, Dun H, Daloze P, Yu Y, Jiang J, Zafarullah M, Chen H. Cartilage regeneration by selected chondrogenic clonal mesenchymal stem cells in the collagenase-induced monkey osteoarthritis model. J Tissue Eng Regen Med 2013; 8:896-905. [PMID: 23335439 DOI: 10.1002/term.1676] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Revised: 09/11/2012] [Accepted: 11/05/2012] [Indexed: 12/29/2022]
Abstract
Osteoarthritis (OA) is the most common form of arthritis, in which cartilage is irreversibly degraded, causing severe pain and disability. Current therapeutic strategies cannot repair damaged cartilage. We evaluated the repair potential of selected chondrogenic clonal MSCs (sC-MSCs) by delivering them into the injured cartilage site in a collagenase-induced OA model in Cynomolgus monkeys. In vitro characterization showed that the isolated monkey sC-MSCs and polyclonal MSCs (P-MSCs) expressed mesenchymal stem cell markers and could differentiate into chondrocytes. The articular cartilage lesions in animals were treated with normal saline (NS), autologous P-MSCs and sC-MSCs, respectively, by direct delivery. The clinical parameters, radiographic images, histological and immunohistochemical examinations at weeks 8, 16 and 24 post-treatment demonstrated that the abrasions of articular cartilage were significantly improved and repaired by MSC-based treatment, particularly in the sC-MSC-treated group, which displayed consistently higher histological scores than those of other groups. In summary, treatment with sC-MSCs can effectively improve the healing of cartilage lesions in the Cynomolgus monkey collagenase-induced OA model. Due to the genetic proximity of monkey and human, the therapeutic strategy presented in this study will have broad applications in clinical practice.
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Affiliation(s)
- Li Jiang
- Department of Surgery, CRCHUM, Notre Dame Hospital, University of Montreal, Quebec, Canada; Department of Orthopaedics, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
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Elsler S, Schetting S, Schmitt G, Kohn D, Madry H, Cucchiarini M. Effective, safe nonviral gene transfer to preserve the chondrogenic differentiation potential of human mesenchymal stem cells. J Gene Med 2012; 14:501-11. [PMID: 22711470 DOI: 10.1002/jgm.2644] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Genetic modification of mesenchymal stem cells (MSCs) comprises a promising tool to generate cell- and gene-based platforms for regenerative approaches of articular cartilage repair. In the present study, we systematically screened a panel of 15 nonviral compounds for their ability to promote safe, efficient and durable gene expression in human bone marrow-derived MSCs (hMSCS) without impeding their commitment towards chondrogenic differentiation. METHODS Primary hMSCs were transfected with plasmid vectors carrying sequences for the Photinus pyralis luciferase Escherichia coli β-galactosidase, or human insulin-like growth factor I via 15 nonviral formulations. Transgene expression and transfection efficiencies were monitored for each component in parallel with the effects on cell viability and cytotoxicity. Upon optimization, the most promising reagent was then evaluated for a possible influence on the chondrogenic potential of hMSCs. RESULTS Among all formulations tested, GeneJammer® gave the best results for transgene expression and transfection efficacy (25-14% from days 2-21 in monolayer cultures and 35% in 21-day aggregate cultures), allowing for high levels of viability (92-94%) and modest cytotoxicity (< 12%). Most notably, the application of this reagent did not affect the potential of the cells for chondrogenic differentiation when maintained in long-term (21 days) three-dimensional (aggregate) cultures. CONCLUSIONS The data indicate that safe, efficient transgene expression can be achieved in hMSCs over time using the nonviral GeneJammer® compound, showing promise for future therapeutic settings aiming to treat human articular cartilage disorders.
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Affiliation(s)
- Sebastian Elsler
- Center of Experimental Orthopaedics, Saarland University Medical Center, Saarland University, Homburg/Saar, Germany
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Choi KH, Song BR, Choi BH, Lee M, Park SR, Min BH. Cartilage tissue engineering using chondrocyte-derived extracellular matrix scaffold suppressed vessel invasion during chondrogenesis of mesenchymal stem cells in vivo. Tissue Eng Regen Med 2012. [DOI: 10.1007/s13770-012-0043-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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Madry H, Cucchiarini M. Clinical potential and challenges of using genetically modified cells for articular cartilage repair. Croat Med J 2012; 52:245-61. [PMID: 21674822 PMCID: PMC3131141 DOI: 10.3325/cmj.2011.52.245] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Articular cartilage defects do not regenerate. Transplantation of autologous articular chondrocytes, which is clinically being performed since several decades, laid the foundation for the transplantation of genetically modified cells, which may serve the dual role of providing a cell population capable of chondrogenesis and an additional stimulus for targeted articular cartilage repair. Experimental data generated so far have shown that genetically modified articular chondrocytes and mesenchymal stem cells (MSC) allow for sustained transgene expression when transplanted into articular cartilage defects in vivo. Overexpression of therapeutic factors enhances the structural features of the cartilaginous repair tissue. Combined overexpression of genes with complementary mechanisms of action is also feasible, holding promises for further enhancement of articular cartilage repair. Significant benefits have been also observed in preclinical animal models that are, in principle, more appropriate to the clinical situation. Finally, there is convincing proof of concept based on a phase I clinical gene therapy study in which transduced fibroblasts were injected into the metacarpophalangeal joints of patients without adverse events. To realize the full clinical potential of this approach, issues that need to be addressed include its safety, the choice of the ideal gene vector system allowing for a long-term transgene expression, the identification of the optimal therapeutic gene(s), the transplantation without or with supportive biomaterials, and the establishment of the optimal dose of modified cells. As safe techniques for generating genetically engineered articular chondrocytes and MSCs are available, they may eventually represent new avenues for improved cell-based therapies for articular cartilage repair. This, in turn, may provide an important step toward the unanswered question of articular cartilage regeneration.
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Affiliation(s)
- Henning Madry
- Experimental Orthopaedics and Osteoarthritis Research, Saarland University Medical Center, Homburg/Saar, Germany.
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Jones E, McGonagle D. Synovial mesenchymal stem cells in vivo: Potential key players for joint regeneration. World J Rheumatol 2011; 1:4-11. [DOI: 10.5499/wjr.v1.i1.4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Unlike bone marrow (BM) mesenchymal stem cells (MSCs), whose in vivo identity has been actively explored in recent years, the biology of MSCs in the synovium remains poorly understood. Synovial MSCs may be of great importance to rheumatology and orthopedics because of the direct proximity and accessibility of the synovium to cartilage, ligament, and meniscus. Their excellent chondrogenic capabilities and suggested transit through the synovial fluid, giving unhindered access to the joint surface, further support a pivotal role for synovial MSCs in homeostatic joint repair. This review highlights several unresolved issues pertaining to synovial MSC isolation, topography, and their relationship with pericytes, synovial fibroblasts, and synovial fluid MSCs. Critically reviewing published data on synovial MSCs, we also draw from our experience of exploring the in vivo biology of MSCs in the BM to highlight key differences. Extending our knowledge of synovial MSCs in vivo could lead to novel therapeutic strategies for arthritic diseases.
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Zhang B, Yang S, Sun Z, Zhang Y, Xia T, Xu W, Ye S. Human mesenchymal stem cells induced by growth differentiation factor 5: an improved self-assembly tissue engineering method for cartilage repair. Tissue Eng Part C Methods 2011; 17:1189-99. [PMID: 21875359 DOI: 10.1089/ten.tec.2011.0011] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Previous studies have shown that novel scaffold-free self-assembled constructs can be an ideal alternative for cartilage tissue engineered based on scaffolds, which has many limitations. However, many questions remain, including the choice of seeding cells and the role of growth differentiation factor 5 (GDF-5) in constructing self-assembled engineered cartilages. Moreover, whether the optimum construct is effective in human chondral defect repair is still unknown. In this study, we generated self-assembled constructs of human mesenchymal stem cells (hMSCs) using four different approaches: direct self-assembly of hMSCs with or without GDF-5, and predifferentiated hMSCs self-assembly with or without GDF-5. Histological, immunohistochemical, and biochemistry analyses indicated that the constructs generated from predifferentiated hMSCs induced by GDF-5 (Group D2) exhibited up-regulated glycosaminoglycan (GAG) and type II collagen expression and contained higher amounts of GAG and total collagen than any other group. After 3-weeks of in vitro culturing of the constructs in a chondral defects explant culture system, the contructs from Group D2 were stably adhered to the surface of the cartilage matrix. Immunohistochemically, the repair tissue was positive for type II collagen, toluidine blue, and safranin O. These data demonstrated that the generation of self-assembled tissue-engineered cartilage from chondrogenically differentiated hMSCs induced by GDF-5 is a promising therapeutic strategy for cartilage repair.
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Affiliation(s)
- Bo Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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Cucchiarini M, Ekici M, Schetting S, Kohn D, Madry H. Metabolic activities and chondrogenic differentiation of human mesenchymal stem cells following recombinant adeno-associated virus-mediated gene transfer and overexpression of fibroblast growth factor 2. Tissue Eng Part A 2011; 17:1921-33. [PMID: 21417714 DOI: 10.1089/ten.tea.2011.0018] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The genetic manipulation of bone marrow-derived mesenchymal stem cells (MSCs) is an attractive approach to produce therapeutic platforms for settings that aim at restoring articular cartilage defects. Here, we examined the effects of recombinant adeno-associated virus (rAAV)-mediated overexpression of human fibroblast growth factor 2 (hFGF-2), a mitogenic factor also known to influence MSC differentiation, upon the proliferative and chondrogenic activities of human MSCs (hMSCs) in a three-dimensional environment that supports chondrogenesis in vitro. Prolonged, significant FGF-2 synthesis was noted in rAAV-hFGF-2-transduced monolayer and aggregate cultures of hMSCs, leading to enhanced, dose-dependent cell proliferation compared with control treatments (rAAV-lacZ transduction and absence of vector administration). Chondrogenic differentiation (proteoglycans, type-II collagen, and SOX9 expression) was successfully achieved in all types of aggregates, without significant difference between conditions. Most remarkably, application of rAAV-hFGF-2 reduced the expression of type-I and type-X collagen, possibly due to increased levels of matrix metalloproteinase-13, a key matrix-degrading enzyme. FGF-2 overexpression also decreased mineralization and the expression of osteogenic markers such as alkaline phosphatase, with diminished levels of RUNX-2, a transcription factor for osteoblast-related genes. Altogether, the present findings show the ability of rAAV-mediated FGF-2 gene transfer to expand hMSCs with an advantageous differentiation potential for future, indirect therapeutic approaches that aim at treating articular cartilage defects in vivo.
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Affiliation(s)
- Magali Cucchiarini
- Experimental Orthopaedics and Osteoarthritis Research, Saarland University Medical Center, Saarland University, Homburg/Saar, Germany.
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Chondrogenic Priming Adipose-Mesenchymal Stem Cells for Cartilage Tissue Regeneration. Pharm Res 2011; 28:1395-405. [DOI: 10.1007/s11095-011-0445-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Accepted: 04/04/2011] [Indexed: 12/26/2022]
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Seo CH, Furukawa K, Suzuki Y, Kasagi N, Ichiki T, Ushida T. A Topographically Optimized Substrate with Well-Ordered Lattice Micropatterns for Enhancing the Osteogenic Differentiation of Murine Mesenchymal Stem Cells. Macromol Biosci 2011; 11:938-45. [DOI: 10.1002/mabi.201000477] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Indexed: 12/26/2022]
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Aung A, Gupta G, Majid G, Varghese S. Osteoarthritic chondrocyte-secreted morphogens induce chondrogenic differentiation of human mesenchymal stem cells. ACTA ACUST UNITED AC 2011; 63:148-158. [PMID: 20954186 DOI: 10.1002/art.30086] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE The potential of stem cells to repair compromised cartilage tissue, such as in osteoarthritis (OA), depends strongly on how transplanted cells respond to factors secreted from the residing OA chondrocytes. This study was undertaken to determine the effect of morphogenetic signals from OA chondrocytes on chondrogenic differentiation of human mesenchymal stem cells (MSCs). METHODS The effect of OA chondrocyte-secreted morphogens on chondrogenic differentiation of human MSCs was evaluated using a coculture system involving both primary and passaged OA chondrocytes. The findings were compared against findings for human MSCs cultured in OA chondrocyte-conditioned medium. Gene expression analysis, biochemical assays, and immunofluorescence staining were used to characterize the chondrogenic differentiation of human MSCs. Mass spectrometry analysis was used to identify the soluble factors. Numerical analysis was carried out to model the concentration profile of soluble factors within the human MSC-laden hydrogels. RESULTS The human MSCs cocultured with primary OA chondrocytes underwent chondrogenic differentiation even in the absence of growth factors; however, the same effect could not be mimicked using OA chondrocyte-conditioned medium or expanded cells. Additionally, the cocultured environment down-regulated hypertrophic differentiation of human MSCs. Mass spectrometry analysis demonstrated cell-cell communication and chondrocyte phenotype-dependent effects on cell-secreted morphogens. CONCLUSION The experimental findings, along with the results of the numerical analysis, suggest a crucial role of soluble morphogens and their local concentrations in the differentiation pattern of human MSCs in a 3-dimensional environment. The concept of using a small number of chondrocytes to promote chondrogenic differentiation of human MSCs while preventing their hypertrophic differentiation could be of great importance in formulating effective stem cell-based cartilage repair.
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Affiliation(s)
- Aereas Aung
- Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Gunjan Gupta
- Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Ghassemian Majid
- Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Shyni Varghese
- Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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Hwang NS, Zhang C, Hwang YS, Varghese S. Mesenchymal stem cell differentiation and roles in regenerative medicine. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2010; 1:97-106. [PMID: 20835984 DOI: 10.1002/wsbm.26] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Adult stem cells with multi or unipotent differentiation potential are present in almost all tissues of adult organisms. The main function of these stem cells is to support normal repair and rejuvenation of diseased and aging tissues. Mesenchymal stem cells (MSCs) isolated from the bone marrow have the potential to differentiate into multiple connective tissues. Advancements in understanding tissue specific differentiation of MSCs in conjunction with global genomic and proteomic profiling of MSCs have not only provided insights into their biology but also made MSC based clinical trials a reality for treating various debilitating diseases and genetic disorders. The emerging evidence that MSCs are immunosuppressive makes them an even more attractive candidate for regenerative medicine as rejections of transplants by the recipient could be a limiting step for moving the stem cells based therapies from "bedside to bed side." To a large extent the therapeutic potential of MSCs is attributed to their differentiation ability. The fate and commitment of MSCs are regulated by various instructive signals from their immediate vicinity or microenvironment, which comprises many biological molecules (soluble and insoluble) and biomechanical forces. These biochemical and biophysical factors play a pivotal role in determining the efficacy of MSC differentiation and their contribution to the repair process. In this review, we discuss the characteristics of MSCs, their differentiation potential toward different skeletal tissues (cartilage and bone), and their emerging role in regenerative medicine.
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Affiliation(s)
- Nathaniel S Hwang
- Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA
| | - Chao Zhang
- Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA
| | - Yong-Sung Hwang
- Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA
| | - Shyni Varghese
- Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0412, USA
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Lee JS, Im GI. Influence of Chondrocytes on the Chondrogenic Differentiation of Adipose Stem Cells. Tissue Eng Part A 2010; 16:3569-77. [DOI: 10.1089/ten.tea.2010.0218] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Jai-Sun Lee
- Department of Orthopaedics, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
| | - Gun-Il Im
- Department of Orthopaedics, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
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da Silva MA, Martins A, Teixeira AA, Reis RL, Neves NM. Impact of biological agents and tissue engineering approaches on the treatment of rheumatic diseases. TISSUE ENGINEERING PART B-REVIEWS 2010; 16:331-9. [PMID: 20025434 DOI: 10.1089/ten.teb.2009.0536] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The treatment of rheumatic diseases has been the focus of many clinical studies aiming to achieve the best combination of drugs for symptom reduction. Although improved understanding of the pathophysiology of rheumatic diseases has led to the identification of effective therapeutic strategies, its cure remains unknown. Biological agents are a breakthrough in the treatment of these diseases. They proved to be more effective than the other conventional therapies in refractory inflammatory rheumatic diseases. Among them, tumor necrosis factor inhibitors are widely used, namely Etanercept, Infliximab, or Adalimumab, alone or in combination with disease-modifying antirheumatic drugs. Nevertheless, severe adverse effects have been detected in patients with history of recurrent infections, including cardiac failure or malignancy. Currently, most of the available therapies for rheumatic diseases do not have sufficient tissue specificity. Consequently, high drug doses must be administrated systemically, leading to adverse side effects associated with its possible toxicity. Drug delivery systems, by its targeted nature, are excellent solutions to overcome this problem. In this review, we will describe the state-of-the-art in clinical studies on the treatment of rheumatic diseases, emphasizing the use of biological agents and target drug delivery systems. Some alternative novel strategies of regenerative medicine and its implications for rheumatic diseases will also be discussed.
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