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Cottrill E, Pennington Z, Sattah N, Jing C, Salven D, Johnson E, Downey M, Varghese S, Rocos B, Richardson W. Gene Therapy and Spinal Fusion: Systematic Review and Meta-Analysis of the Available Data. World Neurosurg 2024; 186:219-234.e4. [PMID: 38583566 DOI: 10.1016/j.wneu.2024.03.174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 03/31/2024] [Indexed: 04/09/2024]
Abstract
OBJECTIVE To analyze the extant literature describing the application of gene therapy to spinal fusion. METHODS A systematic review of the English-language literature was performed. The search query was designed to include all published studies examining gene therapy approaches to promote spinal fusion. Approaches were classified as ex vivo (delivery of genetically modified cells) or in vivo (delivery of growth factors via vectors). The primary endpoint was fusion rate. Random effects meta-analyses were performed to calculate the overall odds ratio (OR) of fusion using a gene therapy approach and overall fusion rate. Subgroup analyses of fusion rate were also performed for each gene therapy approach. RESULTS Of 1179 results, 35 articles met criteria for inclusion (all preclinical), of which 26 utilized ex vivo approaches and 9 utilized in vivo approaches. Twenty-seven articles (431 animals) were included in the meta-analysis. Gene therapy use was associated with significantly higher fusion rates (OR 77; 95% confidence interval {CI}: [31, 192]; P < 0.001); ex vivo strategies had a greater effect (OR 136) relative to in vivo strategies (OR 18) (P = 0.017). The overall fusion rate using a gene therapy approach was 80% (95% CI: [62%, 93%]; P < 0.001); overall fusion rates were significantly higher in subjects treated with ex vivo compared to in vivo strategies (90% vs. 42%; P = 0.011). For both ex vivo and in vivo approaches, the effect of gene therapy on fusion was independent of animal model. CONCLUSIONS Gene therapy may augment spinal fusion; however, future investigation in clinical populations is necessary.
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Affiliation(s)
- Ethan Cottrill
- Department of Orthopaedic Surgery, Duke University Health System, Durham, NC, USA; Department of Biomedical Engineering, Duke University, Durham, NC, USA.
| | | | - Nathan Sattah
- Department of Orthopaedic Surgery, Duke University Health System, Durham, NC, USA
| | - Crystal Jing
- Department of Orthopaedic Surgery, Duke University Health System, Durham, NC, USA
| | - Dave Salven
- Department of Orthopaedic Surgery, Duke University Health System, Durham, NC, USA
| | - Eli Johnson
- Department of Neurosurgery, Duke University Health System, Durham, NC, USA
| | - Max Downey
- Department of Surgery, NYU Grossman School of Medicine, NY, USA
| | - Shyni Varghese
- Department of Orthopaedic Surgery, Duke University Health System, Durham, NC, USA; Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Brett Rocos
- Department of Orthopaedic Surgery, Duke University Health System, Durham, NC, USA
| | - William Richardson
- Department of Orthopaedic Surgery, Duke University Health System, Durham, NC, USA
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2
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Setoguchi F, Sena K, Noguchi K. Low-Intensity Pulsed Ultrasound Promotes BMP9 Induced Osteoblastic Differentiation in Rat Dedifferentiated Fat Cells. Int J Stem Cells 2023; 16:406-414. [PMID: 37385636 PMCID: PMC10686803 DOI: 10.15283/ijsc23027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 07/01/2023] Open
Abstract
Dedifferentiated fat cells (DFATs) isolated from mature adipocytes have a multilineage differentiation capacity similar to mesenchymal stem cells and are considered as promising source of cells for tissue engineering. Bone morphogenetic protein 9 (BMP9) and low-intensity pulsed ultrasound (LIPUS) have been reported to stimulate bone formation both in vitro and in vivo. However, the combined effect of BMP9 and LIPUS on osteoblastic differentiation of DFATs has not been studied. After preparing DFATs from mature adipose tissue from rats, DFATs were treated with different doses of BMP9 and/or LIPUS. The effects on osteoblastic differentiation were assessed by changes in alkaline phosphatase (ALP) activity, mineralization/calcium deposition, and expression of bone related genes; Runx2, osterix, osteopontin. No significant differences for ALP activity, mineralization deposition, as well as expression for bone related genes were observed by LIPUS treatment alone while treatment with BMP9 induced osteoblastic differentiation of DFATs in a dose dependent manner. Further, co-treatment with BMP9 and LIPUS significantly increased osteoblastic differentiation of DFATs compared to those treated with BMP9 alone. In addition, upregulation for BMP9-receptor genes was observed by LIPUS treatment. Indomethacin, an inhibitor of prostaglandin synthesis, significantly inhibited the synergistic effect of BMP9 and LIPUS co-stimulation on osteoblastic differentiation of DFATs. LIPUS promotes BMP9 induced osteoblastic differentiation of DFATs in vitro and prostaglandins may be involved in this mechanism.
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Affiliation(s)
- Fumiaki Setoguchi
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Kotaro Sena
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
- Division of Preventive Dentistry, Department of Community Social Dentistry, Graduate School of Dentistry, Tohoku University, Miyagi, Japan
| | - Kazuyuki Noguchi
- Department of Periodontology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Xu L, Ji C, Yu T, Luo J. The effects of Gli1 and Gli2 on BMP9-induced osteogenic differentiation of mesenchymal stem cells. Tissue Cell 2023; 84:102168. [PMID: 37478645 DOI: 10.1016/j.tice.2023.102168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/23/2023]
Abstract
Diseases, such as bone nonunion with bone defects, osteoporosis, etc, seriously endanger people's quality of life, and bone tissue engineering based on mesenchymal stem cells is an effective method to solve such problems. Several studies have shown that BMP9 can effectively promote osteogenic differentiation of MSCs, but the underlying molecular mechanisms are still unclear. Gli1 and Gli2 were important transcription factors and play an important role in the Hedgehog signaling pathway. In this study, we investigated the role of Gli1 and Gli2 in BMP9-induced osteogenic differentiation of MSCs. We found that inhibition of Gli1 and Gli2 weakened BMP9-induced osteogenic differentiation of MSCs, and early osteogenic markers (alkaline phosphatase, ALP), late osteogenic markers (calcium salt deposition), the expression of pivotal osteogenic markers were attenuated, and inhibition of Gli1 and Gli2 weakened the expression of p-Smad1/5/8 and p-p38 induced by BMP9. In conclusion, our study shows that Gli1 and Gli2 play an important role in BMP9-induced osteogenic differentiation.
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Affiliation(s)
- Li Xu
- Department of Clinical Laboratory, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan 621000, China
| | - Caixia Ji
- Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Tingting Yu
- Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, People's Republic of China
| | - Jinyong Luo
- Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, People's Republic of China.
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Han J, Han SC, Kim YK, Tarafder S, Jeong HJ, Jeong HJ, Chung JY, Lee CH, Oh JH. Bioactive Scaffold With Spatially Embedded Growth Factors Promotes Bone-to-Tendon Interface Healing of Chronic Rotator Cuff Tear in Rabbit Model. Am J Sports Med 2023; 51:2431-2442. [PMID: 37345646 DOI: 10.1177/03635465231180289] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/23/2023]
Abstract
BACKGROUND Functional restoration of the bone-to-tendon interface (BTI) after rotator cuff repair is a challenge. Therefore, numerous biocompatible biomaterials for promoting BTI healing have been investigated. PURPOSE To determine the efficacy of scaffolds with spatiotemporal delivery of growth factors (GFs) to accelerate BTI healing after rotator cuff repair. STUDY DESIGN Controlled laboratory study. METHODS An advanced 3-dimensional printing technique was used to fabricate bioactive scaffolds with spatiotemporal delivery of multiple GFs targeting the tendon, fibrocartilage, and bone regions. In total, 50 rabbits were used: 2 nonoperated controls and 48 rabbits with induced chronic rotator cuff tears (RCTs). The animals with RCTs were divided into 3 groups: (A) saline injection, (B) scaffold without GF, and (C) scaffold with GF. To induce chronic models, RCTs were left unrepaired for 6 weeks; then, surgical repairs with or without bioactive scaffolds were performed. For groups B and C, each scaffold was implanted between the bony footprint and the supraspinatus tendon. Four weeks after repair, quantitative real-time polymerase chain reaction and immunofluorescence analyses were performed to evaluate early signs of regenerative healing. Histological, biomechanical, and micro-computed tomography analyses were performed 12 weeks after repair. RESULTS Group C had the highest mRNA expression of collagen type I alpha 1, collagen type III alpha 1, and aggrecan. Immunofluorescence analysis showed the formation of an aggrecan+/collagen II+ fibrocartilaginous matrix at the BTI when repaired with scaffold with GFs. Histologic analysis revealed greater collagen fiber continuity, denser collagen fibers, and a more mature tendon-to-bone junction in GF-embedded scaffolds than those in the other groups. Group C demonstrated the highest load-to-failure ratio, and modulus mapping showed that the distribution of the micromechanical properties of the BTI repaired with GF-embedded scaffolds was comparable with that of the native BTI. Micro-computed tomography analysis identified the highest bone mineral density and bone volume/total volume ratio in group C. CONCLUSION Bioactive scaffolds with spatially embedded GFs have significant potential to promote the BTI healing of chronic RCTs in a rabbit model. CLINICAL RELEVANCE The scaffolds with spatiotemporal delivery of GF may serve as an off-the-shelf biomaterial graft to promote the healing of RCTs.
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Affiliation(s)
- Jian Han
- Department of Orthopaedic Surgery, The First People's Hospital of Huzhou, Huzhou, Zhejiang Province, China
| | - Sheng Chen Han
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Young Kyu Kim
- Department of Orthopaedic Surgery, Bundang Jesaeng Hospital, Seongnam, Republic of Korea
| | - Solaiman Tarafder
- Regenerative Engineering Laboratory, Center for Dental and Craniofacial Research, Columbia University Irving Medical Center, New York, New York, USA
| | - Hun Jin Jeong
- Regenerative Engineering Laboratory, Center for Dental and Craniofacial Research, Columbia University Irving Medical Center, New York, New York, USA
| | - Hyeon Jang Jeong
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Ju Young Chung
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Chang H Lee
- Regenerative Engineering Laboratory, Center for Dental and Craniofacial Research, Columbia University Irving Medical Center, New York, New York, USA
| | - Joo Han Oh
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
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Deng Z, Luo F, Lin Y, Luo J, Ke D, Song C, Xu J. Research trends of mesenchymal stem cells application in orthopedics: A bibliometric analysis of the past 2 decades. Front Public Health 2022; 10:1021818. [PMID: 36225768 PMCID: PMC9548591 DOI: 10.3389/fpubh.2022.1021818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/07/2022] [Indexed: 01/28/2023] Open
Abstract
Background Bibliometric analysis and visualization tools were used to determine the development trend of mesenchymal stem cells (MSCs) in orthopedics in the past 20 years, so as to guide researchers to explore new directions and hotspots in the field in the future. Methods In the Web of Science Core Collection, all articles about the application of MSCs in orthopedics from 2002 to 2021 were searched. The qualitative and quantitative analysis was performed based on Web of Science and CiteSpace software. Results A total of 2,207 articles were retrieved. After excluding non-article articles such as review and letter and non-English language articles, 1,489 articles were finally included. Over the past 2 decades, the number of publications on the application of MSCs in orthopedic diseases increased. Among them, the United States, China, Japan and the United Kingdom have made significant contributions in this field. The most productive institution was Shanghai Jiao Tong University. Journal of Orthopedic Research published the largest number of publications. The journal with the highest citation frequency was Experimental Hematology. The authors with the highest output and the highest citation frequency on average were Rochy S. Tuan and Scott A. Rodeo, respectively. "Mesenchymal stem cell", "in vitro" and "Differentiation" were the top three keywords that appeared. From the keyword analysis, the current research trend indicates that the primary research hotspots of MSCs in orthopedics are the source of MSCs, in vitro experiments and the differentiation of MSCs into bone and cartilage. The frontiers of this field are the combination of MSCs and platelet-rich plasma (PRP), the treatment of knee diseases such as osteoarthritis, osteogenic differentiation, and the application of biological scaffolds combined with MSCs. Conclusion Over the past 2 decades, the application of MSCs in orthopedic diseases has received increasing attention. Our bibliometric analysis results provide valuable information and research trends for researchers in the field to understand the basic knowledge of the field, identify current research hotspots, potential collaborators, and future research frontiers.
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Affiliation(s)
| | | | | | | | | | | | - Jie Xu
- Department of Orthopedics, Fujian Clinical Research Center for Spinal Nerve and Joint Diseases, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
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Schindeler A, Lee LR, O'Donohue AK, Ginn SL, Munns CF. Curative Cell and Gene Therapy for Osteogenesis Imperfecta. J Bone Miner Res 2022; 37:826-836. [PMID: 35306687 PMCID: PMC9324990 DOI: 10.1002/jbmr.4549] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/03/2022] [Accepted: 02/27/2022] [Indexed: 11/17/2022]
Abstract
Osteogenesis imperfecta (OI) describes a series of genetic bone fragility disorders that can have a substantive impact on patient quality of life. The multidisciplinary approach to management of children and adults with OI primarily involves the administration of antiresorptive medication, allied health (physiotherapy and occupational therapy), and orthopedic surgery. However, advances in gene editing technology and gene therapy vectors bring with them the promise of gene-targeted interventions to provide an enduring or perhaps permanent cure for OI. This review describes emergent technologies for cell- and gene-targeted therapies, major hurdles to their implementation, and the prospects of their future success with a focus on bone disorders. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Aaron Schindeler
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Lucinda R Lee
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Alexandra K O'Donohue
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Samantha L Ginn
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and HealthThe University of Sydney and Sydney Children's Hospitals NetworkWestmeadAustralia
| | - Craig F Munns
- Faculty of MedicineThe University of QueenslandBrisbaneQLDAustralia
- Department of Endocrinology and DiabetesQueensland Children's HospitalBrisbaneQLDAustralia
- Child Health Research Centre and Faculty of MedicineThe University of QueenslandBrisbaneQueenslandAustralia
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Vahabzadeh S, Robertson S, Bose S. Beta-phase Stabilization and Increased Osteogenic Differentiation of Stem Cells by Solid-State Synthesized Magnesium Tricalcium Phosphate. JOURNAL OF MATERIALS RESEARCH 2021; 36:3041-3049. [PMID: 35757291 PMCID: PMC9231631 DOI: 10.1557/s43578-021-00311-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 07/13/2021] [Indexed: 06/15/2023]
Abstract
In this study, magnesium and strontium-doped β-tricalcium phosphates were synthesized to understand dopant impact on substrate chemistry and morphology, and proliferation and osteogenic differentiation of mesenchymal stem cells. Under solid-state synthesis, magnesium doping stabilized the β-phase in tricalcium phosphate, with 22% less α-phase content than control. Strontium doping increased α-phase formation by 17%, and also resulted in greater surface porosity, leading to greater crystal precipitation in vitro. Magnesium also significantly enhanced the proliferation of stem cells (P < 0.05) and differentiation into osteoblasts with increased alkaline phosphatase production (P < 0.05) at all time points. These results indicated that magnesium stabilizes β-tricalcium phosphate in vitro and enhanced early and late-time-point osteoconduction and osteoinduction of mesenchymal stem cells.
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Affiliation(s)
| | | | - Susmita Bose
- Corresponding author , Phone: (509) 335-7461, Fax: (509) 335-4662
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Chen CH, Hsu EL, Stupp SI. Supramolecular self-assembling peptides to deliver bone morphogenetic proteins for skeletal regeneration. Bone 2020; 141:115565. [PMID: 32745692 PMCID: PMC7680412 DOI: 10.1016/j.bone.2020.115565] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 12/15/2022]
Abstract
Recombinant human bone morphogenetic proteins (BMPs) have shown clinical success in promoting bone healing, but they are also associated with unwanted side effects. The development of improved BMP carriers that can retain BMP at the defect site and maximize its efficacy would decrease the therapeutic BMP dose and thus improve its safety profile. In this review, we discuss the advantages of using self-assembling peptides, a class of synthetic supramolecular biomaterials, to deliver recombinant BMPs. Peptide amphiphiles (PAs) are a broad class of self-assembling peptides, and the use of PAs for BMP delivery and bone regeneration has been explored extensively over the past decade. Like many self-assembling peptide systems, PAs can be designed to form nanofibrous supramolecular biomaterials in which molecules are held together by non-covalent bonds. Chemical and biological functionality can be added to PA nanofibers, through conjugation of chemical moieties or biological epitopes to PA molecules. For example, PA nanofibers have been designed to bind heparan sulfate, a natural polysaccharide that is known to bind BMPs and potentiate their signal. Alternatively, PA nanofibers have been designed to synthetically mimic the structure and function of heparan sulfate, or to directly bind BMP specifically. In small animal models, these bio-inspired PA materials have shown the capacity to promote bone regeneration using BMP at doses 10-100 times lower than established therapeutic doses. These promising results have motivated further evaluation of PAs in large animal models, where their safety and efficacy must be established before clinical translation. We conclude with a discussion on the possiblity of combining PAs with other materials used in orthopaedic surgery to maximize their utility for clinical translation.
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Affiliation(s)
- Charlotte H Chen
- Simpson Querrey Institute, Northwestern University, 303 East Superior Street, Chicago, IL 60611, USA; Department of Materials Science and Engineering, Northwestern University, 2220 Campus Drive, Evanston, IL 60208, USA
| | - Erin L Hsu
- Simpson Querrey Institute, Northwestern University, 303 East Superior Street, Chicago, IL 60611, USA; Department of Orthopaedic Surgery, Northwestern University, 676 North St. Clair Street, Chicago, IL 60611, USA
| | - Samuel I Stupp
- Simpson Querrey Institute, Northwestern University, 303 East Superior Street, Chicago, IL 60611, USA; Department of Materials Science and Engineering, Northwestern University, 2220 Campus Drive, Evanston, IL 60208, USA; Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA; Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA; Department of Medicine, Northwestern University, 676 North St. Clair Street, Chicago, IL 60611, USA.
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9
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Lee EJ, Jain M, Alimperti S. Bone Microvasculature: Stimulus for Tissue Function and Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2020; 27:313-329. [PMID: 32940150 DOI: 10.1089/ten.teb.2020.0154] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bone is a highly vascularized organ, providing structural support to the body, and its development, regeneration, and remodeling depend on the microvascular homeostasis. Loss or impairment of vascular function can develop diseases, such as large bone defects, avascular necrosis, osteoporosis, osteoarthritis, and osteopetrosis. In this review, we summarize how vasculature controls bone development and homeostasis in normal and disease cases. A better understanding of this process will facilitate the development of novel disease treatments that promote bone regeneration and remodeling. Specifically, approaches based on tissue engineering components, such as stem cells and growth factors, have demonstrated the capacity to induce bone microvasculature regeneration and mineralization. This knowledge will have relevant clinical implications for the treatment of bone disorders by developing novel pharmaceutical approaches and bone grafts. Finally, the tissue engineering approaches incorporating vascular components may widely be applied to treat other organ diseases by enhancing their regeneration capacity. Impact statement Bone vasculature is imperative in the process of bone development, regeneration, and remodeling. Alterations or disruption of the bone vasculature leads to loss of bone homeostasis and the development of bone diseases. In this study, we review the role of vasculature on bone diseases and how vascular tissue engineering strategies, with a detailed emphasis on the role of stem cells and growth factors, will contribute to bone therapeutics.
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Affiliation(s)
- Eun-Jin Lee
- American Dental Association Science and Research Institute, Gaithersburg, Maryland, USA
| | - Mahim Jain
- Kennedy Krieger Institute, John Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Stella Alimperti
- American Dental Association Science and Research Institute, Gaithersburg, Maryland, USA
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10
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May RD, Frauchiger DA, Albers CE, Tekari A, Benneker LM, Klenke FM, Hofstetter W, Gantenbein B. Application of Cytokines of the Bone Morphogenetic Protein (BMP) Family in Spinal Fusion - Effects on the Bone, Intervertebral Disc and Mesenchymal Stromal Cells. Curr Stem Cell Res Ther 2020; 14:618-643. [PMID: 31455201 PMCID: PMC7040507 DOI: 10.2174/1574888x14666190628103528] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/30/2019] [Accepted: 05/02/2019] [Indexed: 12/17/2022]
Abstract
Low back pain is a prevalent socio-economic burden and is often associated with damaged or degenerated intervertebral discs (IVDs). When conservative therapy fails, removal of the IVD (discectomy), followed by intersomatic spinal fusion, is currently the standard practice in clinics. The remaining space is filled with an intersomatic device (cage) and with bone substitutes to achieve disc height compensation and bone fusion. As a complication, in up to 30% of cases, spinal non-fusions result in a painful pseudoarthrosis. Bone morphogenetic proteins (BMPs) have been clinically applied with varied outcomes. Several members of the BMP family, such as BMP2, BMP4, BMP6, BMP7, and BMP9, are known to induce osteogenesis. Questions remain on why hyper-physiological doses of BMPs do not show beneficial effects in certain patients. In this respect, BMP antagonists secreted by mesenchymal cells, which might interfere with or block the action of BMPs, have drawn research attention as possible targets for the enhancement of spinal fusion or the prevention of non-unions. Examples of these antagonists are noggin, gremlin1 and 2, chordin, follistatin, BMP3, and twisted gastrulation. In this review, we discuss current evidence of the osteogenic effects of several members of the BMP family on osteoblasts, IVD cells, and mesenchymal stromal cells. We consider in vitro and in vivo studies performed in human, mouse, rat, and rabbit related to BMP and BMP antagonists in the last two decades. We give insights into the effects that BMP have on the ossification of the spine. Furthermore, the benefits, pitfalls, and possible safety concerns using these cytokines for the improvement of spinal fusion are discussed.
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Affiliation(s)
- Rahel Deborah May
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | | | - Christoph Emmanuel Albers
- Department of Orthopaedic Surgery and Traumatology, Inselspital, University of Bern, Bern, Switzerland
| | - Adel Tekari
- Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Lorin Michael Benneker
- Department of Orthopaedic Surgery and Traumatology, Inselspital, University of Bern, Bern, Switzerland
| | - Frank Michael Klenke
- Department of Orthopaedic Surgery and Traumatology, Inselspital, University of Bern, Bern, Switzerland
| | - Willy Hofstetter
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Benjamin Gantenbein
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.,Department of Orthopaedic Surgery and Traumatology, Inselspital, University of Bern, Bern, Switzerland
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11
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Chen CM, Chen CF, Wang JY, Madda R, Tsai SW, Wu PK, Chen WM. Bone morphogenetic protein activity preservation with extracorporeal irradiation- and liquid nitrogen freezing-treated recycled autografts for biological reconstruction in malignant bone tumor. Cryobiology 2019; 89:82-89. [PMID: 31067437 DOI: 10.1016/j.cryobiol.2019.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 04/30/2019] [Accepted: 05/01/2019] [Indexed: 02/06/2023]
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12
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Endo K, Fujita N, Nakagawa T, Nishimura R. Comparison of the effect of growth factors on chondrogenesis of canine mesenchymal stem cells. J Vet Med Sci 2019; 81:1211-1218. [PMID: 31167981 PMCID: PMC6715918 DOI: 10.1292/jvms.18-0551] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are proposed to be useful in cartilage regenerative
medicine, however, canine MSCs have been reported to show poor chondrogenic capacity.
Therefore, optimal conditions for chondrogenic differentiation should be determined by
mimicking the developmental process. We have previously established novel and superior
canine MSCs named bone marrow peri-adipocyte cells (BM-PACs) and the objective of this
study was to evaluate the effects of growth factors required for in vivo
chondrogenesis using canine BM-PACs. Spheroids of BM-PACs were cultured in chondrogenic
medium containing 10 ng/ml transforming growth factor-β1
(TGF-β1) with or without 100 ng/ml bone morphogenetic
protein-2 (BMP-2), 100 ng/ml growth differentiation
factor-5 (GDF-5) or 100 ng/ml insulin-like growth
factor-1 (IGF-1). Chondrogenic differentiation was evaluated by the quantification of
glycosaminoglycan and Safranin O staining for proteoglycan production. The expression of
cartilage matrix or hypertrophic gene/protein was also evaluated by qPCR and
immunohistochemistry. Spheroids in all groups were strongly stained with Safranin O.
Although BMP-2 significantly increased glycosaminoglycan production, Safranin O-negative
outer layer was formed and the mRNA expression of COL10 relating to cartilage hypertrophy
was also significantly upregulated (P<0.05). GDF-5 promoted the
production of glycosaminoglycan and type II collagen without increasing COL10 mRNA
expression. The supplementation of IGF-1 did not significantly affect cartilaginous and
hypertrophic differentiation. Our results indicate that GDF-5 is a useful growth factor
for the generation of articular cartilage from canine MSCs.
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Affiliation(s)
- Kentaro Endo
- Laboratory of Veterinary Surgery, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Naoki Fujita
- Laboratory of Veterinary Surgery, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Takayuki Nakagawa
- Laboratory of Veterinary Surgery, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | - Ryohei Nishimura
- Laboratory of Veterinary Surgery, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
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13
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Andrews S, Cheng A, Stevens H, Logun MT, Webb R, Jordan E, Xia B, Karumbaiah L, Guldberg RE, Stice S. Chondroitin Sulfate Glycosaminoglycan Scaffolds for Cell and Recombinant Protein-Based Bone Regeneration. Stem Cells Transl Med 2019; 8:575-585. [PMID: 30666821 PMCID: PMC6525555 DOI: 10.1002/sctm.18-0141] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 12/06/2018] [Indexed: 01/24/2023] Open
Abstract
Bone morphogenetic protein 2 (BMP‐2)‐loaded collagen sponges remain the clinical standard for treatment of large bone defects when there is insufficient autograft, despite associated complications. Recent efforts to negate comorbidities have included biomaterials and gene therapy approaches to extend the duration of BMP‐2 release and activity. In this study, we compared the collagen sponge clinical standard to chondroitin sulfate glycosaminoglycan (CS‐GAG) scaffolds as a delivery vehicle for recombinant human BMP‐2 (rhBMP‐2) and rhBMP‐2 expression via human BMP‐2 gene inserted into mesenchymal stem cells (BMP‐2 MSC). We demonstrated extended release of rhBMP‐2 from CS‐GAG scaffolds compared to their collagen sponge counterparts, and further extended release from CS‐GAG gels seeded with BMP‐2 MSC. When used to treat a challenging critically sized femoral defect model in rats, both rhBMP‐2 and BMP‐2 MSC in CS‐GAG induced comparable bone formation to the rhBMP‐2 in collagen sponge, as measured by bone volume, strength, and stiffness. We conclude that CS‐GAG scaffolds are a promising delivery vehicle for controlling the release of rhBMP‐2 and to mediate the repair of critically sized segmental bone defects. stem cells translational medicine2019;8:575–585
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Affiliation(s)
- Seth Andrews
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.,College of Engineering, University of Georgia, Athens, Georgia, USA
| | - Albert Cheng
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.,Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Hazel Stevens
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Meghan T Logun
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.,Biomedical Health Sciences Institute, University of Georgia, Athens, Georgia, USA
| | - Robin Webb
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA
| | - Erin Jordan
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA
| | - Boao Xia
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Lohitash Karumbaiah
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.,Department of ADS, College of Agriculture and Environmental Science, University of Georgia, Athens, Georgia, USA
| | - Robert E Guldberg
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.,Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Steven Stice
- Regenerative Bioscience Center, University of Georgia, Athens, Georgia, USA.,Department of ADS, College of Agriculture and Environmental Science, University of Georgia, Athens, Georgia, USA
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14
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Liu X, Ji C, Xu L, Yu T, Dong C, Luo J. Hmox1 promotes osteogenic differentiation at the expense of reduced adipogenic differentiation induced by BMP9 in C3H10T1/2 cells. J Cell Biochem 2018; 119:5503-5516. [PMID: 29377252 DOI: 10.1002/jcb.26714] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 01/24/2018] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into a variety of cell types under proper stimuli. Bone morphogenetic protein 9 (BMP9) is able to simultaneously induce both adipogenic and osteogenic differentiation of MSCs although the regulatory molecules involved remain to be fully identified and characterized. Heme oxygenase 1 (Hmox1) plays an essential role not only in fat metabolism, but also in bone development. In the present study, we investigated the functional role of Hmox1 in BMP9-induced osteogenic/adipogenic differentiation in MSCs line C3H10T1/2 and probed the possible mechanism involved. We found that BMP9 promoted the endogenous expression of Hmox1 in C3H10T1/2 cells. Overexpression of Hmox1 or cobalt protoporphyrin (CoPP), an inducer of Hmox1, increased BMP9-induced osteogenic differentiation in vitro. Subcutaneous stem cell implantation in nude mice further confirmed that Hmox1 potentiated BMP9-induced ectopic bone formation in vivo. In contrast, Hmox1 reduced BMP9-induced adipogenic differentiation in C3H10T1/2 cells. Although had no obvious effect on BMP9-induced Smad1/5/8 phosphorylation, Hmox1 enhanced phosphorylation of p38, and AKT, while decreased phosphorylation of ERK1/2. Furthermore, Hmox1 increased total β-catenin protein level, and promoted the nuclear translocation of β-catenin in C3H10T1/2 cells. Taken together, our study strongly suggests that Hmox1 is likely to potentiate osteogenic differentiation and yet decrease adipogenic differentiation induced by BMP9 possibly through regulation of multiple signaling pathways.
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Affiliation(s)
- Xiaohua Liu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
| | - Caixia Ji
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
| | - Li Xu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
| | - TingTing Yu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
| | - Chaoqun Dong
- Department of Orthorpedic, Children Hospital of Chongqing Medical University, Chongqing, P.R. China
| | - Jinyong Luo
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, P.R. China
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15
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Zhou W, Liu Q, Xu B. Improvement of bone defect healing in rats via mesenchymal stem cell supernatant. Exp Ther Med 2018; 15:1500-1504. [PMID: 29399126 PMCID: PMC5774528 DOI: 10.3892/etm.2017.5534] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 11/02/2017] [Indexed: 01/08/2023] Open
Abstract
The effects of mesenchymal stem cells (MSCs) from three different sources in the treatment of bone defect with stem cells, and the differences of curative effects were studied. The umbilical cord, adipose and bone marrow mesen-chymal stem cells (BMSCs) of Sprague-Dawley (SD) rats were isolated and extracted, and the phenotype was identified for the 4th generation. The SD rat model of bone defect was established. The rats were randomly divided into: Normal saline group, umbilical cord mesenchymal stem cell (UMSC) group, adipose mesenchymal stem cell (AMSC) group and BMSC group. Rats were treated with tail intravenous injection, followed by radiological examination. The relative expression levels of factors bone morphogenetic protein-2 (BMP-2), osteocalcin (OCN), alkaline phosphatase (ALP), sclerostin (SOST), collagen carboxy-terminal telopeptide (CTX) and tartrated resistant acid phosphatase (TRACP) were measured via fluorescence quantitative PCR and western blotting. Among the three different kinds of stem cell supernatant, the detection using bicinchoninic acid (BCA) method showed that the content of P4-generation new cytokines was the highest. Wound healing in the three stem cell supernatant groups was significant at 3 weeks after operation, which was faster than that in DF12 control group; the expression levels of BMP-2, OCN and ALP in the bone samples treated with three kinds of MSC supernatants after 5 weeks were significantly increased compared with those in control group. The expression levels of SOST, CTX and TRACP were significantly decreased compared with those in control group. Three kinds of MSC supernatants can promote the bone regeneration through promoting the secretion of relatively more osteoblast factors, and inhibit the bone loss. The concentration of cytokines in UMSC supernatant was the highest under the same culture condition, and BMSC supernatant has a better effect in improving the bone defect repair of rats under the same concentration of cytokines.
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Affiliation(s)
- Wanshan Zhou
- Department of Surgery, Dezhou People's Hospital, Dezhou, Shandong 253014, P.R. China
| | - Qian Liu
- Department of Orthopedics, Dezhou People's Hospital, Dezhou, Shandong 253014, P.R. China
| | - Bo Xu
- Department of Orthopedics, Dezhou People's Hospital, Dezhou, Shandong 253014, P.R. China
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16
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Bondarava M, Cattaneo C, Ren B, Thasler WE, Jansson V, Müller PE, Betz OB. Osseous differentiation of human fat tissue grafts: From tissue engineering to tissue differentiation. Sci Rep 2017; 7:39712. [PMID: 28054585 PMCID: PMC5213995 DOI: 10.1038/srep39712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 11/25/2016] [Indexed: 12/27/2022] Open
Abstract
Conventional bone tissue engineering approaches require isolation and in vitro propagation of autologous cells, followed by seeding on a variety of scaffolds. Those protracted procedures impede the clinical applications. Here we report the transdifferentiation of human fat tissue fragments retrieved from subcutaneous fat into tissue with bone characteristics in vitro without prior cell isolation and propagation. 3D collagen-I cultures of human fat tissue were cultivated either in growth medium or in osteogenic medium (OM) with or without addition of Bone Morphogenetic Proteins (BMPs) BMP-2, BMP-7 or BMP-9. Ca2+ depositions were observed after two weeks of osteogenic induction which visibly increased when either type of BMP was added. mRNA levels of alkaline phosphatase (ALP) and osteocalcin (OCN) increased when cultured in OM alone but addition of BMP-2, BMP-7 or BMP-9 caused significantly higher expression levels of ALP and OCN. Immunofluorescent staining for OCN, osteopontin and sclerostin supported the observed real-time-PCR data. BMP-9 was the most effective osteogenic inducer in this system. Our findings reveal that tissue regeneration can be remarkably simplified by omitting prior cell isolation and propagation, therefore removing significant obstacles on the way to clinical applications of much needed regeneration treatments.
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Affiliation(s)
- Maryna Bondarava
- University Hospital of Munich (LMU), Campus Grosshadern, Department of Orthopedic Surgery, Physical Medicine and Rehabilitation, Munich, DE, Germany
| | - Chiara Cattaneo
- University Hospital of Munich (LMU), Campus Grosshadern, Department of Orthopedic Surgery, Physical Medicine and Rehabilitation, Munich, DE, Germany
| | - Bin Ren
- University Hospital of Munich (LMU), Campus Grosshadern, Department of Orthopedic Surgery, Physical Medicine and Rehabilitation, Munich, DE, Germany
| | - Wolfgang E Thasler
- University Hospital of Munich (LMU), Biobank under the administration of the Human Tissue and Cell Research (HTCR) Foundation, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Munich, DE, Germany
| | - Volkmar Jansson
- University Hospital of Munich (LMU), Campus Grosshadern, Department of Orthopedic Surgery, Physical Medicine and Rehabilitation, Munich, DE, Germany
| | - Peter E Müller
- University Hospital of Munich (LMU), Campus Grosshadern, Department of Orthopedic Surgery, Physical Medicine and Rehabilitation, Munich, DE, Germany
| | - Oliver B Betz
- University Hospital of Munich (LMU), Campus Grosshadern, Department of Orthopedic Surgery, Physical Medicine and Rehabilitation, Munich, DE, Germany
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17
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Yan X, Kang D, Pan J, Jiang C, Lin Y, Qi S. Osteoblastic differentiation and cell calcification of adamantinomatous craniopharyngioma induced by bone morphogenetic protein-2. Cancer Biomark 2017; 18:191-198. [PMID: 27983534 DOI: 10.3233/cbm-161576] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The calcification of adamantinomatous craniopharyngioma (ACP) often creates difficulties for surgical therapy. Nevertheless, the mechanism of ACP calcification is unclear. Our previous studies demonstrated that osteoblastic factors might play important roles in ACP calcification. OBJECTIVE We examined the effects of recombinant human Bmp2 on ACP cell differentiation by testing osteoblastic proteins and calcium deposition. METHODS The expression of osteoblastic factors including osteopontin (OPN), Runx2, and osterix in Bmp2-treated ACP cells was examined by western blot and/or real time PCR. ALP activity and calcium deposition after Bmp2 induction were also tested. RESULTS Bmp2 significantly amplified the expression of Runx2, Osterix and OPN, as well as ALP activity. Both of these effects could be repressed by noggin treatment. Bmp2 also significantly induced the calcification of ACP, and noggin inhibited this calcium deposition. CONCLUSION Our study demonstrated for the first time that ACP cells could differentiate into an osteoblastic lineage via induction by Bmp2. The mechanism of ACP calcification likely involves osteoblastic differentiation modulated by Bmp2. Further studies targeting Bmp2 cascades could result in novel therapeutic interventions for recurrent ACP.
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Affiliation(s)
- Xiaorong Yan
- Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Dezhi Kang
- Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jun Pan
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Changzhen Jiang
- Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yuanxiang Lin
- Department of Neurosurgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Songtao Qi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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18
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Fazeli Z, Omrani MD, Ghaderian SMH. Down-regulation of nestin in mesenchymal stem cells derived from peripheral blood through blocking bone morphogenesis pathway. J Cell Commun Signal 2016; 10:273-282. [PMID: 27287702 PMCID: PMC5143318 DOI: 10.1007/s12079-016-0334-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 06/06/2016] [Indexed: 12/31/2022] Open
Abstract
Different signaling pathways are implicated in proliferation and differentiation of stem cells. Bone Morphogenesis Pathway (BMP) signaling was known to display an important function in osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs). In the present study, the authors investigated whether blocking BMP signaling was associated with down regulation of Nestin expression as neural stem cell marker in peripheral blood derived mesenchymal stem cells (PB-MSCs). At first, MSCs were isolated from peripheral blood by plastic adherent ability and flow cytometry analysis. After reaching the confluence, the cells were treated with medium containing Noggin as antagonist of BMP signaling upon 8 days. Real time PCR analysis indicated that the expression of Nestin was diminished in PB-MSCs by attenuating BMP signaling. The obtained results suggested that BMP signaling might have a regulatory function on the Nestin expression in mesenchymal stem cells.
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Affiliation(s)
- Zahra Fazeli
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mir Davood Omrani
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, No 23, Shahid Labbafi Nejad Educational Hospital, Amir Ebrahimi St, Pasdaran Ave, Tehran, Iran.
| | - Sayyed Mohammad Hossein Ghaderian
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, No 23, Shahid Labbafi Nejad Educational Hospital, Amir Ebrahimi St, Pasdaran Ave, Tehran, Iran.
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19
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Tollemar V, Collier ZJ, Mohammed MK, Lee MJ, Ameer GA, Reid RR. Stem cells, growth factors and scaffolds in craniofacial regenerative medicine. Genes Dis 2016; 3:56-71. [PMID: 27239485 PMCID: PMC4880030 DOI: 10.1016/j.gendis.2015.09.004] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 09/22/2015] [Indexed: 02/08/2023] Open
Abstract
Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging. Critical-sized defects are unable to heal via natural regenerative processes and require surgical intervention, traditionally involving autologous bone (mainly in the form of nonvascularized grafts) or alloplasts. Autologous bone grafts remain the gold standard of care in spite of the associated risk of donor site morbidity. Tissue engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal defects. This strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials, osteoblastic stem cells, as well as osteoinductive growth factors and small molecules. One of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone regeneration. These properties include osteoconduction, osetoinduction, biocompatibility, biodegradability, vascularization, and progenitor cell retention. This review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials.
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Affiliation(s)
- Viktor Tollemar
- The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
- Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Biology and Development, Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago Medicine, Chicago, IL 60637, USA
| | - Zach J. Collier
- The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
- Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Maryam K. Mohammed
- The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
- Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael J. Lee
- Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Guillermo A. Ameer
- Department of Surgery, Feinberg School of Medicine, Chicago, IL 60611, USA
- Biomedical Engineering Department, Northwestern University, Evanston, IL 60208, USA
| | - Russell R. Reid
- Laboratory of Craniofacial Biology and Development, Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago Medicine, Chicago, IL 60637, USA
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20
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Scarfì S. Use of bone morphogenetic proteins in mesenchymal stem cell stimulation of cartilage and bone repair. World J Stem Cells 2016; 8:1-12. [PMID: 26839636 PMCID: PMC4723717 DOI: 10.4252/wjsc.v8.i1.1] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 12/04/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
The extracellular matrix-associated bone morphogenetic proteins (BMPs) govern a plethora of biological processes. The BMPs are members of the transforming growth factor-β protein superfamily, and they actively participate to kidney development, digit and limb formation, angiogenesis, tissue fibrosis and tumor development. Since their discovery, they have attracted attention for their fascinating perspectives in the regenerative medicine and tissue engineering fields. BMPs have been employed in many preclinical and clinical studies exploring their chondrogenic or osteoinductive potential in several animal model defects and in human diseases. During years of research in particular two BMPs, BMP2 and BMP7 have gained the podium for their use in the treatment of various cartilage and bone defects. In particular they have been recently approved for employment in non-union fractures as adjunct therapies. On the other hand, thanks to their potentialities in biomedical applications, there is a growing interest in studying the biology of mesenchymal stem cell (MSC), the rules underneath their differentiation abilities, and to test their true abilities in tissue engineering. In fact, the specific differentiation of MSCs into targeted cell-type lineages for transplantation is a primary goal of the regenerative medicine. This review provides an overview on the current knowledge of BMP roles and signaling in MSC biology and differentiation capacities. In particular the article focuses on the potential clinical use of BMPs and MSCs concomitantly, in cartilage and bone tissue repair.
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Affiliation(s)
- Sonia Scarfì
- Sonia Scarfì, Department of Earth, Environment and Life Sciences, University of Genova, 16132 Genova, Italy
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21
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Chen MH, Chen HA, Chen WS, Chen MH, Tsai CY, Chou CT. Upregulation of BMP-2 expression in peripheral blood mononuclear cells by proinflammatory cytokines and radiographic progression in ankylosing spondylitis. Mod Rheumatol 2015; 25:913-8. [PMID: 25835314 DOI: 10.3109/14397595.2015.1029221] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVES To investigate the effect of inflammation on expressions of bone morphogenetic proteins (BMPs) in peripheral blood mononuclear cells (PBMCs) and its association with individual radiographic changes in patients with ankylosing spondylitis (AS). METHODS The changes in BMP-2, -4, and -7 gene expressions in PBMCs were measured after stimulation by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The correlation of increase in gene expression with clinical and radiographic findings in patients with AS were analyzed. RESULTS Both TNF-α and IL-1β could enhance BMP-2 expression in PBMCs from AS patients. Increases in BMP-2, -4, and -7 expressions in PBMCs positively correlated with total modified Stoke Ankylosing Spondylitis Spinal Score (all p < 0.05). Moreover, increases in BMP-2, -4, and -7 gene expressions after TNF-α and IL-1β stimulation were greater among AS patients with versus without severe sacroiliitis (all p < 0.05). Increases in BMP-2 and -7 expressions were greater in PBMCs from 4 patients with total (cervical, thoracic, and lumbar) spinal ankylosis than in the 8 patients who did not have total spinal ankylosis (all p < 0.05). CONCLUSIONS In AS, inflammation upregulates the expression of BMPs in PBMCs which may lead to the radiographic progression with new bone formation.
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Affiliation(s)
- Ming-Han Chen
- a Department of Medicine , National Yang-Ming University , Taipei , Taiwan.,b Division of Allergy, Immunology and Rheumatology, Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Hung-An Chen
- c Division of Allergy-Immunology-Rheumatology, Department of Medicine , Chi Mei Medical Center , Tainan , Taiwan
| | - Wei-Sheng Chen
- a Department of Medicine , National Yang-Ming University , Taipei , Taiwan.,b Division of Allergy, Immunology and Rheumatology, Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Ming-Huang Chen
- a Department of Medicine , National Yang-Ming University , Taipei , Taiwan
| | - Chang-Youh Tsai
- a Department of Medicine , National Yang-Ming University , Taipei , Taiwan.,b Division of Allergy, Immunology and Rheumatology, Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan
| | - Chung-Tei Chou
- a Department of Medicine , National Yang-Ming University , Taipei , Taiwan.,b Division of Allergy, Immunology and Rheumatology, Department of Medicine , Taipei Veterans General Hospital , Taipei , Taiwan
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22
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Roux BM, Cheng MH, Brey EM. Engineering clinically relevant volumes of vascularized bone. J Cell Mol Med 2015; 19:903-14. [PMID: 25877690 PMCID: PMC4420594 DOI: 10.1111/jcmm.12569] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 01/29/2015] [Indexed: 12/15/2022] Open
Abstract
Vascularization remains one of the most important challenges that must be overcome for tissue engineering to be consistently implemented for reconstruction of large volume bone defects. An extensive vascular network is needed for transport of nutrients, waste and progenitor cells required for remodelling and repair. A variety of tissue engineering strategies have been investigated in an attempt to vascularize tissues, including those applying cells, soluble factor delivery strategies, novel design and optimization of bio-active materials, vascular assembly pre-implantation and surgical techniques. However, many of these strategies face substantial barriers that must be overcome prior to their ultimate translation into clinical application. In this review recent progress in engineering vascularized bone will be presented with an emphasis on clinical feasibility.
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Affiliation(s)
- Brianna M Roux
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA; Research Service, Edward Hines Jr. V.A. Hospital, Hines, IL, USA
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23
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Nguyen A, Scott MA, Dry SM, James AW. Roles of bone morphogenetic protein signaling in osteosarcoma. INTERNATIONAL ORTHOPAEDICS 2014; 38:2313-22. [PMID: 25209345 DOI: 10.1007/s00264-014-2512-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 08/14/2014] [Indexed: 02/07/2023]
Abstract
PURPOSE Since the original extraction of bone morphogenetic proteins (BMPs) from bovine bone, research interest and clinical use has increased exponentially. With this, a concomitant analysis of BMP expression in bone tumours has been performed. BMP ligands, receptors, and signaling activity have been observed in diverse benign and malignant bone tumours. However, the reported expression, function, and importance of BMPs in bone tumours, and specifically osteosarcomas, have been far from uniform. This review highlights recent advances in understanding the role of BMP signaling in osteosarcoma biology, focusing on the sometimes divergent findings by various researchers and the challenges inherent in the study of osteosarcoma. METHODS We performed a literature review of all studies examining BMP signaling in osteosarcoma. RESULTS Overall, multiple BMP ligands and receptors are expressed in most osteosarcoma cell lines and subtypes, although BMP signaling may be reduced in comparison with benign bone-forming tumours. Studies suggest that osteosarcomas with different lineages of differentiation may have differential expression of BMP ligands. Although significant disagreement in the literature exists, the presence of BMP signaling in osteosarcoma may impart a worse prognosis. On the cellular level, BMP signaling appears to mediate promigratory effects in osteosarcoma and chondrosarcoma cell types, possibly via interaction and activation of Integrin β1. CONCLUSIONS BMP signaling has clear biologic importance in osteosarcoma, although it is not yet fully understood. Future questions for study include assessing the utility of BMP signaling in prognostication of osteosarcoma and the potential modulation of BMP signaling for inhibition of osteosarcomagenesis, growth and invasion.
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Affiliation(s)
- Alan Nguyen
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, 10833 Le Conte Ave, CHS A3-251, Los Angeles, CA, 90077, USA
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24
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Song-Tao Q, Xiao-Rong Y, Jun P, Yong-Jian D, Jin L, Guang-Long H, Yun-Tao L, Jian R, Xiang-Zhao L, Jia-Ming X. Does the calcification of adamantinomatous craniopharyngioma resemble the calcium deposition of osteogenesis/odontogenesis? Histopathology 2014; 64:336-47. [PMID: 24387671 DOI: 10.1111/his.12071] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 11/23/2012] [Indexed: 11/30/2022]
Abstract
AIMS Calcification in adamantinomatous craniopharyngioma (ACP) is troublesome for surgical intervention. The aim of this study was to examine the osteogenic proteins that play important roles in the calcium deposition of the odontogenic/osteogenic tissues in craniopharyngioma. METHODS AND RESULTS Craniopharyngiomas (n = 89) were investigated for the presence and expression pattern of the osteoinductive/odontoinductive factor bone morphogenetic protein-2 (Bmp2) and two osteoblastic differentiation makers, Runt-related transcription factor-2 (Runx2) and Osterix, using immunohistochemistry and Western blotting. Our results showed that Bmp2, Runx2 and Osterix levels increased in cases with high calcification and correlated positively with the degree of calcification in ACP, whereas they showed little or no expression in squamous papillary craniopharyngioma. In ACP, Bmp2 was expressed primarily in the stellate reticulum and whorl-like array cells; Runx2 and Osterix tended to be expressed in calcification-related epithelia, including whorl-like array cells and epithelia in/around wet keratin and calcification lesions. CONCLUSIONS Our study indicated, for the first time, that osteogenic factor Bmp2 may play an important role in the calcification of ACP via autocrine or paracrine mechanisms. Given the presence of osteogenic markers (Runx2 and Osterix), craniopharyngioma cells could differentiate into an osteoblast-like lineage, and the process of craniopharyngioma calcification resembles that which occurs in osteogenesis/odontogenesis.
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Affiliation(s)
- Qi Song-Tao
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guang Zhou, China
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Spinal fusion in the next generation: gene and cell therapy approaches. ScientificWorldJournal 2014; 2014:406159. [PMID: 24672316 PMCID: PMC3927763 DOI: 10.1155/2014/406159] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 10/28/2013] [Indexed: 12/24/2022] Open
Abstract
Bone fusion represents a challenge in the orthopedics practice, being especially indicated for spine disorders. Spinal fusion can be defined as the bony union between two vertebral bodies obtained through the surgical introduction of an osteoconductive, osteoinductive, and osteogenic compound. Autogenous bone graft provides all these three qualities and is considered the gold standard. However, a high morbidity is associated with the harvest procedure. Intensive research efforts have been spent during the last decades to develop new approaches and technologies for successful spine fusion. In recent years, cell and gene therapies have attracted great interest from the scientific community. The improved knowledge of both mesenchymal stem cell biology and osteogenic molecules allowed their use in regenerative medicine, representing attractive approaches to achieve bone regeneration also in spinal surgery applications. In this review we aim to describe the developing gene- and cell-based bone regenerative approaches as promising future trends in spine fusion.
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Wei L, Lei GH, Yi HW, Sheng PY. Bone formation in rabbit's leg muscle after autologous transplantation of bone marrow-derived mesenchymal stem cells expressing human bone morphogenic protein-2. Indian J Orthop 2014; 48:347-53. [PMID: 25143636 PMCID: PMC4137510 DOI: 10.4103/0019-5413.136208] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND To test whether autologous transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) expressing human bone morphogenic protein-2 (hBMP-2) can produce bone in rabbit leg muscles. MATERIALS AND METHODS MSCs were isolated from BM of the iliac crest of rabbits and then infected with lentiviral vectors (LVs) bearing hBMP-2 and green fluorescent protein under the control of the cytomegalovirus (immediate early promoter). Differentiation of transduced MSCs to osteoblasts in vitro was evaluated with an alkaline phosphatase activity assay and immuohistochemistry against osteoblast specific markers. MSCs expressing hBMP-2 were placed in an absorbable gelatin sponge, which was then transplanted into the gastrocnemius of rabbits from which MSCs were isolated. Bone formation was examined by X-ray and histological analysis. RESULTS LVs efficiently mediated hBMP-2 gene expression in rabbit BM-MSCs. Ectopic expression of hBMP in these MSCs induced osteoblastic differentiation in vitro. Bone was formed after the MSCs expressing hBMP-2 were transplanted into rabbit muscles. CONCLUSION Ectopic expression of hBMP-2 in rabbit MSCs induces them to differentiate into osteoblasts in vitro and to form a bone in vivo.
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Affiliation(s)
- Licheng Wei
- Department of Orthopaedics, The 8th Hospital, Changsha, Hunan 410008, China,Address for correspondence: Dr. Licheng Wei, Department of Orthopaedics, The 8th Hospital, Changsha, No. 22, Xin Sha Road, Changsha, Hunan 410008, China. E-mail:
| | - Guang-Hua Lei
- Department of Orthopaedics, XiangYa Hospital, Central South University, 87 XiangYa Road, Changsha, Hunan 410008, China
| | - Han-Wen Yi
- Department of Orthopaedics, The 8th Hospital, Changsha, Hunan 410008, China
| | - Pu-yi Sheng
- Department of Orthopaedics, The First Affilliated Hospital, Sun YAT-SEN University, 58 The Second ZhongShan Road, GuangZhou, GuangDong 510080, China
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Lee KL, Hoey DA, Spasic M, Tang T, Hammond HK, Jacobs CR. Adenylyl cyclase 6 mediates loading-induced bone adaptation in vivo. FASEB J 2013; 28:1157-65. [PMID: 24277577 DOI: 10.1096/fj.13-240432] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Primary cilia are single, nonmotile, antenna-like structures extending from the apical membrane of most mammalian cells. They may mediate mechanotransduction, the conversion of external mechanical stimuli into biochemical intracellular signals. Previously we demonstrated that adenylyl cyclase 6 (AC6), a membrane-bound enzyme enriched in primary cilia of MLO-Y4 osteocyte-like cells, may play a role in a primary cilium-dependent mechanism of osteocyte mechanotransduction in vitro. In this study, we determined whether AC6 deletion impairs loading-induced bone formation in vivo. Skeletally mature mice with a global knockout of AC6 exhibited normal bone morphology and responded to osteogenic chemical stimuli similar to wild-type mice. Following ulnar loading over 3 consecutive days, bone formation parameters were assessed using dynamic histomorphometry. Mice lacking AC6 formed significantly less bone than control animals (41% lower bone formation rate). Furthermore, there was an attenuated flow-induced increase in COX-2 mRNA expression levels in primary bone cells isolated from AC6 knockout mice compared to controls (1.3±0.1- vs. 2.6±0.2-fold increase). Collectively, these data indicate that AC6 plays a role in loading-induced bone adaptation, and these findings are consistent with our previous studies implicating primary cilia and AC6 in a novel mechanism of osteocyte mechanotransduction.
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Affiliation(s)
- Kristen L Lee
- 1Columbia University, 351 Engineering Terr., 1210 Amsterdam Ave., Mail Code 8904, New York, NY 10027, USA.
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Beederman M, Lamplot JD, Nan G, Wang J, Liu X, Yin L, Li R, Shui W, Zhang H, Kim SH, Zhang W, Zhang J, Kong Y, Denduluri S, Rogers MR, Pratt A, Haydon RC, Luu HH, Angeles J, Shi LL, He TC. BMP signaling in mesenchymal stem cell differentiation and bone formation. JOURNAL OF BIOMEDICAL SCIENCE AND ENGINEERING 2013; 6:32-52. [PMID: 26819651 PMCID: PMC4725591 DOI: 10.4236/jbise.2013.68a1004] [Citation(s) in RCA: 225] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily and have diverse functions during development and organogenesis. BMPs play a major role in skeletal development and bone formation, and disruptions in BMP signaling cause a variety of skeletal and extraskeletal anomalies. Several knockout models have provided insight into the mechanisms responsible for these phenotypes. Proper bone formation requires the differentiation of osteoblasts from mesenchymal stem cell (MSC) precursors, a process mediated in part by BMP signaling. Multiple BMPs, including BMP2, BMP6, BMP7 and BMP9, promote osteoblastic differentiation of MSCs both in vitro and in vivo. BMP9 is one of the most osteogenic BMPs yet is a poorly characterized member of the BMP family. Several studies demonstrate that the mechanisms controlling BMP9-mediated osteogenesis differ from other osteogenic BMPs, but little is known about these specific mechanisms. Several pathways critical to BMP9-mediated osteogenesis are also important in the differentiation of other cell lineages, including adipocytes and chondrocytes. BMP9 has also demonstrated translational promise in spinal fusion and bone fracture repair. This review will summarize our current knowledge of BMP-mediated osteogenesis, with a focus on BMP9, by presenting recently completed work which may help us to further elucidate these pathways.
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Affiliation(s)
- Maureen Beederman
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Joseph D Lamplot
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Guoxin Nan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; Stem Cell Biology and Therapy Laboratory of the Key Laboratory for Pediatrics Co-Designated by Chinese Ministry of Education, The Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jinhua Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xing Liu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; Stem Cell Biology and Therapy Laboratory of the Key Laboratory for Pediatrics Co-Designated by Chinese Ministry of Education, The Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Liangjun Yin
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ruidong Li
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Wei Shui
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hongyu Zhang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Stephanie H Kim
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Wenwen Zhang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Jiye Zhang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yuhan Kong
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Sahitya Denduluri
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Mary Rose Rogers
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Abdullah Pratt
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Rex C Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Hue H Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Jovito Angeles
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Lewis L Shi
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery, The University of Chicago Medical Center, Chicago, USA; Stem Cell Biology and Therapy Laboratory of the Key Laboratory for Pediatrics Co-Designated by Chinese Ministry of Education, The Children's Hospital of Chongqing Medical University, Chongqing, China; The Affiliated Hospitals and the Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
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James AW. Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation. SCIENTIFICA 2013; 2013:684736. [PMID: 24416618 PMCID: PMC3874981 DOI: 10.1155/2013/684736] [Citation(s) in RCA: 325] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 11/21/2013] [Indexed: 05/07/2023]
Abstract
Mesenchymal stem cells (MSC) are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor- γ (PPAR γ ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPAR γ and Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These include β -catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP) signaling and insulin growth factor (IGF) signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.
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Affiliation(s)
- Aaron W. James
- Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS A3-251, Los Angeles, CA 90077, USA
- *Aaron W. James:
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Umehara K, Iimura T, Sakamoto K, Lin Z, Kasugai S, Igarashi Y, Yamaguchi A. Canine oral mucosal fibroblasts differentiate into osteoblastic cells in response to BMP-2. Anat Rec (Hoboken) 2012; 295:1327-35. [PMID: 22678770 DOI: 10.1002/ar.22510] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 01/23/2012] [Indexed: 01/09/2023]
Abstract
Several lines of evidence show that transplantation of osteoblastic cells or genetically engineered nonosteogenic cells expressing osteoblast-related genes into bone defects effectively promotes bone regeneration. To extend this possibility, we investigated whether oral mucosal fibroblasts are capable of differentiating into osteoblastic cells by conducting in vitro and in vivo experiments. We investigated the effects of bone morphogenetic protein-2 (BMP-2) on osteoblast differentiation of cultured fibroblasts isolated from canine buccal mucosa. We also transplanted green fluorescence protein (GFP)-expressing fibroblasts with gelatin/BMP-2 complexes into the subfascial regions of athymic mice, and investigated the localization of GFP-positive cells in the ectopically formed bones. The cultured canine buccal mucosal fibroblasts differentiated into osteoblastic cells by increasing their alkaline phosphatase (ALP) activity and Osteocalcin, Runx2, and Osterix mRNA expression levels in response to BMP-2. Transplantation experiments of GFP-expressing oral mucosal fibroblasts with gelatin/BMP-2 complexes revealed that 17.1% of the GFP-positive fibroblasts differentiated into ALP-positive cells, and these cells accounted for 6.2% of total ALP-positive cells in the ectopically formed bone. This study suggests that oral mucosal fibroblasts can differentiate into osteogenic cells in response to BMP-2. Thus, these cells are potential candidates for cell-mediated bone regeneration therapy in dentistry.
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Affiliation(s)
- Kohsuke Umehara
- Section of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
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31
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Ramseier CA, Rasperini G, Batia S, Giannobile WV. Advanced reconstructive technologies for periodontal tissue repair. Periodontol 2000 2012; 59:185-202. [PMID: 22507066 PMCID: PMC3335769 DOI: 10.1111/j.1600-0757.2011.00432.x] [Citation(s) in RCA: 120] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Reconstructive therapies to promote the regeneration of lost periodontal support have been investigated through both preclinical and clinical studies. Advanced regenerative technologies using new barrier-membrane techniques, cell-growth-stimulating proteins or gene-delivery applications have entered the clinical arena. Wound-healing approaches using growth factors to target the restoration of tooth-supporting bone, periodontal ligament and cementum are shown to significantly advance the field of periodontal-regenerative medicine. Topical delivery of growth factors, such as platelet-derived growth factor, fibroblast growth factor or bone morphogenetic proteins, to periodontal wounds has demonstrated promising results. Future directions in the delivery of growth factors or other signaling models involve the development of innovative scaffolding matrices, cell therapy and gene transfer, and these issues are discussed in this paper.
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Affiliation(s)
- Christoph A. Ramseier
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Giulio Rasperini
- Unit of Periodontology, department of Surgical, Regenerative and Diagnostic Science, Foundation IRCCS Cà Granda Policlinico, University of Milan, Milan Italy
| | - Salvatore Batia
- Unit of Periodontology, department of Surgical, Regenerative and Diagnostic Science, Foundation IRCCS Cà Granda Policlinico, University of Milan, Milan Italy
| | - William V. Giannobile
- Deptartment of Periodontics and Oral Medicine and Michigan Center for Oral Health Research, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078, USA
- Department of Biomedical Engineering, College of Engineering, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078, USA
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32
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Yun YR, Jang JH, Jeon E, Kang W, Lee S, Won JE, Kim HW, Wall I. Administration of growth factors for bone regeneration. Regen Med 2012; 7:369-85. [DOI: 10.2217/rme.12.1] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Growth factors (GFs) such as BMPs, FGFs, VEGFs and IGFs have significant impacts on osteoblast behavior, and thus have been widely utilized for bone tissue regeneration. Recently, securing biological stability for a sustainable and controllable release to the target tissue has been a challenge to practical applications. This challenge has been addressed to some degree with the development of appropriate carrier materials and delivery systems. This review highlights the importance and roles of those GFs, as well as their proper administration for targeting bone regeneration. Additionally, the in vitro and in vivo performance of those GFs with or without the use of carrier systems in the repair and regeneration of bone tissue is systematically addressed. Moreover, some recent advances in the utility of the GFs, such as using fusion technology, are also reviewed.
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Affiliation(s)
- Ye-Rang Yun
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, Korea
| | - Jun Hyeog Jang
- Department of Biochemistry, Inha University School of Medicine, Incheon 400-712, Korea
| | - Eunyi Jeon
- Department of Biochemistry, Inha University School of Medicine, Incheon 400-712, Korea
| | - Wonmo Kang
- Department of Biochemistry, Inha University School of Medicine, Incheon 400-712, Korea
| | - Sujin Lee
- Department of Biochemistry, Inha University School of Medicine, Incheon 400-712, Korea
| | - Jong-Eun Won
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 330-714, Korea
- Department of Nanobiomedical Science & WCU Research Center, Dankook University Graduate School, Cheonan 330-714, Korea
| | - Hae Won Kim
- Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan 330-714, Korea
| | - Ivan Wall
- Department of Nanobiomedical Science & WCU Research Center, Dankook University Graduate School, Cheonan 330-714, Korea
- Department of Biochemical Engineering, University College London, Torrington Place, London WC1E 7JE, UK
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Li Y, Lu Y, Maciejewska I, Galler KM, Cavender A, D'Souza RN. TWIST1 promotes the odontoblast-like differentiation of dental stem cells. Adv Dent Res 2011; 23:280-4. [PMID: 21677079 DOI: 10.1177/0022034511405387] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Stem cells derived from the dental pulp of extracted human third molars (DPSCs) have the potential to differentiate into odontoblasts, osteoblasts, adipocytes, and neural cells when provided with the appropriate conditions. To advance the use of DPSCs for dentin regeneration, it is important to replicate the permissive signals that drive terminal events in odontoblast differentiation during tooth development. Such a strategy is likely to restore a dentin matrix that more resembles the tubular nature of primary dentin. Due to the limitations of culture conditions, the use of ex vivo gene therapy to drive the terminal differentiation of mineralizing cells holds considerable promise. In these studies, we asked whether the forced expression of TWIST1 in DPSCs could alter the potential of these cells to differentiate into odontoblast-like cells. Since the partnership between Runx2 and Twist1 proteins is known to control the onset of osteoblast terminal differentiation, we hypothesized that these genes act to control lineage determination of DPSCs. For the first time, our results showed that Twist1 overexpression in DPSCs enhanced the expression of DSPP, a gene that marks odontoblast terminal differentiation. Furthermore, co-transfection assays showed that Twist1 stimulates Dspp promoter activity by antagonizing Runx2 function in 293FT cells. Analysis of our in vitro data, taken together, suggests that lineage specification of DPSCs can be modulated through ex vivo gene modifications.
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Affiliation(s)
- Y Li
- Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, 75246, USA
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Xia L, Xu Y, Chang Q, Sun X, Zeng D, Zhang W, Zhang X, Zhang Z, Jiang X. Maxillary sinus floor elevation using BMP-2 and Nell-1 gene-modified bone marrow stromal cells and TCP in rabbits. Calcif Tissue Int 2011; 89:53-64. [PMID: 21584647 DOI: 10.1007/s00223-011-9493-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Accepted: 04/19/2011] [Indexed: 12/24/2022]
Abstract
This study evaluated the synergistic osteogenic effect of bone morphogenetic protein-2 (BMP-2) and Nel-like molecule-1 (Nell-1) genes in a rabbit maxillary sinus floor elevation model. Bone marrow stromal cells (bMSCs) were cultured and transduced with AdEGFP, AdNell-1, AdBMP-2, or AdNell-1 + AdBMP-2 overexpression virus. These gene-modified autologous bMSCs were then combined with a β-tricalcium phosphate (β-TCP) granule scaffold and used to elevate the maxillary sinus floor in rabbits. bMSCs cotransduced with AdNell-1 + AdBMP-2 demonstrated a synergistic effect on osteogenic differentiation as detected by real-time PCR analysis on markers of runt-related transcription factor-2, osteocalcin, collagen type 1, alkaline phosphatase activity, and calcium deposits in vitro. As for maxillary sinus floor elevation in a rabbit model in vivo, AdNell-1 + AdBMP-2 gene-transduced autologeous bMSCs/β-TCP complex had the largest bone area and most mature bone structure among the groups, as detected by HE staining and immunohistochemistry at weeks 2 and 8 after implantation. Our data suggested that the BMP-2 and Nell-1 genes possessed a synergistic effect on osteogenic differentiation of bMSCs, while bMSCs modified with the BMP-2 and Nell-1 genes could promote new bone formation and maturation in the rabbit maxillary sinus model.
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Affiliation(s)
- Lunguo Xia
- Department of Oral and Maxillofacial Surgery, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China
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Uemura T, Kojima H. Bone formation in vivo induced by Cbfa1-carrying adenoviral vectors released from a biodegradable porous β-tricalcium phosphate (β-TCP) material. SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS 2011; 12:034405. [PMID: 27877396 PMCID: PMC5090468 DOI: 10.1088/1468-6996/12/3/034405] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2010] [Revised: 05/03/2011] [Accepted: 03/25/2011] [Indexed: 06/06/2023]
Abstract
Overexpression of Cbfa1 (a transcription factor indispensable for osteoblastic differentiation) is expected to induce the formation of bone directly and indirectly in vivo by accelerating osteoblastic differentiation. Adenoviral vectors carrying the cDNA of Cbfa1/til-1(Adv-Cbf1) were allowed to be adsorbed onto porous blocks of β-tricalcium phosphate (β-TCP), a biodegradable ceramic, which were then implanted subcutaneously and orthotopically into bone defects. The adenoviral vectors were released sustainingly by biodegradation, providing long-term expression of the genes. Results of the subcutaneous implantation of Adv-Cbfa1-adsorbed β-TCP/osteoprogenitor cells suggest that a larger amount of bone formed in the pores of the implant than in the control material. Regarding orthotopic implantation into bone defects, the released Adv-Cbfa1 accelerated regeneration in the cortical bone, whereas it induced bone resorption in the marrow cavity. A safer gene transfer using a smaller amount of the vector was achieved using biodegradable porous β-TCP as a carrier.
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Affiliation(s)
- Toshimasa Uemura
- Nanosystem Research Institute (NRI), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba Central-4, Tsukuba, Ibaraki 305-8562, Japan
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Shah P, Keppler L, Rutkowski J. Bone morphogenic protein: an elixir for bone grafting--a review. J ORAL IMPLANTOL 2011; 38:767-78. [PMID: 21574851 DOI: 10.1563/aaid-joi-d-10-00196] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor beta superfamily. This literature review focuses on the molecular biology of BMPs, their mechanism of action, and subsequent applications. It also discusses uses of BMPs in the fields of dentistry and orthopedics, research on methods of delivering BMPs, and their role in tissue regeneration. BMP has positive effects on bone grafts, and their calculated and timely use with other growth factors can provide extraordinary results in fractured or nonhealing bones. Use of BMP introduces new applications in the field of implantology and bone grafting. This review touches on a few unknown facts about BMP and this ever-changing field of research to improve human life.
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Affiliation(s)
- Prasun Shah
- St Vincent Charity Hospital, Cleveland, OH, USA.
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Endogenous BMPR-IB signaling is required for early osteoblast differentiation of human bone cells. In Vitro Cell Dev Biol Anim 2010; 47:251-9. [DOI: 10.1007/s11626-010-9378-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Accepted: 11/19/2010] [Indexed: 01/01/2023]
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38
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Han D, Li J, Guan X. Ectopic osteogenesis of hBMP-2 gene-transduced human bone mesenchymal stem cells/BCB. Connect Tissue Res 2010; 51:274-81. [PMID: 20175710 DOI: 10.3109/03008200903318295] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We determined the feasibility of using scaffolds of adenoviral human BMP2 gene (AdBMP2)-modified human bone marrow mesenchymal stem cells (hBMSCs) and antigen-free bovine cancellous bone (BCB) to construct bone tissue. hMSCs were infected with AdBMP-2. Expression of BMP-2 and alkaline phosphatase confirmed successful secretion of active BMP-2. The osteogenic capability of a composite of AdBMP2-modified hMSCs with BCB was evaluated in athymic mice (group A). BCB (group B), hMSCs/BCB (group C), adenoviral beta-galactosidase genes (Adbetagal)-transfected hMSCs/BCB (group D) were controls. Formation of bone tissue was assessed by histological methods 4 weeks and 8 weeks after implantation. Implanted cells were identified by human Y-chromosome-specific fluorescence in-situ hybridization (FISH). hMSCs differentiated into osteogenic cells, and bone formation was observed. Obvious bone formation was not noted at any time point in control groups. We hypothesize that the described method is a promising method for bone regeneration.
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Affiliation(s)
- Dong Han
- Department of Plastic & Reconstructive Surgery, Ninth People's Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, China
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Shakhbazau AV, Kosmacheva SM, Kartel’ NA, Potapnev MP. Gene therapy based on human mesenchymal stem cells: Strategies and methods. CYTOL GENET+ 2010. [DOI: 10.3103/s0095452710010111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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40
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Intini G. Future approaches in periodontal regeneration: gene therapy, stem cells, and RNA interference. Dent Clin North Am 2010; 54:141-55. [PMID: 20103477 DOI: 10.1016/j.cden.2009.09.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Periodontal disease is a major public health issue and the development of effective therapies to treat the disease and regenerate periodontal tissue is an important goal of today's medicine. This article highlights recent scientific advancements in gene therapy, stem cell biology, and RNA interference with the intent of identifying their potential in periodontal tissue regeneration. Results from basic research, preclinical, and clinical studies indicate that these fields of research may soon contribute to more effective regenerative therapies for periodontal disease.
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Affiliation(s)
- Giuseppe Intini
- Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, REB 513, Boston, MA 02115, USA.
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41
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Cucchiarini M, Heiligenstein S, Kohn D, Madry H. [Molecular tools to remodel osteoarthritic articular cartilage : growth, transcription, and signaling factors]. DER ORTHOPADE 2009; 38:1063-70. [PMID: 19876615 DOI: 10.1007/s00132-009-1495-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Osteoarthritis (OA) is a chronic disorder of the diarthrodial joints, mostly characterized by gradual deterioration of the articular cartilage. This disease still has no effective treatment. An emerging strategy for treating OA is based on molecular concepts using growth factors, transcription factors, and signaling molecules in light of their effects on the restoration of cartilage integrity. Recent studies have demonstrated that overexpression of such candidate molecules using direct gene transfer or ex vivo protocols is capable of stimulating cell proliferation and matrix synthesis in normal human and OA cartilage explants in vitro as well as in animal models in vivo. As a result, the structure of the articular cartilage can be improved. More insights into the pathophysiology of human OA and further studies in animal models are needed, however, to facilitate clinical translation of these molecular approaches. In conclusion, recent experimental findings permit cautious optimism, holding promise for treating human OA in the future.
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Affiliation(s)
- M Cucchiarini
- Labor für Experimentelle Orthopädie, Klinik für Orthopädie und Orthopädische Chirurgie, Universitätsklinikum des Saarlandes, Kirrbergerstrasse 37, 66421, Homburg/Saar, Deutschland.
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42
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Seo HS, Jung JK, Lim MH, Hyun DK, Oh NS, Yoon SH. Evaluation of Spinal Fusion Using Bone Marrow Derived Mesenchymal Stem Cells with or without Fibroblast Growth Factor-4. J Korean Neurosurg Soc 2009; 46:397-402. [PMID: 19893733 DOI: 10.3340/jkns.2009.46.4.397] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2009] [Revised: 06/24/2009] [Accepted: 10/15/2009] [Indexed: 01/27/2023] Open
Abstract
OBJECTIVE In this study, the authors assessed the ability of rat bone marrow derived mesenchymal stem cells (BMDMSCs), in the presence of a growth factor, fibroblast growth factor-4 (FGF-4) and hydroxyapatite, to act as a scaffold for posterolateral spinal fusion in a rat model. METHODS Using a rat posterolateral spine fusion model, the experimental study comprised 3 groups. Group 1 was composed of 6 animals that were implanted with 0.08 gram hydroxyapatite only. Group 2 was composed of 6 animals that were implanted with 0.08 gram hydroxyapatite containing 1 x 10(6)/ 60 microL rat of BMDMSCs. Group 3 was composed of 6 animals that were implanted with 0.08 gram hydroxyapatite containing 1 x 10(6)/ 60 microL of rat BMDMSCs and FGF-4 1 microG to induce the bony differentiation of the BMDMSCs. Rats were assessed using radiographs obtained at 4, 6, and 8 weeks postoperatively. After sacrifice, spines were explanted and assessed by manual palpation, high-resolution microcomputerized tomography, and histological analysis. RESULTS Radiographic, high-resolution microcomputerized tomographic, and manual palpation revealed spinal fusion in five rats (83%) in Group 2 at 8 weeks. However, in Group 1, three (60%) rats developed fusion at L4-L5 by radiography and two (40%) by manual palpation in radiographic examination. In addition, in Group 3, bone fusion was observed in only 50% of rats by manual palpation and radiographic examination at this time. CONCLUSION The present study demonstrates that 0.08 gram of hydroxyapatite with 1 x 10(6)/ 60 microL rat of BMDMSCs induced bone fusion. FGF-4, added to differentiate primitive 1 x 10(6)/ 60 microL rat of BMDMSCs did not induce fusion. Based on histologic data, FGF-4 appears to induce fibrotic change rather than differentiation to bone by 1 x 10(6)/ 60 microL rat of BMDMSCs.
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Affiliation(s)
- Hyun Sung Seo
- Department of Neurosurgery, School of Medicine, Inha University, Incheon, Korea
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43
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Steinhardt Y, Aslan H, Regev E, Zilberman Y, Kallai I, Gazit D, Gazit Z. Maxillofacial-derived stem cells regenerate critical mandibular bone defect. Tissue Eng Part A 2009; 14:1763-73. [PMID: 18636943 DOI: 10.1089/ten.tea.2008.0007] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Stem cell-based bone tissue regeneration in the maxillofacial complex is a clinical necessity. Genetic engineering of mesenchymal stem cells (MSCs) to follow specific differentiation pathways may enhance the ability of these cells to regenerate and increase their clinical relevance. MSCs isolated from maxillofacial bone marrow (BM) are good candidates for tissue regeneration at sites of damage to the maxillofacial complex. In this study, we hypothesized that MSCs isolated from the maxillofacial complex can be engineered to overexpress the bone morphogenetic protein-2 gene and induce bone tissue regeneration in vivo. To demonstrate that the cells isolated from the maxillofacial complex were indeed MSCs, we performed a flow cytometry analysis, which revealed a high expression of mesenchyme-related markers and an absence of non-mesenchyme-related markers. In vitro, the MSCs were able to differentiate into osteogenic, chondrogenic, and adipogenic lineages. Gene delivery of the osteogenic gene BMP2 via an adenoviral vector revealed high expression levels of BMP2 protein that induced osteogenic differentiation of these cells in vitro and induced bone formation in an ectopic site in vivo. In addition, implantation of genetically engineered maxillofacial BM-derived MSCs into a mandibular defect led to regeneration of tissue at the site of the defect; this was confirmed by performing micro-computed tomography analysis. Histological analysis of the mandibles revealed osteogenic differentiation of implanted cells as well as bone tissue regeneration. We conclude that maxillofacial BM-derived MSCs can be genetically engineered to induce bone tissue regeneration in the maxillofacial complex and that this finding may be clinically relevant.
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Affiliation(s)
- Yair Steinhardt
- Skeletal Biotechnology Laboratory, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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44
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Kuh SU, Zhu Y, Li J, Tsai KJ, Fei Q, Hutton WC, Yoon ST. The AdLMP-1 transfection in two different cells; AF cells, chondrocytes as potential cell therapy candidates for disc degeneration. Acta Neurochir (Wien) 2008; 150:803-10. [PMID: 18618069 DOI: 10.1007/s00701-008-1617-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2007] [Accepted: 05/20/2008] [Indexed: 12/25/2022]
Abstract
BACKGROUND LMP-1 is known to increase proteoglycan production through the upregulating the BMPs and it is also known that BMP-2 acts on anulus fibrosus cells and chondrocytes to increase proteoglycan production. METHOD We carried out an experiment, the effect of AdLMP-1 transfection on AF cells and chondrocytes in the production of sulfated-glycosaminoglycans, mRNA expression (aggrecan, type I, II collagen, LMP-1, BMP-2, and BMP-7), and immunofluorescence staining. AF cells and chondrocytes were grown in monolayer and treated for 6 days with AdLMP1-green fluorescence protein (GFP) (10, 20, and 30 multiplicity of infection [MOI]). After 6 days, the sGAG content in the media was quantified using 1,9-dimethylmethylene blue staining. The mRNA expression was measured with real-time PCR after 20 MOI infection of AdLMP1-GFP. The each cells treated with 20 MOI infection of AdGFP was used as a control group for the mRNA expression. The each cell group was immunofluorescence stained with each antibodies in the chamber slide at 3 x 10(4) cells/chamber. FINDINGS 1) The sGAG production was maximum in 20 MOI AdLMP1-GFP infection on the AdLMP-1 treatment for both of AF cells and chondrocytes. 2) The mRNA expression of aggrecan, type I collagen, type II collagen, LMP-1, BMP-2, and BMP-7 is increased in both AF cells and chondrocytes in 20 MOI AdLMP1-GFP infection. 3) On the immunofluorescence staining results, the positive immunofluorescence stained cell numbers are increased after 20 MOI AdLMP1-GFP infection concordant with upregulation of mRNA expression. CONCLUSIONS The AdLMP-1 treatments in AF cells and chondrocytes may be useful for cell transplantation therapy in disc degeneration.
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Affiliation(s)
- S U Kuh
- Department of Neurosurgery, The Spine and Spinal Cord Institute, Yonsei University Medical College, Seoul, Korea
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45
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Inkson CA, Ono M, Kuznetsov SA, Fisher LW, Gehron Robey P, Young MF. TGF-beta1 and WISP-1/CCN-4 can regulate each other's activity to cooperatively control osteoblast function. J Cell Biochem 2008; 104:1865-78. [PMID: 18404666 PMCID: PMC2729692 DOI: 10.1002/jcb.21754] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Wnt-induced secreted protein-1 (WISP-1), like other members of the CCN family, is expressed in skeletal tissues. Its mechanism of action remains unknown. Expression of WISP-1 was analyzed in human bone marrow stroma cells (hBMSC) by RT-PCR. We identified two major transcripts corresponding to those of full-length WISP-1, and of the splice variant WISP-1va which lacks a putative BMP/TGF-beta binding site. To investigate the function of WISP-1 in bone, hBMSC cultures were treated with recombinant human (rh)WISP-1 and analyzed for proliferation and osteogenic differentiation. WISP-1 treatment increased both BrdU incorporation and alkaline phosphatase (AP) activity. Considering the known functional synergy found between the TGF-beta super-family and members of the CCN family, we next tested the effect of WISP-1 on TGF-beta1 activity. We found that rhWISP-1 could reduce rhTGF-beta1 induced BrdU incorporation. Similarly, rhTGF-beta1 inhibited rhWISP-1 induction of AP activity. To explore functional differences between the WISP-1 variants, WISP-1 or WISP-1va were transfected into hBMSC. Both variants could strongly induce BrdU incorporation. However, there were no effects of either variant on AP activity without an additional osteogenic stimulus such as TGF-beta1. Taken together our results suggest a functional relationship between WISP-1 and TGF-beta1. To further define this relationship we analyzed the effect of WISP-1 on TGF-beta signaling. rhWISP-1 significantly reduced TGF-beta1 induced phosphorylation of Smad-2. Our data indicates that full-length WISP-1 and its variant WISP-1va are modulators of proliferation and osteogenic differentiation, and may be novel regulators of TGF-beta1 signaling in osteoblast-like cells.
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Affiliation(s)
- Colette A. Inkson
- Craniofacial and Skeletal Diseases Branch, National Institutes of Craniofacial and Dental Research, NIH, Bethesda, MD, USA, 20892
| | | | - Sergei A. Kuznetsov
- Craniofacial and Skeletal Diseases Branch, National Institutes of Craniofacial and Dental Research, NIH, Bethesda, MD, USA, 20892
| | - Larry W. Fisher
- Craniofacial and Skeletal Diseases Branch, National Institutes of Craniofacial and Dental Research, NIH, Bethesda, MD, USA, 20892
| | - Pamela Gehron Robey
- Craniofacial and Skeletal Diseases Branch, National Institutes of Craniofacial and Dental Research, NIH, Bethesda, MD, USA, 20892
| | - Marian F. Young
- Craniofacial and Skeletal Diseases Branch, National Institutes of Craniofacial and Dental Research, NIH, Bethesda, MD, USA, 20892
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46
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Petrie TA, Raynor JE, Reyes CD, Burns KL, Collard DM, García AJ. The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration. Biomaterials 2008; 29:2849-57. [PMID: 18406458 PMCID: PMC2397448 DOI: 10.1016/j.biomaterials.2008.03.036] [Citation(s) in RCA: 163] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2008] [Accepted: 03/20/2008] [Indexed: 10/22/2022]
Abstract
Implant osseointegration, defined as bone apposition and functional fixation, is a requisite for clinical success in orthopaedic and dental applications, many of which are restricted by implant loosening. Modification of implants to present bioactive motifs such as the RGD cell-adhesive sequence from fibronectin (FN) represents a promising approach in regenerative medicine. However, these biomimetic strategies have yielded only marginal enhancements in tissue healing in vivo. In this study, clinical-grade titanium implants were grafted with a non-fouling oligo(ethylene glycol)-substituted polymer coating functionalized with controlled densities of ligands of varying specificity for target integrin receptors. Biomaterials presenting the alpha5beta1-integrin-specific FN fragment FNIII 7-10 enhanced osteoblastic differentiation in bone marrow stromal cells compared to unmodified titanium and RGD-presenting surfaces. Importantly, FNIII 7-10-functionalized titanium significantly improved functional implant osseointegration compared to RGD-functionalized and unmodified titanium in vivo. This study demonstrates that bioactive coatings that promote integrin binding specificity regulate marrow-derived progenitor osteoblastic differentiation and enhance healing responses and functional integration of biomedical implants. This work identifies an innovative strategy for the rational design of biomaterials for regenerative medicine.
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Affiliation(s)
- Timothy A. Petrie
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
| | - Jenny E. Raynor
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332
| | - Catherine D. Reyes
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
| | - Kellie L. Burns
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
| | - David M. Collard
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332
| | - Andrés J. García
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332
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Singhatanadgit W, Mordan N, Salih V, Olsen I. Changes in bone morphogenetic protein receptor-IB localisation regulate osteogenic responses of human bone cells to bone morphogenetic protein-2. Int J Biochem Cell Biol 2008; 40:2854-64. [PMID: 18619554 DOI: 10.1016/j.biocel.2008.06.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2008] [Revised: 06/03/2008] [Accepted: 06/09/2008] [Indexed: 12/20/2022]
Abstract
Cell responses to bone morphogenetic proteins (BMP) depend on the expression and surface localisation of transmembrane receptors BMPR-IA, -IB and -II. The present study shows that all three antigens are readily detected in human bone cells. However, only BMPR-II was found primarily at the plasma membrane, whereas BMPR-IA was expressed equally in the cytoplasm and at the cell surface. Notably, BMPR-IB was mainly intracellular, where it was associated with a number of cytoplasmic structures and possibly the nucleus. Treatment with transforming growth factor beta1 (TGF-beta1) caused rapid translocation of BMPR-IB to the cell surface, mediated via the p38 mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) pathways. The TGF-beta1-induced increase in surface BMPR-IB resulted in significantly elevated BMP-2 binding and Smad1/5/8 phosphorylation, although the receptor was subsequently internalised and the functional response to BMP-2 consequently down-regulated. The results show, for the first time, that BMPR-IB is localised primarily in intracellular compartments in bone cells and that TGF-beta1 induces rapid surface translocation from the cytoplasm to the cell surface, resulting in increased sensitivity of the cells to BMP-2.
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Affiliation(s)
- Weerachai Singhatanadgit
- Division of Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, University College London, 256 Gray's Inn Road, London WC1X 8LD, United Kingdom
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Cheng SL, Shao JS, Cai J, Sierra OL, Towler DA. Msx2 exerts bone anabolism via canonical Wnt signaling. J Biol Chem 2008; 283:20505-22. [PMID: 18487199 DOI: 10.1074/jbc.m800851200] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Msx2 is a homeodomain transcription factor first identified in craniofacial bone and human femoral osteoblasts. We hypothesized that Msx2 might activate skeletal Wnt signaling. Therefore, we analyzed the effects of CMV-Msx2 transgene (Msx2Tg) expression on skeletal physiology and composition. Skeletal Msx2 expression was increased 2-3-fold by Msx2Tg, with expanded protein accumulation in marrow, secondary ossification centers, and periosteum. Microcomputed tomography established increased bone volume in Msx2Tg mice, with increased numbers of plate-like trabeculae. Histomorphometry revealed increased bone formation in Msx2Tg mice versus non-Tg siblings, arising from increased osteoblast numbers. While decreasing adipogenesis, Msx2Tg increased osteogenic differentiation via mechanisms inhibited by Dkk1, an antagonist of Wnt receptors LRP5 and LRP6. Bone from Msx2Tg mice elaborated higher levels of Wnt7 canonical agonists, with diminished Dkk1, changes that augment canonical signaling. Analysis of non-Tg and Msx2Tg siblings possessing the TOPGAL reporter confirmed this; Msx2Tg up-regulated skeletal beta-galactosidase expression (p </= 0.01), along with Wnt7a and Wnt7b, and reduced circulating Dkk1. To better understand molecular mechanisms, we studied C3H10T1/2 osteoprogenitor cells. As in bone, Msx2 increased Wnt7 genes and down-regulated Dkk1, while inducing the osteoblast gene alkaline phosphatase. Msx2-directed RNA interference increased Dkk1 expression and promoter activity, while reducing Wnt7a, Wnt7b, and alkaline phosphatase. Moreover, Msx2 inhibited Dkk1 promoter activity and reduced RNA polymerase association with Dkk1 chromatin. RNA interference-mediated knockdown of Wnt7a, Wnt7b, and LRP6 significantly reduced Msx2-induced alkaline phosphatase. Msx2 exerts bone anabolism in part by reducing Dkk1 expression and enhancing Wnt signaling, thus promoting osteogenic differentiation of skeletal progenitors.
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Affiliation(s)
- Su-Li Cheng
- Department of Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, St Louis, MO 63110, USA
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49
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Zhang X, Zhang C, Tang T, Qu Z, Lou J, Dai K. Immunomodulatory and osteogenic differentiation effects of mesenchymal stem cells by adenovirus-mediated coexpression of CTLA4Ig and BMP2. J Orthop Res 2008; 26:314-21. [PMID: 17960657 DOI: 10.1002/jor.20489] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Many reports have previously utilized a human bone morphogenetic protein 2 (BMP2)-expressing recombinant adenoviral vector (AdBMP2) and mesenchymal stem cells (MSCs) for osteoinductive gene therapy. However, immunosuppression is essential for osteoinduction by AdBMP2, and this is one of the major impediments to its clinical use. In the present study, in vitro propagated MSCs were transduced using an adenoviral (Ad) vector to express the gene encoding cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4Ig). Lymphocyte response was induced by allogeneic-irradiated MSCs as stimulators. We also examined the effects of cotransfection with a combination of the CTLA4Ig and the BMP2 gene on osteoblastic cell differentiation. The results showed that BMP2 gene transfected MSC elicited significant stimulatory responses, and one-way MLR reactions were significantly blunted by CTLA4Ig. Further study demonstrates that cotransfection of MSCs with the combination of the CTLA4Ig and the BMP2 gene stimulates osteoblastic cell differentiation in vitro. The findings suggest that genetic engineering of MSCs to express an immunosuppressive molecule in combination with an osteogenic protein gene may have potential application in the treatment of several genetic diseases and in bone reconstruction.
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Affiliation(s)
- Xiaoling Zhang
- Joint Orthopaedic Laboratory of Institute of Health Sciences and Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai, People's Republic of China
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50
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Han D, Sun X, Zhang X, Tang T, Dai K. Ectopic osteogenesis by ex vivo gene therapy using beta tricalcium phosphate as a carrier. Connect Tissue Res 2008; 49:343-50. [PMID: 18991087 DOI: 10.1080/03008200802325029] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Injuries and other damage to large bone can result in defects that do not heal spontaneously and lead to severe functional impairment. Better therapies are greatly needed to address this worldwide problem. The objective of the present study was to determine whether adenoviral delivery of modified human BMP2 gene (AdBMP2) using beta tricalcium phosphate (ss-TCP) as a carrier could promote osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs) and ectopic bone formation. Rabbit BMSCs were separated from tibia aspirates and expanded in vitro. The BMSCs were then infected with AdBMP-2. Expression of BMP2, alkaline phosphatase, type I collagen, osteonectin, osteopontin, and mineralization of the cells confirmed secretion of active BMP2. Cells were observed to differentiate and maintain the osteoblast phenotype. For additional in vivo experiments, subcutaneous pockets were created on the backs of nude mice, which were then implanted with AdBMP2-BMSCs/ss-TCP, Adbetagal-BMSCs/ss-TCP, BMSCs/ss-TCP, or ss-TCP alone. The nude mice were sacrificed after 4 weeks for histological evaluation. Adbetagal-BMSCs/ss-TCP, BMSCs/ss-TCP, and ss-TCP did not show bone formation, although extensive fibrous tissue formed in the subcutaneous space in the rats implanted with ss-TCP. However, new bone tissue formation was observed on the inner walls of the pores of the ss-TCP-treated animals, and ectopic bone formation (mainly ''cartilage-bone inducing'') was observed in the AdBMP2-BMSCs/ss-TCP composite. These results confirmed the osteogenic potential of BMSCs after AdBMP2 transduction and revealed that AdBMP2-BMSC/ss-TCP composites could provide the capacity for bone formation and maturation during the more advanced stages of healing.
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Affiliation(s)
- Dong Han
- Department of Orthopedics, Ninth People's Hospital, Medical School of Shanghai Jiao Tong University, Shanghai City, China
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