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Zhao D, Saiding Q, Li Y, Tang Y, Cui W. Bone Organoids: Recent Advances and Future Challenges. Adv Healthc Mater 2024; 13:e2302088. [PMID: 38079529 DOI: 10.1002/adhm.202302088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 11/23/2023] [Indexed: 12/21/2023]
Abstract
Bone defects stemming from tumorous growths, traumatic events, and diverse conditions present a profound conundrum in clinical practice and research. While bone has the inherent ability to regenerate, substantial bone anomalies require bone regeneration techniques. Bone organoids represent a new concept in this field, involving the 3D self-assembly of bone-associated stem cells guided in vitro with or without extracellular matrix material, resulting in a tissue that mimics the structural, functional, and genetic properties of native bone tissue. Within the scientific panorama, bone organoids ascend to an esteemed status, securing significant experimental endorsement. Through a synthesis of current literature and pioneering studies, this review offers a comprehensive survey of the bone organoid paradigm, delves into the quintessential architecture and ontogeny of bone, and highlights the latest progress in bone organoid fabrication. Further, existing challenges and prospective directions for future research are identified, advocating for interdisciplinary collaboration to fully harness the potential of this burgeoning domain. Conclusively, as bone organoid technology continues to mature, its implications for both clinical and research landscapes are poised to be profound.
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Affiliation(s)
- Ding Zhao
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Qimanguli Saiding
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Yihan Li
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Yunkai Tang
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
| | - Wenguo Cui
- Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China
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Shamszadeh S, Shirvani A, Torabzadeh H, Asgary S. Effects of Growth Factors on the Differentiation of Dental Stem Cells: A Systematic Review and Meta-analysis (Part I). Curr Stem Cell Res Ther 2024; 19:523-543. [PMID: 35762556 DOI: 10.2174/1574888x17666220628125048] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/04/2022] [Accepted: 04/22/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION To evaluate the biological interaction between dental stem cells (DSCs) and different growth factors in the field of regenerative endodontics. METHODS A systematic search was conducted in the electronic databases up to October 2021. This study followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Ex vivo studies evaluating the biological interactions of DSCs and growth factors were included. The meta-analysis was performed according to the type of growth factor. The outcomes were cell viability/ proliferation and mineralization. Standardized mean differences (SMDs) were estimated using the random-effect maximum-likelihood method (P < .05). Additional analysis was performed to find any potential source of heterogeneity. RESULTS Twenty articles were included in the systematic review; meta-analysis was performed for fibroblast growth factor-2 (FGF-2) and Transforming growth factor-ß1 (TGF-β1) (n = 5). Results showed that use of FGF-2 significantly increased cell proliferation on day 1-(SMD = 3.56, P = 0.00), 3-(SMD = 9.04, P = 0.00), 5-(SMD = 8.37, P = 0.01), and 7 (SMD=8.51, P=0.00) than the control group. TGF-ß1 increased alkaline phosphatase (ALP) activity more than control only on day 3 (SMD = 3.68, P = 0.02). TGF-β1 had no significant effect on cell proliferation on days 1 and 3 (P > 0.05) and on ALP activity on days 5 and 7 (P > 0.05). Meta-regression analysis showed that different covariates (i.e., cell type, passage number, and growth factors' concentration) could significantly influence the effect sizes at different follow- ups (P < 0.05). CONCLUSION Specific growth factors might enhance the proliferation and mineralization of DSCs; however, the obtained evidence was weak. Due to the high heterogeneity among the included studies, other growth factors' inhibitory/stimulatory effects on DSCs could not be evaluated.
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Affiliation(s)
- Sayna Shamszadeh
- Iranian Center for Endodontic Research, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Armin Shirvani
- Iranian Center for Endodontic Research, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Torabzadeh
- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Asgary
- Iranian Center for Endodontic Research, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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3
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Kuhn LT, Peng T, Gronowicz G, Hurley MM. Endogenous FGF-2 levels impact FGF-2/BMP-2 growth factor delivery dosing in aged murine calvarial bone defects. J Biomed Mater Res A 2021; 109:2545-2555. [PMID: 34173706 PMCID: PMC9943554 DOI: 10.1002/jbm.a.37249] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/20/2021] [Accepted: 06/11/2021] [Indexed: 12/12/2022]
Abstract
Bone repair in elderly mice has been shown to be improved or negatively impacted by supplementing the highly osteogenic bone morphogenetic protein-2 (BMP-2) with fibroblast growth factor-2 (FGF-2). To better predict the outcome of FGF-2 supplementation, we investigated whether endogenous levels of FGF-2 play a role in optimal dosing of FGF-2 for augmenting BMP-2 activity in elderly mice. In vivo calvarial bone defect studies in Fgf2 knockout mice with wildtype controls were conducted with the growth factors delivered in a highly localized manner from a biomimetic calcium phosphate/polyelectrolyte multilayer coating applied to a bone graft substitute. Endogenous FGF-2 levels were measured in old mice versus young and found to decrease with age. Optimal dosing for improving bone defect repair correlated with levels of endogenous FGF-2, with a larger dose of FGF-2 required to have a positive effect on bone healing in the Fgf2 knockout mice. The same dose in wildtype old mice, with higher levels of FGF-2, promoted chondrogenesis and increased osteoclast activity. The results suggest a personalized medicine approach, based on a knowledge of endogenous levels of FGF-2, should guide FGF-2 supplementation in order to avoid provoking excessive bone resorption and cartilage formation, both of which inhibited calvarial bone repair.
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Affiliation(s)
- Liisa T Kuhn
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Tao Peng
- Department of Biomedical Engineering, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Gloria Gronowicz
- Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Marja M Hurley
- Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA
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Go G, Jeon J, Lee G, Lee JH, Lee SH. Bovine milk extracellular vesicles induce the proliferation and differentiation of osteoblasts and promote osteogenesis in rats. J Food Biochem 2021; 45:e13705. [PMID: 33748986 DOI: 10.1111/jfbc.13705] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 02/19/2021] [Accepted: 03/05/2021] [Indexed: 12/20/2022]
Abstract
Bone is constantly balanced between the formation of new bone by osteoblasts and the absorption of old bone by osteoclasts. To promote bone growth and improve bone health, it is necessary to promote the proliferation and differentiation of osteoblasts. Although bovine milk is known to exert a beneficial effect on bone formation, the study on the effect of bovine milk extracellular vesicles (EVs) on osteogenesis in osteoblasts is limited. In this study, we demonstrated that bovine milk EVs promoted the proliferation of human osteogenic Saos-2 cells by increasing the expression of cell cycle-related proteins. In addition, bovine milk EVs also induced the differentiation of Saos-2 cells by increasing the expression of RUNX2 and Osterix which are key transcription factors for osteoblast differentiation. Oral administration of milk EVs did not cause toxicity in Sprague-Dawley rats. Furthermore, milk EVs promoted longitudinal bone growth and increased the bone mineral density of the tibia. Our findings suggest that milk EVs could be a safe and powerful applicant for enhancing osteogenesis. PRACTICAL APPLICATIONS: Until now, calcium and vitamin D have been prescribed to promote bone formation or to prevent bone diseases such as osteoporosis. Recently, several studies to find bioactive molecules that regulate cellular functions of osteoblasts or osteoclasts are actively underway. Milk basic proteins and lactoferrin present in milk are known to promote bone formation, but they exist in small quantities and the isolation of these proteins is complicated making mass production difficult. Recently, it has been found that milk contains large quantities of EVs, and that they promote bone formation. Studies on the effect of Milk EVs on osteoblasts during osteogenesis will help in the development of biomaterials for osteogenesis.
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Affiliation(s)
- Gyeongyun Go
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea.,Department of Biochemistry, BK21FOUR Project2, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
| | | | - Gaeun Lee
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea.,Department of Biochemistry, BK21FOUR Project2, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
| | - Jun Hee Lee
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, Republic of Korea.,Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Republic of Korea.,Department of Oral Anatomy, College of Dentistry, Dankook University, Cheonan, Republic of Korea.,Cell & Matter Institute, Dankook University, Cheonan, Republic of Korea
| | - Sang Hun Lee
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea.,Department of Biochemistry, BK21FOUR Project2, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea.,Stembio, Ltd, Asan, Republic of Korea.,Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
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Zhang Y, Yu T, Peng L, Sun Q, Wei Y, Han B. Advancements in Hydrogel-Based Drug Sustained Release Systems for Bone Tissue Engineering. Front Pharmacol 2020; 11:622. [PMID: 32435200 PMCID: PMC7218105 DOI: 10.3389/fphar.2020.00622] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 04/20/2020] [Indexed: 12/13/2022] Open
Abstract
Bone defects caused by injury, disease, or congenital deformity remain a major health concern, and efficiently regenerating bone is a prominent clinical demand worldwide. However, bone regeneration is an intricate process that requires concerted participation of both cells and bioactive factors. Mimicking physiological bone healing procedures, the sustained release of bioactive molecules plays a vital role in creating an optimal osteogenic microenvironment and achieving promising bone repair outcomes. The utilization of biomaterial scaffolds can positively affect the osteogenesis process by integrating cells with bioactive factors in a proper way. A high water content, tunable physio-mechanical properties, and diverse synthetic strategies make hydrogels ideal cell carriers and controlled drug release reservoirs. Herein, we reviewed the current advancements in hydrogel-based drug sustained release systems that have delivered osteogenesis-inducing peptides, nucleic acids, and other bioactive molecules in bone tissue engineering (BTE).
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Affiliation(s)
- Yunfan Zhang
- Department of Orthodontics, Peking University School and Hospital of Stomatology & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Tingting Yu
- Department of Orthodontics, Peking University School and Hospital of Stomatology & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Liying Peng
- Department of Orthodontics, Peking University School and Hospital of Stomatology & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Qiannan Sun
- Department of Orthodontics, Peking University School and Hospital of Stomatology & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yan Wei
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing, China
| | - Bing Han
- Department of Orthodontics, Peking University School and Hospital of Stomatology & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China
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Shafaei H, Kalarestaghi H. Adipose-derived stem cells: An appropriate selection for osteogenic differentiation. J Cell Physiol 2020; 235:8371-8386. [PMID: 32239731 DOI: 10.1002/jcp.29681] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Accepted: 03/13/2020] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSCs) are a major component of various forms of tissue engineering. MSCs have self-renewal and multidifferential potential. Osteogenic differentiation of MSCs is an area of attention in bone regeneration. One form of MSCs are adipose-derived stem cells (ASCs), which can be simply harvested and differentiated into several cell lineages, such as chondrocytes, adipocytes, or osteoblasts. Due to special properties, ASCs are frequently used in vitro and in vivo bone regeneration. Identifying factors involved in osteogenic differentiation of ASCs is important for better understanding the mechanism of osteogenic differentiation. Different methods are used to stimulate osteogenesis of ASCs in literature, including common osteogenic media, growth factors, hormones, hypoxia, mechanical and chemical stimuli, genetic modification, and nanotechnology. This review article provides an overview describing the isolation procedure, characterization, properties, current methods for osteogenic differentiation of ASCs, and their basic biological mechanism.
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Affiliation(s)
- Hajar Shafaei
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Kalarestaghi
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences and Pathology, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
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7
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Cheng Y, Lin K, Young T, Cheng N. The influence of fibroblast growth factor 2 on the senescence of human adipose-derived mesenchymal stem cells during long-term culture. Stem Cells Transl Med 2020; 9:518-530. [PMID: 31840944 PMCID: PMC7103622 DOI: 10.1002/sctm.19-0234] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 11/25/2019] [Indexed: 12/22/2022] Open
Abstract
Adipose-derived mesenchymal stem cells (ASCs) exhibit great potential in regenerative medicine, and in vitro expansion is frequently necessary to obtain a sufficient number of ASCs for clinical use. Fibroblast growth factor 2 (FGF2) is a common supplement in the ASC culture medium to enhance cell proliferation. To achieve clinical applicability of ASC-based products, prolonged culture of ASCs is sometimes required to obtain sufficient quantity of ASCs. However, the effect of FGF2 on ASCs during prolonged culture has not been previously determined. In this study, ASCs were subjected to prolonged in vitro culture with or without FGF2. FGF2 maintained the small cell morphology and expedited proliferation kinetics in early ASC passages. After prolonged in vitro expansion, FGF2-treated ASCs exhibited increased cell size, arrested cell proliferation, and increased cellular senescence relative to the control ASCs. We observed an upregulation of FGFR1c and enhanced expression of downstream STAT3 in the initial passages of FGF2-treated ASCs. The application of an FGFR1 or STAT3 inhibitor effectively blocked the enhanced proliferation of ASCs induced by FGF2 treatment. FGFR1c upregulation and enhanced STAT3 expression were lost in the later passages of FGF2-treated ASCs, suggesting that the continuous stimulation of FGF2 becomes ineffective because of the refractory downstream FGFR1 and the STAT3 signaling pathway. In addition, no evidence of tumorigenicity was noted in vitro and in vivo after prolonged expansion of FGF2-cultured ASCs. Our data indicate that ASCs have evolved a STAT3-dependent response to continuous FGF2 stimulation which promotes the initial expansion but limits their long-term proliferation.
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Affiliation(s)
- Yin Cheng
- Department of SurgeryNational Taiwan University Hospital and College of MedicineTaipeiTaiwan
| | - Kai‐Hsuan Lin
- Department of SurgeryNational Taiwan University Hospital and College of MedicineTaipeiTaiwan
| | - Tai‐Horng Young
- Department of Biomedical Engineering, College of Medicine and College of EngineeringNational Taiwan UniversityTaipeiTaiwan
| | - Nai‐Chen Cheng
- Department of SurgeryNational Taiwan University Hospital and College of MedicineTaipeiTaiwan
- Research Center for Developmental Biology and Regenerative MedicineNational Taiwan UniversityTaipeiTaiwan
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8
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Kuterbekov M, Jonas AM, Glinel K, Picart C. Osteogenic Differentiation of Adipose-Derived Stromal Cells: From Bench to Clinics. TISSUE ENGINEERING PART B-REVIEWS 2020; 26:461-474. [PMID: 32098603 DOI: 10.1089/ten.teb.2019.0225] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
In addition to mesenchymal stem cells, adipose-derived stem/stromal cells (ASCs) are an attractive source for a large variety of cell-based therapies. One of their most important potential applications is related to the regeneration of bone tissue thanks to their capacity to differentiate in bone cells. However, this requires a proper control of their osteogenic differentiation, which depends not only on the initial characteristics of harvested cells but also on the conditions used for their culture. In this review, we first briefly describe the preclinical and clinical trials using ASCs for bone regeneration and present the quantitative parameters used to characterize the osteogenic differentiation of ASCs. We then focus on the soluble factors influencing the osteogenic differentiation of ACS, including the steroid hormones and various growth factors, notably the most osteoinductive ones, the bone morphogenetic proteins (BMPs). Impact statement Adipose-derived stromal/stem cells are reviewed for their use in bone regeneration.
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Affiliation(s)
- Mirasbek Kuterbekov
- Institute of Condensed Matter & Nanosciences (Bio & Soft Matter), Université Catholique de Louvain, Louvain-la-Neuve, Belgium.,Grenoble Institute of Technology, University Grenoble Alpes, LMGP, Grenoble, France
| | - Alain M Jonas
- Institute of Condensed Matter & Nanosciences (Bio & Soft Matter), Université Catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Karine Glinel
- Institute of Condensed Matter & Nanosciences (Bio & Soft Matter), Université Catholique de Louvain, Louvain-la-Neuve, Belgium
| | - Catherine Picart
- Grenoble Institute of Technology, University Grenoble Alpes, LMGP, Grenoble, France.,Biomimetism and Regenerative Medicine Lab, CEA, Institute of Interdisciplinary Research of Grenoble (IRIG), Université Grenoble-Alpes/CEA/CNRS, Grenoble, France
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9
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Inthanon K, Janvikul W, Ongchai S, Chomdej S. Intrinsic Cellular Responses of Human Wharton's Jelly Mesenchymal Stem Cells Influenced by O 2-Plasma-Modified and Unmodified Surface of Alkaline-Hydrolyzed 2D and 3D PCL Scaffolds. J Funct Biomater 2019; 10:E52. [PMID: 31752199 PMCID: PMC6963654 DOI: 10.3390/jfb10040052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/31/2019] [Accepted: 11/17/2019] [Indexed: 01/09/2023] Open
Abstract
Polycaprolactone (PCL), a hydrophobic-degradable polyester, has been widely investigated and extensively developed, to increase the biocompatibility for tissue engineering. This research was the first trial to evaluate the intrinsic biological responses of human Wharton's Jelly Mesenchymal Stem Cells (hWJMSCs) cultured on alkaline hydrolysis and low-pressure oxygen plasma modified 2D and 3D PCL scaffolds, without adding any differentiation inducers; this has not been reported before. Four types of the substrate were newly established: 2D plasma-treated PCL (2D-TP), 2D non-plasma-treated PCL (2D-NP), 3D plasma-treated PCL (3D-TP), and 3D non-plasma-treated PCL (3D-NP). Physicochemical characterization revealed that only plasma-treated PCL scaffolds significantly increased the hydrophilicity and % oxygen/carbon ratio on the surfaces. The RMS roughness of 3D was higher than 2D conformation, whilst the plasma-treated surfaces were rougher than the non-plasma treated ones. The cytocompatibility test demonstrated that the 2D PCLs enhanced the initial cell attachment in comparison to the 3Ds, indicated by a higher expression of focal adhesion kinase. Meanwhile, the 3Ds promoted cell proliferation and migration as evidence of higher cyclin-A expression and filopodial protrusion, respectively. The 3Ds potentially protected the cell from apoptosis/necrosis but also altered the pluripotency/differentiation-related gene expression. In summary, the different configuration and surface properties of PCL scaffolds displayed the significant potential and effectiveness for facilitating stem cell growth and differentiation in vitro. The cell-substrate interactions on modified surface PCL may provide some information which could be further applied in substrate architecture for stem cell accommodation in cell delivery system for tissue repair.
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Affiliation(s)
- Kewalin Inthanon
- Department of Biotechnology, Faculty of Science and Technology, Thammasat University, Lampang 52190, Thailand
| | - Wanida Janvikul
- National Metal and Materials Technology Center, Pathumthani 12120, Thailand;
| | - Siriwan Ongchai
- Thailand Excellence Centre for Tissue Engineering and Stem Cells, Department of Biochemistry and the Center of Excellence for Innovation in Chemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Siriwadee Chomdej
- Center of Excellence in Bioresources for Agriculture, Industry and Medicine Chiang Mai University, Chiang Mai 50200, Thailand
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10
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Review of the Pathways Involved in the Osteogenic Differentiation of Adipose-Derived Stem Cells. J Craniofac Surg 2019; 30:703-708. [PMID: 30839467 DOI: 10.1097/scs.0000000000005447] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Grafts and prosthetic materials used for the repair of bone defects are often accompanied by comorbidity and rejection. Therefore, there is an immense need for novel approaches to combating the issues surrounding such defects. Because of their accessibility, substantial proportion, and osteogenic differentiation potential, adipose-derived stem cells (ASCs) make for an ideal source of bone tissue in regenerative medicine. However, efficient induction of ASCs toward an osteoblastic lineage in vivo is met with challenges, and many signaling pathways must come together to secure osteoblastogenesis. Among them are bone morphogenic protein, wingless-related integration site protein, Notch, Hedgehog, fibroblast growth factor, vascular endothelial growth factor, and extracellular regulated-signal kinase. The goal of this literature review is to conglomerate the present research on these pathways to formulate a better understanding of how ASCs are most effectively transformed into bone in the context of tissue engineering.
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11
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Shin HR, Bae HS, Kim BS, Yoon HI, Cho YD, Kim WJ, Choi KY, Lee YS, Woo KM, Baek JH, Ryoo HM. PIN1 is a new therapeutic target of craniosynostosis. Hum Mol Genet 2019; 27:3827-3839. [PMID: 30007339 PMCID: PMC6216213 DOI: 10.1093/hmg/ddy252] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 07/05/2018] [Indexed: 01/14/2023] Open
Abstract
Gain-of-function mutations in fibroblast growth factor receptors (FGFRs) cause congenital skeletal anomalies, including craniosynostosis (CS), which is characterized by the premature closure of craniofacial sutures. Apert syndrome (AS) is one of the severest forms of CS, and the only treatment is surgical expansion of prematurely fused sutures in infants. Previously, we demonstrated that the prolyl isomerase peptidyl-prolyl cis-trans isomerase interacting 1 (PIN1) plays a critical role in mediating FGFR signaling and that Pin1+/- mice exhibit delayed closure of cranial sutures. In this study, using both genetic and pharmacological approaches, we tested whether PIN1 modulation could be used as a therapeutic regimen against AS. In the genetic approach, we crossbred Fgfr2S252W/+, a mouse model of AS, and Pin1+/- mice. Downregulation of Pin1 gene dosage attenuated premature cranial suture closure and other phenotypes of AS in Fgfr2S252W/+ mutant mice. In the pharmacological approach, we intraperitoneally administered juglone, a PIN1 enzyme inhibitor, to pregnant Fgfr2S252W/+ mutant mice and found that this treatment successfully interrupted fetal development of AS phenotypes. Primary cultured osteoblasts from Fgfr2S252W/+ mutant mice expressed high levels of FGFR2 downstream target genes, but this phenotype was attenuated by PIN1 inhibition. Post-translational stabilization and activation of Runt-related transcription factor 2 (RUNX2) in Fgfr2S252W/+ osteoblasts were also attenuated by PIN1 inhibition. Based on these observations, we conclude that PIN1 enzyme activity is important for FGFR2-induced RUNX2 activation and craniofacial suture morphogenesis. Moreover, these findings highlight that juglone or other PIN1 inhibitors represent viable alternatives to surgical intervention for treatment of CS and other hyperostotic diseases.
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Affiliation(s)
- H R Shin
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - H S Bae
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - B S Kim
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - H I Yoon
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - Y D Cho
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.,Department of Periodontology, School of Dentistry, Seoul National University, Seoul, Republic of Korea
| | - W J Kim
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - K Y Choi
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Y S Lee
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - K M Woo
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - J H Baek
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
| | - H M Ryoo
- BK21 Program, Department of Molecular Genetics and Dental Pharmacology and Therapeutics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
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12
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Rivera-Izquierdo M, Cabeza L, Láinez-Ramos-Bossini A, Quesada R, Perazzoli G, Alvarez P, Prados J, Melguizo C. An updated review of adipose derived-mesenchymal stem cells and their applications in musculoskeletal disorders. Expert Opin Biol Ther 2019; 19:233-248. [PMID: 30653367 DOI: 10.1080/14712598.2019.1563069] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 12/20/2018] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Adipose-derived mesenchymal stem cells (ASCs) represent a new therapeutic strategy in biomedicine with many potential applications, especially in musculoskeletal disorders. Preclinical and clinical studies based on the administration of ASCs support their efficacy in bone regeneration, joint repair, tendon injury and skeletal muscle alterations. Many of these novel treatments may improve patients' quality of life and prognosis. However, several concerns about the use of stem cells remain unsolved, particularly regarding their safety and side effects. The present work aims to review the nature, clinical trials and patents involving the use of ASCs in musculoskeletal disorders. AREAS COVERED In this article, we describe ASCs' isolation, culture and differentiation in vivo and in vitro, advances on ASCs' applications in bone, cartilage, muscle and tendon repair, and patents involving the use of ASCs. EXPERT OPINION The use of ASCs in musculoskeletal disorders presents significant therapeutic advantages, including limited autoimmune response, potential cell expansion ex vivo, high plasticity to differentiate into several mesodermal cell lineages, and additional effects of therapeutic interest such as secretion of neurotrophic factors and anti-inflammatory properties. For these reasons, ASCs are promising therapeutic agents for clinical applications in musculoskeletal disorders.
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Affiliation(s)
- Mario Rivera-Izquierdo
- a Department of Anatomy and Embryology, Faculty of Medicine , University of Granada , Granada , Spain
| | - Laura Cabeza
- a Department of Anatomy and Embryology, Faculty of Medicine , University of Granada , Granada , Spain
- b Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM) , University of Granada , Granada , Spain
- c Biosanitary Institute of Granada (IBS GRANADA) , SAS -Universidad de Granada , Granada , Spain
| | - Antonio Láinez-Ramos-Bossini
- c Biosanitary Institute of Granada (IBS GRANADA) , SAS -Universidad de Granada , Granada , Spain
- d Department of Radiology , Hospital Universitario Virgen de las Nieves , Granada , Spain
| | - Raul Quesada
- a Department of Anatomy and Embryology, Faculty of Medicine , University of Granada , Granada , Spain
- b Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM) , University of Granada , Granada , Spain
- c Biosanitary Institute of Granada (IBS GRANADA) , SAS -Universidad de Granada , Granada , Spain
| | - Gloria Perazzoli
- b Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM) , University of Granada , Granada , Spain
| | - Pablo Alvarez
- b Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM) , University of Granada , Granada , Spain
| | - Jose Prados
- a Department of Anatomy and Embryology, Faculty of Medicine , University of Granada , Granada , Spain
- b Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM) , University of Granada , Granada , Spain
- c Biosanitary Institute of Granada (IBS GRANADA) , SAS -Universidad de Granada , Granada , Spain
| | - Consolación Melguizo
- a Department of Anatomy and Embryology, Faculty of Medicine , University of Granada , Granada , Spain
- b Institute of Biopathology and Regenerative Medicine (IBIMER), Biomedical Research Center (CIBM) , University of Granada , Granada , Spain
- c Biosanitary Institute of Granada (IBS GRANADA) , SAS -Universidad de Granada , Granada , Spain
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13
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Petridis X, Beems BP, Tomson PL, Scheven B, Giepmans BNG, Kuipers J, van der Sluis LWM, Harmsen MC. Effect of Dentin Matrix Components on the Mineralization of Human Mesenchymal Stromal Cells. Tissue Eng Part A 2018; 25:1104-1115. [PMID: 30444193 DOI: 10.1089/ten.tea.2018.0192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
IMPACT STATEMENT This research has been conducted with the aim to contribute to the development of treatment modalities for the reconstruction of lost/damaged mineralized tissues. Currently, determining the most appropriate stromal cell population and signaling cues stands at the core of developing effective treatments. We provide new insights into the effect of innate inductive cues found in human dentin matrix components, on the osteogenic differentiation of various human stromal cell types. The effects of dentin extracellular matrix components on umbilical cord mesenchymal stromal cells have not been investigated before. The findings of this study could underpin translational research based on the development of techniques for mineralized tissue engineering and will be of great interest for the readership of Tissue Engineering Part A.
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Affiliation(s)
- Xenos Petridis
- 1Center for Dentistry and Oral Hygiene, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Bas P Beems
- 1Center for Dentistry and Oral Hygiene, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Phillip L Tomson
- 2School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Ben Scheven
- 2School of Dentistry, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Ben N G Giepmans
- 3Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jeroen Kuipers
- 3Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Luc W M van der Sluis
- 1Center for Dentistry and Oral Hygiene, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Martin C Harmsen
- 4Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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14
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MicroRNA 210 Mediates VEGF Upregulation in Human Periodontal Ligament Stem Cells Cultured on 3DHydroxyapatite Ceramic Scaffold. Int J Mol Sci 2018; 19:ijms19123916. [PMID: 30563289 PMCID: PMC6320762 DOI: 10.3390/ijms19123916] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 12/03/2018] [Accepted: 12/05/2018] [Indexed: 12/19/2022] Open
Abstract
The aim of the present research was the evaluation of the behavior of human periodontal ligament stem cells (hPDLSCs), cultured in presence of Endobon® Xenograft Granules (G), a fully deproteinated hydroxyapatite ceramic scaffold derived from cancellous bovine bone. hPDLSCs were seeded with and without G for 24 h to 1 week. The cell growth, morphological features, adhesiveness, differentiation ability, modulation of miR-210 and Vascular Endothelial Growth Factor (VEGF) secretion were analyzed by means of MTT assay, Scanning Electron Microscopy (SEM), Confocal Laser Scanning Microscopy (CLSM), Alizarin Red S assay, RT-PCR and ELISA test, respectively. hPDLSCs grown on the biomaterial showed the ability to form focal adhesion on the substrate, as demonstrated by vinculin expression. These data were supported by SEM analysis showing that an adhesiveness process associated to cell growth occurs between cells and biomaterials. The osteogenic differentiation, evaluated by morphological, biochemical, and RT-PCR analysis, was pronounced in the hPDLSCs grown in the three-dimensional inorganic bovine bone substitute in the presence of osteoinductive conditions. In addition, an upregulation of miR-210 and VEGF was evident in cells cultured in presence of the biomaterial. Our results inspire us to consider granules not only an adequate biocompatible three-dimensional biomaterial, but also an effective inductor of miR-210 and VEGF; in fact, the involvement of miR-210 in VEGF secretion could offer a novel regulatory system in the early steps of the bone-regeneration process.
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15
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Haumer A, Bourgine PE, Occhetta P, Born G, Tasso R, Martin I. Delivery of cellular factors to regulate bone healing. Adv Drug Deliv Rev 2018; 129:285-294. [PMID: 29357301 DOI: 10.1016/j.addr.2018.01.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 01/08/2018] [Accepted: 01/13/2018] [Indexed: 02/06/2023]
Abstract
Bone tissue has a strong intrinsic regenerative capacity, thanks to a delicate and complex interplay of cellular and molecular processes, which tightly involve the immune system. Pathological settings of anatomical, biomechanical or inflammatory nature may lead to impaired bone healing. Innovative strategies to enhance bone repair, including the delivery of osteoprogenitor cells or of potent cytokines/morphogens, indicate the potential of 'orthobiologics', but are not fully satisfactory. Here, we review different approaches based on the delivery of regenerative cues produced by cells but in cell-free, possibly off-the-shelf configurations. Such strategies exploit the paracrine effect of the secretome of mesenchymal stem/stromal cells, presented in soluble form, shuttled through extracellular vesicles, or embedded within the network of extracellular matrix molecules. In addition to osteoinductive molecules, attention is given to factors targeting the resident immune cells, to reshape inflammatory and immunity processes from scarring to regenerative patterns.
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Affiliation(s)
- Alexander Haumer
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
| | - Paul Emile Bourgine
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
| | - Paola Occhetta
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
| | - Gordian Born
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
| | - Roberta Tasso
- Ospedale Policlinico San Martino-IST, IRCCS per l'Oncologia, Genova, Italy
| | - Ivan Martin
- Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland; Department of Biomedical Engineering, University of Basel, Switzerland.
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16
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Graziano ACE, Avola R, Perciavalle V, Nicoletti F, Cicala G, Coco M, Cardile V. Physiologically based microenvironment for in vitro neural differentiation of adipose-derived stem cells. World J Stem Cells 2018; 10:23-33. [PMID: 29588808 PMCID: PMC5867480 DOI: 10.4252/wjsc.v10.i3.23] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 03/20/2018] [Accepted: 03/21/2018] [Indexed: 02/06/2023] Open
Abstract
The limited capacity of nervous system to promote a spontaneous regeneration and the high rate of neurodegenerative diseases appearance are keys factors that stimulate researches both for defining the molecular mechanisms of pathophysiology and for evaluating putative strategies to induce neural tissue regeneration. In this latter aspect, the application of stem cells seems to be a promising approach, even if the control of their differentiation and the maintaining of a safe state of proliferation should be troubled. Here, we focus on adipose tissue-derived stem cells and we seek out the recent advances on the promotion of their neural differentiation, performing a critical integration of the basic biology and physiology of adipose tissue-derived stem cells with the functional modifications that the biophysical, biomechanical and biochemical microenvironment induces to cell phenotype. The pre-clinical studies showed that the neural differentiation by cell stimulation with growth factors benefits from the integration with biomaterials and biophysical interaction like microgravity. All these elements have been reported as furnisher of microenvironments with desirable biological, physical and mechanical properties. A critical review of current knowledge is here proposed, underscoring that a real advance toward a stable, safe and controllable adipose stem cells clinical application will derive from a synergic multidisciplinary approach that involves material engineer, basic cell biology, cell and tissue physiology.
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Affiliation(s)
| | - Rosanna Avola
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy
| | - Vincenzo Perciavalle
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, Section of Pathology and Oncology, University of Catania, Catania 95123, Italy
| | - Gianluca Cicala
- Department of Civil Engineering and Architecture, University of Catania, Catania 95125, Italy
| | - Marinella Coco
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy
| | - Venera Cardile
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy
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17
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Pizzute T, Li J, Zhang Y, Davis ME, Pei M. Fibroblast Growth Factor Ligand Dependent Proliferation and Chondrogenic Differentiation of Synovium-Derived Stem Cells and Concomitant Adaptation of Wnt/Mitogen-Activated Protein Kinase Signals. Tissue Eng Part A 2017; 22:1036-46. [PMID: 27411850 DOI: 10.1089/ten.tea.2016.0102] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Cell expansion techniques commonly utilize exogenous factors to increase cell proliferation and create a larger cell population for use in cell-based therapies. One strategy for cartilage regenerative therapies is autologous stem cell expansion and fibroblast growth factor (FGF) supplementation during cell expansion, particularly FGF-2. However, it is unknown whether FGF-10, another FGF implicated in limb and skeletal development, can elicit the same rejuvenation responses in terms of proliferation and differentiation of human synovium-derived stem cells (SDSCs). In this study, we expanded SDSCs in either FGF-2 or FGF-10 for 7 days; a control group had no treatment. FGF-2 and FGF-10 supplementation was also exclusively tested during the differentiation phase. Expanded SDSCs were evaluated for their ability to successfully engage in chondrogenic and osteogenic differentiation. We found that FGF-2 supplementation during proliferation, but not differentiation, was able to increase glycosaminoglycan deposition, pellet size, and chondrogenic gene expression following chondrogenic induction, as well as increased calcium deposition, alkaline phosphatase activity, and expression of vital osteogenic differentiation genes following osteogenic induction. FGF-10 did not elicit a similar preconditioning effect. We also observed changes of both Wnt signals and mitogen-activated protein kinase expression during SDSC chondrogenesis, which occurred in a manner dependent upon the supplementation phase of FGF-2 administration. These results indicated that FGF-2, but not FGF-10, may be supplemented during stem cell expansion to prime cells for successful chondrogenesis and osteogenesis.
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Affiliation(s)
- Tyler Pizzute
- 1 Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University , Morgantown, West Virginia.,2 Exercise Physiology, West Virginia University , Morgantown, West Virginia
| | - Jingting Li
- 1 Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University , Morgantown, West Virginia.,2 Exercise Physiology, West Virginia University , Morgantown, West Virginia
| | - Ying Zhang
- 1 Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University , Morgantown, West Virginia.,3 Mechanical and Aerospace Engineering, West Virginia University , Morgantown, West Virginia
| | - Mary E Davis
- 4 Department of Physiology and Pharmacology, West Virginia University , Morgantown, West Virginia
| | - Ming Pei
- 1 Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University , Morgantown, West Virginia.,2 Exercise Physiology, West Virginia University , Morgantown, West Virginia.,3 Mechanical and Aerospace Engineering, West Virginia University , Morgantown, West Virginia
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18
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Xu R, Zhao H, Muhammad H, Dong M, Besenbacher F, Chen M. Dual-delivery of FGF-2/CTGF from Silk Fibroin/PLCL-PEO Coaxial Fibers Enhances MSC Proliferation and Fibrogenesis. Sci Rep 2017; 7:8509. [PMID: 28819120 PMCID: PMC5561253 DOI: 10.1038/s41598-017-08226-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 07/10/2017] [Indexed: 02/04/2023] Open
Abstract
The success of mesenchymal stem cell transplantation is highly dependent on their survival and controlled fate regulation. This study demonstrates that dual-delivery of connective tissue growth factor (CTGF) and fibroblast growth factor 2 (FGF-2) from a core-shell fiber of Silk Fibroin/poly(L-lactic acid-co-ε-caprolactone)-polyethylene oxide (SF/PLCL-PEO) enhanced fibrogenic lineage differentiation of MSCs. The core-shell structure was confirmed by transmission electron microscopy (TEM), fluorescence microscopy and attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy. A sequential release of FGF-2 and CTGF was successfully achieved in this manner. FGF-2 plays an important role in stem cell proliferation and, meanwhile when accompanied with CTGF, has a slightly additive effect on fibrogenic differentiation of MSCs, whereas CTGF promotes fibrogenesis and alleviates osteogenesis, chondrogenesis and adipogenesis.
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Affiliation(s)
- Ruodan Xu
- Department of Engineering, Aarhus University, DK-8000, Aarhus C, Denmark
| | - Huiling Zhao
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, DK-8000, Aarhus C, Denmark
| | - Hanif Muhammad
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, DK-8000, Aarhus C, Denmark
| | - Mingdong Dong
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, DK-8000, Aarhus C, Denmark
| | - Flemming Besenbacher
- Interdisciplinary Nanoscience Center (iNANO), Aarhus University, DK-8000, Aarhus C, Denmark
| | - Menglin Chen
- Department of Engineering, Aarhus University, DK-8000, Aarhus C, Denmark. .,Interdisciplinary Nanoscience Center (iNANO), Aarhus University, DK-8000, Aarhus C, Denmark.
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19
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Lee SH, Park YB, Moon HS, Shim JS, Jung HS, Kim HJ, Chung MK. The role of rhFGF-2 soaked polymer membrane for enhancement of guided bone regeneration. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2017; 29:825-843. [DOI: 10.1080/09205063.2017.1354676] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Sang-Hoon Lee
- Department of Prosthodontics, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Korea
| | - Young-Bum Park
- Department of Prosthodontics, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Korea
- BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea
| | - Hong-Seok Moon
- Department of Prosthodontics, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Korea
| | - June-Sung Shim
- Department of Prosthodontics, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Korea
| | - Han-Sung Jung
- BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea
- Division in Anatomy and Developmental Biology, Department of Oral Biology, Oral Science Research Center, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea
| | - Hyung Jun Kim
- Department of Oral & Maxillofacial Surgery, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Korea
| | - Moon-Kyu Chung
- Department of Prosthodontics, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, Korea
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20
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Lee JH, Lee JE, Kang KJ, Jang YJ. Functional efficacy of human recombinant FGF-2s tagged with (His) 6 and (His-Asn) 6 at the N- and C-termini in human gingival fibroblast and periodontal ligament-derived cells. Protein Expr Purif 2017; 135:37-44. [PMID: 28487257 DOI: 10.1016/j.pep.2017.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 05/03/2017] [Accepted: 05/05/2017] [Indexed: 12/24/2022]
Abstract
Fibroblast growth factor (FGF) is a multifunctional growth factor that induces cell proliferation, survival, migration, and differentiation in various cell types and tissues. With these biological functions, FGF-2 has been evaluated for clinical use in the regeneration of damaged tissues. The expression of hFGF-2 in Escherichia coli and a purification system using the immobilized metal affinity chromatography (IMAC) is well established to generate a continuous supply of FGF-2. Although hexa-histidine tag (H6) is commonly used for IMAC purification, hexa-histidine-asparagine tag (HN6) is also efficient for purification as it is easily exposed on the surface of the protein. In this study, four different tagging constructs of hFGF-2 based on tag positions and types (H6-FGF2, FGF2-H6, HN6-FGF2, and FGF2-HN6) were designed and expressed under the inducible T7 expression system in E. coli. The experimental conditions of expression and purification of each recombinant protein were optimized. The effective dosages of the recombinant proteins were determined based on the increase of cell proliferation in human gingival fibroblast. ED50s of H6-FGF2, FGF2-H6, HN6-FGF2, and FGF2-HN6 were determined (4.42 ng/ml, 3.55 ng/ml, 3.54 ng/ml, and 4.14 ng/ml, respectively) and found to be comparable to commercial FGF-2 (3.67 ng/ml). All the recombinant hFGF-2s inhibit the osteogenic induction and mineralization in human periodontal ligament-derived cells. Our data suggested that biological activities of the recombinant hFGF-2 are irrelevant to types and positions of tags, but may have an influence on the expression efficiency and solubility.
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Affiliation(s)
- Ji-Hye Lee
- Department of Nanobiomedical Science & BK21 PLUS Global Research Center for Regenerative Medicine, Dankook University, 29 Anseo-Dong, Cheonan, 330-714, South Korea
| | - Ji-Eun Lee
- Department of Nanobiomedical Science & BK21 PLUS Global Research Center for Regenerative Medicine, Dankook University, 29 Anseo-Dong, Cheonan, 330-714, South Korea
| | - Kyung-Jung Kang
- Department of Nanobiomedical Science & BK21 PLUS Global Research Center for Regenerative Medicine, Dankook University, 29 Anseo-Dong, Cheonan, 330-714, South Korea
| | - Young-Joo Jang
- Department of Nanobiomedical Science & BK21 PLUS Global Research Center for Regenerative Medicine, Dankook University, 29 Anseo-Dong, Cheonan, 330-714, South Korea.
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Bayati V, Gazor R, Nejatbakhsh R, Negad Dehbashi F. Enrichment of skin-derived neural precursor cells from dermal cell populations by altering culture conditions. Stem Cell Investig 2016; 3:83. [PMID: 28066785 DOI: 10.21037/sci.2016.10.10] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 10/25/2016] [Indexed: 01/26/2023]
Abstract
BACKGROUND As stem cells play a critical role in tissue repair, their manipulation for being applied in regenerative medicine is of great importance. Skin-derived precursors (SKPs) may be good candidates for use in cell-based therapy as the only neural stem cells which can be isolated from an accessible tissue, skin. Herein, we presented a simple protocol to enrich neural SKPs by monolayer adherent cultivation to prove the efficacy of this method. METHODS To enrich neural SKPs from dermal cell populations, we have found that a monolayer adherent cultivation helps to increase the numbers of neural precursor cells. Indeed, we have cultured dermal cells as monolayer under serum-supplemented (control) and serum-supplemented culture, followed by serum free cultivation (test) and compared. Finally, protein markers of SKPs were assessed and compared in both experimental groups and differentiation potential was evaluated in enriched culture. RESULTS The cells of enriched culture concurrently expressed fibronectin, vimentin and nestin, an intermediate filament protein expressed in neural and skeletal muscle precursors as compared to control culture. In addition, they possessed a multipotential capacity to differentiate into neurogenic, glial, adipogenic, osteogenic and skeletal myogenic cell lineages. CONCLUSIONS It was concluded that serum-free adherent culture reinforced by growth factors have been shown to be effective on proliferation of skin-derived neural precursor cells (skin-NPCs) and drive their selective and rapid expansion.
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Affiliation(s)
- Vahid Bayati
- Cellular and Molecular Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;; Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Rohoullah Gazor
- Department of Anatomy and Cell Biology, Gilan University of Medical Sciences, Rasht, Iran
| | - Reza Nejatbakhsh
- Department of Anatomical Sciences, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fereshteh Negad Dehbashi
- Cellular and Molecular Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Quan L, Wang Y, Liang J, Qiu T, Wang H, Zhang Y, Zhang Y, Hui Q, Tao K. Screening for genes, transcription factors and miRNAs associated with the myogenic and osteogenic differentiation of human adipose tissue-derived stem cells. Int J Mol Med 2016; 38:1839-1849. [PMID: 27779643 DOI: 10.3892/ijmm.2016.2788] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 09/09/2016] [Indexed: 11/05/2022] Open
Abstract
In the present study, we aimed to reveal the molecular mechanisms responsible for the differentiation of human adipose tissue-derived stem cells (hASCs) into myocytes and osteoblasts. Microarray data GSE37329 were obtained from the Gene Expression Omnibus database, including three hASC cell lines from healthy donors, two osteogenic lineages and two myogenic lineages from the in vitro‑induction of hASCs. Differentially expressed genes (DEGs) in the two lineages were firstly screened. Subsequently, the underlying functions of the two sets of DEGs were investigated by Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, followed by protein-protein interaction (PPI) network construction. Regulatory relationships between transcription factors (TFs) and microRNAs (miRNAs or miRs) with target genes were finally explored using different algorithms. A total of 665 and 485 DEGs were identified from the hASC‑derived myogenic and osteogenic lineages, respectively. The shared upregulated genes (n=205) in the two sets of DEGs were mainly involved in metabolism-related pathways, whereas the shared downregulated genes (n=128) were significantly enriched in the transforming growth factor-β (TGF-β) signaling pathway. Four genes, vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF2), nerve growth factor (NGF) and interleukin 1B (IL1B), presented with relatively higher degrees in both PPI networks. The transcription factor RAD21 was predicted to target shared upregulated and downregulated genes as well as specific downregulated genes in the myogenic and the osteogenic lineages. In addition, miRNA-DEG interaction analysis revealed that hsa-miR-1 regulated the most shared DEGs in the two lineages. There may be a correlation between the four genes, VEGFA, FGF2, IL1B and NGF, and the differentiation of hASCs into myocytes and osteoblasts. The TF RAD21 and hsa-miR-1 may play important roles in regulating the expression of differentiation-associated genes.
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Affiliation(s)
- Liangliang Quan
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
| | - Yang Wang
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
| | - Jiulong Liang
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
| | - Tao Qiu
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
| | - Hongyi Wang
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
| | - Ye Zhang
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
| | - Yu Zhang
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
| | - Qiang Hui
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
| | - Kai Tao
- Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China
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Development of Synthetic and Natural Materials for Tissue Engineering Applications Using Adipose Stem Cells. Stem Cells Int 2016; 2016:5786257. [PMID: 26977158 PMCID: PMC4764745 DOI: 10.1155/2016/5786257] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 01/09/2016] [Accepted: 01/12/2016] [Indexed: 12/12/2022] Open
Abstract
Adipose stem cells have prominent implications in tissue regeneration due to their abundance and relative ease of harvest from adipose tissue and their abilities to differentiate into mature cells of various tissue lineages and secrete various growth cytokines. Development of tissue engineering techniques in combination with various carrier scaffolds and adipose stem cells offers great potential in overcoming the existing limitations constraining classical approaches used in plastic and reconstructive surgery. However, as most tissue engineering techniques are new and highly experimental, there are still many practical challenges that must be overcome before laboratory research can lead to large-scale clinical applications. Tissue engineering is currently a growing field of medical research; in this review, we will discuss the progress in research on biomaterials and scaffolds for tissue engineering applications using adipose stem cells.
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Moghaddam A, Breier L, Haubruck P, Bender D, Biglari B, Wentzensen A, Zimmermann G. Non-unions treated with bone morphogenic protein 7: introducing the quantitative measurement of human serum cytokine levels as promising tool in evaluation of adjunct non-union therapy. JOURNAL OF INFLAMMATION-LONDON 2016; 13:3. [PMID: 26807043 PMCID: PMC4724145 DOI: 10.1186/s12950-016-0111-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 01/19/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND In this study we sought to determine if application of bone morphogenic protein 7 (BMP-7) promotes physiological bone healing of non-unions and to investigate if serum cytokine analysis may serve as a promising tool in the analysis of adjunct non-union therapy. Therefore we analyzed the influence of BMP-7 application on the serum cytokine expression patterns on patients with impaired bone healing compared to patients that showed proper bone healing. METHODS Our study involved analyzing blood samples from 208 patients with long bone fractures together with patients that subsequently developed non-unions. From this large pool, 15 patients with atrophic non-union were matched to 15 patients with atrophic non-union treated with local application of BMP-7 as well as normal bone healing. Changes in the cytokine expression patterns were monitored during the 1st, 2nd, 4th, 8th, 12th and 52nd week. The patients were followed both clinically and radiologically for the entire duration of the study. Serum cytokine expression levels of transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were analyzed and compared. RESULTS Serum expression of TGF-β were nearly parallel in all three groups, however serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p < 0.05). bFGF serum concentrations increased initially in patients with proper bone healing and in those treated with BMP-7. Afterwards, values decreased; bFGF serum concentrations in the BMP-7 group were significantly higher than in the other groups (p < 0.05). PDGF serum concentration levels were nearly parallel in all groups, serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p < 0.05). CONCLUSION Treatment with BMP-7 in patients with former non-unions led to similar cytokine expression patterns after treatment as those found in patients with proper bone healing. Our results suggest that treatment with BMP-7 promote healing of non-unions. Furthermore, quantitative measurement of serum cytokine expression is a promising tool for evaluating the effectiveness of additional non-union therapies such as adjunct application of growth factors.
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Affiliation(s)
- Arash Moghaddam
- HTRG - Heidelberg Trauma Research Group, Trauma and Reconstructive Surgery, Center of Orthopaedics, Traumatology and Paraplegiology, Heidelberg University Hospital, Schlierbacher Landstraße 200a, D-69118 Heidelberg, Germany
| | - Lisa Breier
- Department of Orthopaedics and Traumatology, St. Marienkrankenhaus, Salzburger Str. 15, 67067 Ludwigshafen, Germany
| | - Patrick Haubruck
- HTRG - Heidelberg Trauma Research Group, Trauma and Reconstructive Surgery, Center of Orthopaedics, Traumatology and Paraplegiology, Heidelberg University Hospital, Schlierbacher Landstraße 200a, D-69118 Heidelberg, Germany
| | - Daniel Bender
- Department for anesthesiology, Stadtklinik Frankenthal, Elsa-Brändenström Str. 1, D-67227 Frankenthal, Germany
| | - Bahram Biglari
- Berufsgenossenschaftliche Unfallklinik Ludwigshafen, Department of Paraplegiology, Ludwig-Guttmann-Straße-13, D-67071 Ludwigshafen, Germany
| | - Andreas Wentzensen
- Berufsgenossenschaftliche Unfallklinik Ludwigshafen, Trauma Center, Ludwig-Guttmann-Straße-13, D-67071 Ludwigshafen, Germany
| | - Gerald Zimmermann
- Department for Trauma Surgery, Theresienkrankenhaus und St. Hedwigs-Klinik GmbH, Bassermannstr. 1, D-68165 Mannheim, Germany
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Quarto N, Senarath-Yapa K, Renda A, Longaker MT. TWIST1 silencing enhances in vitro and in vivo osteogenic differentiation of human adipose-derived stem cells by triggering activation of BMP-ERK/FGF signaling and TAZ upregulation. Stem Cells 2015; 33:833-47. [PMID: 25446627 DOI: 10.1002/stem.1907] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 10/06/2014] [Accepted: 10/15/2014] [Indexed: 01/10/2023]
Abstract
Mesenchymal stem cells (MSCs) show promise for cellular therapy and regenerative medicine. Human adipose tissue-derived stem cells (hASCs) represent an attractive source of seed cells in bone regeneration. How to effectively improve osteogenic differentiation of hASCs in the bone tissue engineering has become a very important question with profound translational implications. Numerous regulatory pathways dominate osteogenic differentiation of hASCs involving transcriptional factors and signaling molecules. However, how these factors combine with each other to regulate hASCs osteogenic differentiation still remains to be illustrated. The highly conserved developmental proteins TWIST play key roles for transcriptional regulation in mesenchymal cell lineages. This study investigates TWIST1 function in hASCs osteogenesis. Our results show that TWIST1 shRNA silencing increased the osteogenic potential of hASCs in vitro and their skeletal regenerative ability when applied in vivo. We demonstrate that the increased osteogenic capacity observed with TWIST1 knockdown in hASCs is mediated through endogenous activation of BMP and ERK/FGF signaling leading, in turn, to upregulation of TAZ, a transcriptional modulator of MSCs differentiation along the osteoblast lineage. Inhibition either of BMP or ERK/FGF signaling suppressed TAZ upregulation and the enhanced osteogenesis in shTWIST1 hASCs. Cosilencing of both TWIST1 and TAZ abrogated the effect elicited by TWIST1 knockdown thus, identifying TAZ as a downstream mediator through which TWIST1 knockdown enhanced osteogenic differentiation in hASCs. Our functional study contributes to a better knowledge of molecular mechanisms governing the osteogenic ability of hASCs, and highlights TWIST1 as a potential target to facilitate in vivo bone healing.
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Affiliation(s)
- Natalina Quarto
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University, School of Medicine, Stanford, California, USA; Dipartimento di Scienze Biomediche Avanzate, Universita' degli Studi di Napoli Federico II, Napoli, Italy
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26
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Osteogenic stimulation of human adipose-derived stem cells by pre-treatment with fibroblast growth factor 2. Cell Tissue Res 2015; 364:137-47. [DOI: 10.1007/s00441-015-2311-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 10/04/2015] [Indexed: 12/14/2022]
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The Effect of Covalently Immobilized FGF-2 on Biphasic Calcium Phosphate Bone Substitute on Enhanced Biological Compatibility and Activity. BIOMED RESEARCH INTERNATIONAL 2015; 2015:742192. [PMID: 26436096 PMCID: PMC4576004 DOI: 10.1155/2015/742192] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 04/13/2015] [Accepted: 04/20/2015] [Indexed: 12/30/2022]
Abstract
The purpose of this research was to covalently graft fibroblast growth factor 2 (FGF-2) onto biphasic calcium phosphate (BCP) via a bifunctional cross-linker technique and to estimate the optimal dose of FGF-2 resulting in the best osteogenic differentiation of human mesenchymal stem cells (hMSCs). SEM observation revealed that the surface of the 100 ng FGF-2 coated BCP was completely covered with the nanoparticles expected to be from the silane coupling agent. XRD, FT-IR, and XPS analysis showed that silane treatment, bifunctional cross-linker coating, and FGF-2 covalent grafts were conducted successfully without deforming the crystalline structure of BCP. An MTT assay demonstrated that FGF-2 coated BCP had good biocompatibility, regardless of the concentration of FGF-2, after 24 or 48 h of incubation. An alkaline phosphatase (ALP) activity assay (14 days of incubation) and the ALP gene expression level of real-time PCR analysis (7 days of incubation) revealed that 50, 100, and 200 ng FGF-2 coated BCP induced the highest activities among all experimental groups and control group (P < 0.05). Thus, low concentrations of FGF-2 facilitated excellent osteogenesis and were effective at enhancing osteogenic potential. Also, the bifunctional cross-linker technique is expected to be a more feasible way to induce osteogenic differentiation while minimizing the risk of FGF-2 overdose.
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Park DS, Park JC, Lee JS, Kim TW, Kim KJ, Jung BJ, Shim EK, Choi EY, Park SY, Cho KS, Kim CS. Effect of FGF-2 on Collagen Tissue Regeneration by Human Vertebral Bone Marrow Stem Cells. Stem Cells Dev 2015; 24:228-43. [DOI: 10.1089/scd.2014.0148] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Dong-Soo Park
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Jung-Chul Park
- Department of Periodontology, College of Dentistry, Dankook University, Cheonan, Korea
| | - Jung-Seok Lee
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Tae-Wan Kim
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Ki-Joon Kim
- Department of Neurosurgery, Naeun Hospital, Anyang, Korea
| | - Byung-Joo Jung
- Department of Neurosurgery, Naeun Hospital, Anyang, Korea
| | - Eun-Kyung Shim
- Biomedical Research Institute, iBMT Co., Ltd., Anyang, Korea
| | - Eun-Young Choi
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - So-Yon Park
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Kyoo-Sung Cho
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
| | - Chang-Sung Kim
- Department of Periodontology, Research Institute for Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, Korea
- BK21 PLUS Project, Department of Applied Life Science, College of Dentistry, Yonsei University, Seoul, Korea
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Aguilar E, Bagó JR, Soler-Botija C, Alieva M, Rigola MA, Fuster C, Vila OF, Rubio N, Blanco J. Fast-proliferating adipose tissue mesenchymal-stromal-like cells for therapy. Stem Cells Dev 2014; 23:2908-20. [PMID: 25019281 DOI: 10.1089/scd.2014.0231] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Human mesenchymal stromal cells, whether from the bone marrow or adipose tissue (hASCs), are promising cell therapy agents. However, generation of abundant cells for therapy remains to be a challenge, due to the need of lengthy expansion and the risk of accumulating genomic defects during the process. We show that hASCs can be easily induced to a reversible fast-proliferating phenotype (FP-ASCs) that allows rapid generation of a clinically useful quantity of cells in <2 weeks of culture. Expanded FP-ASCs retain their finite expansion capacity and pluripotent properties. Despite the high proliferation rate, FP-ASCs show genomic stability by array-comparative genomic hybridization, and did not generate tumors when implanted for a long time in an SCID mouse model. Comparative analysis of gene expression patterns revealed a set of genes that can be used to characterize FP-ASCs and distinguish them from hASCs. As potential candidate therapeutic agents, FP-ASCs displayed high vasculogenic capacity in Matrigel assays. Moreover, application of hASCs and FP-ASCs in a fibrin scaffold over a myocardium infarct model in SCID mice showed that both cell types can differentiate to endothelial and myocardium lineages, although FP-ASCs were more potent angiogenesis inducers than hASCs, at promoting myocardium revascularization.
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Affiliation(s)
- Elisabet Aguilar
- 1 Human DNA Variability Department, GENYO-Centre for Genomic and Oncological Research (Pfizer/University of Granada/Andalusian Regional Government) , PTS Granada, Granada, Spain
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30
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Tsuji W, Rubin JP, Marra KG. Adipose-derived stem cells: Implications in tissue regeneration. World J Stem Cells 2014; 6:312-321. [PMID: 25126381 PMCID: PMC4131273 DOI: 10.4252/wjsc.v6.i3.312] [Citation(s) in RCA: 265] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 05/16/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSCs) that are obtained from abundant adipose tissue, adherent on plastic culture flasks, can be expanded in vitro, and have the capacity to differentiate into multiple cell lineages. Unlike bone marrow-derived MSCs, ASCs can be obtained from abundant adipose tissue by a minimally invasive procedure, which results in a high number of cells. Therefore, ASCs are promising for regenerating tissues and organs damaged by injury and diseases. This article reviews the implications of ASCs in tissue regeneration.
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31
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Efficient derivation of osteoprogenitor cells from induced pluripotent stem cells for bone regeneration. INTERNATIONAL ORTHOPAEDICS 2014; 38:1779-85. [DOI: 10.1007/s00264-014-2440-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 06/20/2014] [Indexed: 10/25/2022]
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32
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Tissue extracellular matrix nanoparticle presentation in electrospun nanofibers. BIOMED RESEARCH INTERNATIONAL 2014; 2014:469120. [PMID: 24971329 PMCID: PMC4058126 DOI: 10.1155/2014/469120] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 04/09/2014] [Indexed: 12/27/2022]
Abstract
Biomaterials derived from the decellularization of mature tissues retain biological and architectural features that profoundly influence cellular activity. However, the clinical utility of such materials remains limited as the shape and physical properties are difficult to control. In contrast, scaffolds based on synthetic polymers can be engineered to exhibit specific physical properties, yet often suffer from limited biological functionality. This study characterizes composite materials that present decellularized extracellular matrix (DECM) particles in combination with synthetic nanofibers and examines the ability of these materials to influence stem cell differentiation. Mechanical processing of decellularized tissues yielded particles with diameters ranging from 71 to 334 nm. Nanofiber scaffolds containing up to 10% DECM particles (wt/wt) derived from six different tissues were engineered and evaluated to confirm DECM particle incorporation and to measure bioactivity. Scaffolds containing bone, cartilage, and fat promoted osteogenesis at 1 and 3 weeks compared to controls. In contrast, spleen and lung DECM significantly reduced osteogenic outcomes compared to controls. These findings highlight the potential to incorporate appropriate source DECM nanoparticles within nanofiber composites to design a scaffold with bioactivity targeted to specific applications.
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Senarath-Yapa K, McArdle A, Renda A, Longaker MT, Quarto N. Adipose-derived stem cells: a review of signaling networks governing cell fate and regenerative potential in the context of craniofacial and long bone skeletal repair. Int J Mol Sci 2014; 15:9314-30. [PMID: 24865492 PMCID: PMC4100096 DOI: 10.3390/ijms15069314] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 05/16/2014] [Accepted: 05/20/2014] [Indexed: 02/07/2023] Open
Abstract
Improvements in medical care, nutrition and social care are resulting in a commendable change in world population demographics with an ever increasing skew towards an aging population. As the proportion of the world's population that is considered elderly increases, so does the incidence of osteodegenerative disease and the resultant burden on healthcare. The increasing demand coupled with the limitations of contemporary approaches, have provided the impetus to develop novel tissue regeneration therapies. The use of stem cells, with their potential for self-renewal and differentiation, is one potential solution. Adipose-derived stem cells (ASCs), which are relatively easy to harvest and readily available have emerged as an ideal candidate. In this review, we explore the potential for ASCs to provide tangible therapies for craniofacial and long bone skeletal defects, outline key signaling pathways that direct these cells and describe how the developmental signaling program may provide clues on how to guide these cells in vivo. This review also provides an overview of the importance of establishing an osteogenic microniche using appropriately customized scaffolds and delineates some of the key challenges that still need to be overcome for adult stem cell skeletal regenerative therapy to become a clinical reality.
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Affiliation(s)
- Kshemendra Senarath-Yapa
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, School of Medicine, Stanford University, Stanford, CA 94305-2200, USA; E-Mails: (K.S.-Y.); (A.M.)
| | - Adrian McArdle
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, School of Medicine, Stanford University, Stanford, CA 94305-2200, USA; E-Mails: (K.S.-Y.); (A.M.)
| | - Andrea Renda
- Dipartimento di Scienze Biomediche Avanzate, Universita’ degli Studi di Napoli Federico II, Napoli 80131, Italy; E-Mail:
| | - Michael T. Longaker
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, School of Medicine, Stanford University, Stanford, CA 94305-2200, USA; E-Mails: (K.S.-Y.); (A.M.)
| | - Natalina Quarto
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, School of Medicine, Stanford University, Stanford, CA 94305-2200, USA; E-Mails: (K.S.-Y.); (A.M.)
- Dipartimento di Scienze Biomediche Avanzate, Universita’ degli Studi di Napoli Federico II, Napoli 80131, Italy; E-Mail:
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35
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Dombrowski C, Helledie T, Ling L, Grünert M, Canning CA, Jones CM, Hui JH, Nurcombe V, van Wijnen AJ, Cool SM. FGFR1 Signaling Stimulates Proliferation of Human Mesenchymal Stem Cells by Inhibiting the Cyclin-Dependent Kinase Inhibitors p21Waf1and p27Kip1. Stem Cells 2013; 31:2724-36. [DOI: 10.1002/stem.1514] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 06/27/2013] [Accepted: 07/22/2013] [Indexed: 11/10/2022]
Affiliation(s)
- Christian Dombrowski
- Institute of Medical Biology; Glycotherapeutics Group; 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore Singapore
| | - Torben Helledie
- Institute of Medical Biology; Glycotherapeutics Group; 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore Singapore
| | - Ling Ling
- Institute of Medical Biology; Glycotherapeutics Group; 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore Singapore
| | - Martin Grünert
- Institute of Medical Biology; Glycotherapeutics Group; 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore Singapore
| | - Claire A. Canning
- Institute of Medical Biology; Glycotherapeutics Group; 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore Singapore
| | - C. Michael Jones
- Institute of Medical Biology; Glycotherapeutics Group; 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore Singapore
| | - James H. Hui
- Department of Orthopaedic Surgery; Yong Loo Lin School of Medicine, National University of Singapore; Singapore
| | - Victor Nurcombe
- Institute of Medical Biology; Glycotherapeutics Group; 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore Singapore
| | - Andre J. van Wijnen
- Department of Orthopaedic Surgery; Yong Loo Lin School of Medicine, National University of Singapore; Singapore
- Department of Orthopedic Surgery; Mayo Clinic; Rochester Minnesota USA
| | - Simon M. Cool
- Institute of Medical Biology; Glycotherapeutics Group; 8A Biomedical Grove, #06-06 Immunos, A*STAR, Singapore Singapore
- Department of Orthopaedic Surgery; Yong Loo Lin School of Medicine, National University of Singapore; Singapore
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36
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Wei C, Liu X, Tao J, Wu R, Zhang P, Bian Y, Li Y, Fang F, Zhang Y. Effects of vitamin C on characteristics retaining of in vitro-cultured mouse adipose-derived stem cells. In Vitro Cell Dev Biol Anim 2013; 50:75-86. [PMID: 23949782 DOI: 10.1007/s11626-013-9673-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 07/19/2013] [Indexed: 12/19/2022]
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37
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Hu F, Wang X, Liang G, Lv L, Zhu Y, Sun B, Xiao Z. Effects of epidermal growth factor and basic fibroblast growth factor on the proliferation and osteogenic and neural differentiation of adipose-derived stem cells. Cell Reprogram 2013; 15:224-32. [PMID: 23713433 PMCID: PMC3666248 DOI: 10.1089/cell.2012.0077] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Stem cells used for clinical tissue regeneration therapy should have the capacity of self-renewal, high proliferation, and differentiation and be able to be transplanted in large numbers. Although high concentrations of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) may induce the differentiation of stem cells, these factors have been widely used to enhance the propagation of stem cells, including adipose-derived mesenchymal stem cells (ASCs). However, the effects of low concentrations of EGF and bFGF on stem cells need to be evaluated carefully. This study illustrates that low concentrations of EGF (5 ng/mL) and bFGF (10 ng/mL) increase the proliferative ability of ASCs and induce the typical spindle-shaped cell morphology. EGF and bFGF added to medium promoted neural lineage differentiation and impaired the mesodermal differentiation ability of ASCs. This study demonstrates that even low concentrations of EGF and bFGF may limit the differentiation ability of stem cells during stem cell expansion in vitro. EGF and bFGF supplementation should be carefully considered in stem cells for clinical applications.
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Affiliation(s)
- Feihu Hu
- State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, People's Republic of China
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38
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Palumbo S, Li WJ. Osteoprotegerin enhances osteogenesis of human mesenchymal stem cells. Tissue Eng Part A 2013; 19:2176-87. [PMID: 23597005 DOI: 10.1089/ten.tea.2012.0550] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can differentiate into osteoblasts and hold promise for applications of bone regeneration such as bone tissue engineering. However, current approaches for in vitro osteogenesis cannot effectively induce osteogenesis and need to be modified to produce quality bone for clinical applications. Previous studies have shown that the conditioned medium (CM) from osteoblast culture enhances osteogenesis of MSCs, and soluble osteogenic factors in the CM may be involved in the regulation. However, these factors are not fully identified. In this study, we profiled soluble factors secreted from MG-63 cells using a comparative protein array and found that osteoprotegerin (OPG), known as a potent anti-osteoclastogenic protein, was at the highest relative level among 507 soluble molecules detected by the array. Furthermore, treating hMSCs with OPG before osteogenic induction significantly increased the expression of osteocalcin mRNA transcript and the production of calcium deposits compared to the untreated control cells, suggesting that OPG is capable of priming undifferentiated hMSCs for the enhancement of subsequent osteogenesis. Furthermore, we showed that the nuclear factor-kappaB (NF-κB) was activated by OPG in undifferentiated hMSCs and that blocking NF-κB activation before osteogenic induction decreased osteogenesis of OPG-pretreated cells upon receiving osteogenic stimuli. Taken together, our results suggest that OPG is a pro-osteogenic factor that can be used as an osteogenic supplement in a growth medium to prime the osteogenic capacity of undifferentiated hMSCs to enhance osteogenesis for bone tissue engineering.
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Affiliation(s)
- SunMi Palumbo
- Musculoskeletal Biology and Regenerative Medicine Laboratory, Department of Orthopedics and Rehabilitation, School of Medicine and Public Health, University of Wisconsin-Madison, WI 53705, USA
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Hutton DL, Moore EM, Gimble JM, Grayson WL. Platelet-derived growth factor and spatiotemporal cues induce development of vascularized bone tissue by adipose-derived stem cells. Tissue Eng Part A 2013; 19:2076-86. [PMID: 23582144 DOI: 10.1089/ten.tea.2012.0752] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Vasculature is essential to the functional integration of a tissue-engineered bone graft to enable sufficient nutrient delivery and viability after implantation. Native bone and vasculature develop through intimately coupled, tightly regulated spatiotemporal cell-cell signaling. The complexity of these developmental processes has been a challenge for tissue engineers to recapitulate, resulting in poor codevelopment of both bone and vasculature within a unified graft. To address this, we cultured adipose-derived stromal/stem cells (ASCs), a clinically relevant, single cell source that has been previously investigated for its ability to give rise to vascularized bone grafts, and studied the effects of initial spatial organization of cells, the temporal addition of growth factors, and the presence of exogenous platelet-derived growth factor-BB (PDGF-BB) on the codevelopment of bone and vascular tissue structures. Human ASCs were aggregated into multicellular spheroids via the hanging drop method before encapsulation and subsequent outgrowth in fibrin gels. Cellular aggregation substantially increased vascular network density, interconnectivity, and pericyte coverage compared to monodispersed cultures. To form robust vessel networks, it was essential to culture ASCs in a purely vasculogenic medium for at least 8 days before the addition of osteogenic cues. Physiologically relevant concentrations of exogenous PDGF-BB (20 ng/mL) substantially enhanced both vascular network stability and osteogenic differentiation. Comparisons with the bone morphogenetic protein-2, another pro-osteogenic and proangiogenic growth factor, indicated that this potential to couple the formation of both lineages might be unique to PDGF-BB. Furthermore, the resulting tissue structure demonstrated the close association of mineral deposits with pre-existing vascular structures that have been described for developing tissues. This combination of a single cell source with a potent induction factor used at physiological concentrations can provide a clinically relevant approach to engineering highly vascularized bone grafts.
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Affiliation(s)
- Daphne L Hutton
- Department of Biomedical Engineering, Translational Tissue Engineering Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA
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Santos TC, Morton TJ, Moritz M, Pfeifer S, Reise K, Marques AP, Castro AG, Reis RL, van Griensven M. Vascular Endothelial Growth Factor and Fibroblast Growth Factor-2 Incorporation in Starch-Based Bone Tissue-Engineered Constructs Promote theIn VivoExpression of Neovascularization Mediators. Tissue Eng Part A 2013; 19:834-48. [DOI: 10.1089/ten.tea.2010.0741] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
- Tírcia C. Santos
- 3B's Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Taipas, Guimarães, Portugal
- ICVS-3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Tatjana J. Morton
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Martina Moritz
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Sabine Pfeifer
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Kathrin Reise
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Alexandra P. Marques
- 3B's Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Taipas, Guimarães, Portugal
- ICVS-3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - António G. Castro
- ICVS-3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
- Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
| | - Rui L. Reis
- 3B's Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Taipas, Guimarães, Portugal
- ICVS-3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Martijn van Griensven
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Austrian Cluster for Tissue Regeneration, Vienna, Austria
- Department of Trauma Surgery, Institute for Experimental Trauma Surgery, Technical University Munich, Munich, Germany
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Senarath-Yapa K, Li S, Meyer NP, Longaker MT, Quarto N. Integration of multiple signaling pathways determines differences in the osteogenic potential and tissue regeneration of neural crest-derived and mesoderm-derived calvarial bones. Int J Mol Sci 2013; 14:5978-97. [PMID: 23502464 PMCID: PMC3634461 DOI: 10.3390/ijms14035978] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Revised: 03/05/2013] [Accepted: 03/12/2013] [Indexed: 12/24/2022] Open
Abstract
The mammalian skull vault, a product of a unique and tightly regulated evolutionary process, in which components of disparate embryonic origin are integrated, is an elegant model with which to study osteoblast biology. Our laboratory has demonstrated that this distinct embryonic origin of frontal and parietal bones confer differences in embryonic and postnatal osteogenic potential and skeletal regenerative capacity, with frontal neural crest derived osteoblasts benefitting from greater osteogenic potential. We outline how this model has been used to elucidate some of the molecular mechanisms which underlie these differences and place these findings into the context of our current understanding of the key, highly conserved, pathways which govern the osteoblast lineage including FGF, BMP, Wnt and TGFβ signaling. Furthermore, we explore recent studies which have provided a tantalizing insight into way these pathways interact, with evidence accumulating for certain transcription factors, such as Runx2, acting as a nexus for cross-talk.
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Affiliation(s)
- Kshemendra Senarath-Yapa
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University, School of Medicine, Stanford, CA 94305, USA; E-Mails: (K.S.-Y.); (S.L.); (N.P.M.)
| | - Shuli Li
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University, School of Medicine, Stanford, CA 94305, USA; E-Mails: (K.S.-Y.); (S.L.); (N.P.M.)
| | - Nathaniel P. Meyer
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University, School of Medicine, Stanford, CA 94305, USA; E-Mails: (K.S.-Y.); (S.L.); (N.P.M.)
| | - Michael T. Longaker
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University, School of Medicine, Stanford, CA 94305, USA; E-Mails: (K.S.-Y.); (S.L.); (N.P.M.)
- Authors to whom correspondence should be addressed; E-Mails: (M.T.L.); (N.Q.); Tel.: +1-650-7361-704; Fax: +1-650-7361-705
| | - Natalina Quarto
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University, School of Medicine, Stanford, CA 94305, USA; E-Mails: (K.S.-Y.); (S.L.); (N.P.M.)
- Department of Advanced Biomedical Science, University of Studies of Naples Federico II, Naples 80131, Italy
- Authors to whom correspondence should be addressed; E-Mails: (M.T.L.); (N.Q.); Tel.: +1-650-7361-704; Fax: +1-650-7361-705
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Cholas R, Hsu HP, Spector M. Collagen Scaffolds Incorporating Select Therapeutic Agents to Facilitate a Reparative Response in a Standardized Hemiresection Defect in the Rat Spinal Cord. Tissue Eng Part A 2012; 18:2158-72. [DOI: 10.1089/ten.tea.2011.0577] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Rahmatullah Cholas
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts
- Tissue Engineering Laboratories, Veterans Affairs Boston Healthcare System, Boston, Massachusetts
| | - Hu-Ping Hsu
- Tissue Engineering Laboratories, Veterans Affairs Boston Healthcare System, Boston, Massachusetts
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Myron Spector
- Tissue Engineering Laboratories, Veterans Affairs Boston Healthcare System, Boston, Massachusetts
- Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Kaewsuwan S, Song SY, Kim JH, Sung JH. Mimicking the functional niche of adipose-derived stem cells for regenerative medicine. Expert Opin Biol Ther 2012; 12:1575-88. [PMID: 22953993 DOI: 10.1517/14712598.2012.721763] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION A stem cell (SC) niche is defined as the microenvironment in which the adult SC resides and includes surrounding cells, low oxygen content and growth factor gradients. Crosstalk between SCs and their niche provides signals that keep SCs quiescent, or modulates their activation. AREAS COVERED This review discusses the characterization of niche conditions in the adipose-derived stem cell (ASC) in vivo environment, and introduces key signalling pathways and autocrine/paracrine regulators of ASCs. EXPERT OPINION Control of in vivo niche factors (such as low oxygen content, generation of reactive oxygen species and activation of platelet-derived growth factor receptor signalling) should increase ASC yields synergistically and reduce production costs. Additionally, the preconditioning of ASCs with these niche factors prior to transplantation might enhance their regenerative potential. ASC niche is complex, and there are components of the niche that we may not yet understand. Therefore, future research needs to focus on identifying the key regulatory factors of the ASC niche in vivo, and developing a novel method to mimic these niche factors for in vitro manipulation.
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Gioia R, Panaroni C, Besio R, Palladini G, Merlini G, Giansanti V, Scovassi IA, Villani S, Villa I, Villa A, Vezzoni P, Tenni R, Rossi A, Marini JC, Forlino A. Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy. Stem Cells 2012; 30:1465-76. [PMID: 22511244 PMCID: PMC3459187 DOI: 10.1002/stem.1107] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The molecular basis underlying the clinical phenotype in bone diseases is customarily associated with abnormal extracellular matrix structure and/or properties. More recently, cellular malfunction has been identified as a concomitant causative factor and increased attention has focused on stem cells differentiation. Classic osteogenesis imperfecta (OI) is a prototype for heritable bone dysplasias: it has dominant genetic transmission and is caused by mutations in the genes coding for collagen I, the most abundant protein in bone. Using the Brtl mouse, a well-characterized knockin model for moderately severe dominant OI, we demonstrated an impairment in the differentiation of bone marrow progenitor cells toward osteoblasts. In mutant mesenchymal stem cells (MSCs), the expression of early (Runx2 and Sp7) and late (Col1a1 and Ibsp) osteoblastic markers was significantly reduced with respect to wild type (WT). Conversely, mutant MSCs generated more colony-forming unit-adipocytes compared to WT, with more adipocytes per colony, and increased number and size of triglyceride drops per cell. Autophagy upregulation was also demonstrated in mutant adult MSCs differentiating toward osteogenic lineage as consequence of endoplasmic reticulum stress due to mutant collagen retention. Treatment of the Brtl mice with the proteasome inhibitor Bortezomib ameliorated both osteoblast differentiation in vitro and bone properties in vivo as demonstrated by colony-forming unit-osteoblasts assay and peripheral quantitative computed tomography analysis on long bones, respectively. This is the first report of impaired MSC differentiation to osteoblasts in OI, and it identifies a new potential target for the pharmacological treatment of the disorder.
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Affiliation(s)
- Roberta Gioia
- Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Pavia, Italy
| | - Cristina Panaroni
- Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Pavia, Italy
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan, Italy
| | - Roberta Besio
- Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Pavia, Italy
| | - Giovanni Palladini
- Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Pavia, Italy
- Amyloidosis Research and Treatment Center, Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Giampaolo Merlini
- Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Pavia, Italy
- Amyloidosis Research and Treatment Center, Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | | | - Simona Villani
- Department of Health Sciences, Section of Medical Statistic and Epidemiology, University of Pavia, Pavia, Italy
| | - Isabella Villa
- Bone Metabolic Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Anna Villa
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan, Italy
- Istituto Clinico Humanitas, Rozzano, Italy
| | - Paolo Vezzoni
- Milan Unit, Istituto di Ricerca Genetica e Biomedica, CNR, Milan, Italy
- Istituto Clinico Humanitas, Rozzano, Italy
| | - Ruggero Tenni
- Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Pavia, Italy
| | - Antonio Rossi
- Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Pavia, Italy
| | - Joan C. Marini
- Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland, USA
| | - Antonella Forlino
- Department of Molecular Medicine, Section of Biochemistry, University of Pavia, Pavia, Italy
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Effects of VEGF and FGF-2 on proliferation and differentiation of human periodontal ligament stem cells. Cell Tissue Res 2012; 348:475-84. [PMID: 22437875 DOI: 10.1007/s00441-012-1392-x] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2011] [Accepted: 02/27/2012] [Indexed: 02/06/2023]
Abstract
Human periodontal ligament stem cells (PDLSCs) from extracted third molar teeth are a type of adult stem cell originating from dental tissue. PDLSCs are known to have a self-renewal capacity and multi-lineage differentiation potential. Vascular endothelial growth factor (VEGF), an angiogenic/vasculogenic factor, has been shown to stimulate endothelial cell mitogenesis and cell migration. Another growth factor, fibroblast growth factor-2 (FGF-2), a mitogenic factor, enhances osteogenesis in mesenchymal stem cells (MSCs). This study examines the effects of VEGF and FGF-2 on PDLSCs in vitro and in vivo compared with those on bone marrow stem cells (BMSCs) as a positive control. Treatment of PDLSCs with VEGF increases the accumulation of calcium nodules, alkaline phosphatase (ALP) activity and the formation of hard tissue and up-regulates the mRNA level of runt-related transcription factor 2 (Runx2). In contrast, FGF-2 enhances the proliferation of PDLSCs in vitro in cell culture, where it significantly decreases calcium accumulation and ALP activity and down-regulates the expression of osteogenic gene markers (i.e., Runx2, ALP, type I collagen) involved in osteogenic induction. We have also transplanted PDLSCs with hydroxyapatite/tricalcium phosphate particles (HA/TCP) as carriers for each factor (VEGF, FGF-2) into nude mice and, after 8 weeks, observed the in vivo formation of hard tissue at the dorsal surface. Based on our results, we suggest that VEGF has positive effects on odonto-/osteogenic differentiation in vitro and on the formation of mineralized structure in vivo. FGF-2 might be a powerful promoter of the proliferation of progenitor cells in hard tissue regeneration but exogenous FGF-2 might inhibit terminal differentiation.
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Wu J, Huang GTJ, He W, Wang P, Tong Z, Jia Q, Dong L, Niu Z, Ni L. Basic fibroblast growth factor enhances stemness of human stem cells from the apical papilla. J Endod 2012; 38:614-22. [PMID: 22515889 DOI: 10.1016/j.joen.2012.01.014] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Revised: 01/10/2012] [Accepted: 01/30/2012] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Stem cells from the apical papilla (SCAP) are a type of mesenchymal stem cells found in the developing tissue, apical papilla, of immature permanent teeth. Studies have shown that SCAP are likely to be a source of primary odontoblasts that are responsible for the formation of root dentin. Basic fibroblast growth factor (bFGF) is a signaling molecule and pleiotropic growth factor involved in tooth root development, and it promotes proliferation of a variety of cell types. The effects of bFGF on SCAP, however, have not been examined. METHODS We investigated the regulatory effects of bFGF on the proliferation and differentiation potential of human SCAP in vitro. Changes in the cell cycle and proliferation, colony-forming unit-fibroblastic formation, alkaline phosphatase (ALP) activity, osteogenic/dentinogenic differentiation, and stem cell gene makers of SCAP, cultured in the presence or absence of bFGF, were evaluated. RESULTS Treatment with 5 ng/mL bFGF significantly increased SCAP proliferation and their colony-forming unit-fibroblastic formation efficiency. The growth factor also increased the expression of STRO-1 and the stem cell gene makers Nanog, Oct4, Sox2, and Rex1 in SCAP. In contrast, bFGF reduced the ALP activity, mineral nodule formation, and the expression of ALP, osteocalcin, bone sialoprotein, and dentin sialophosphoprotein. When SCAP cultures were expanded in the presence of bFGF for 1 week, subsequent stimulation of the osteogenic/dentinogenic condition resulted in enhanced differentiation. CONCLUSIONS Under certain conditions, bFGF enhances SCAP stemness by up-regulating stem cell gene expression, increasing proliferation ability, and potentiating differentiation potency.
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Affiliation(s)
- Jiayuan Wu
- Department of Endodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shanxi, People's Republic of China
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Differences in osteogenic differentiation of adipose-derived stromal cells from murine, canine, and human sources in vitro and in vivo. Plast Reconstr Surg 2011; 128:373-386. [PMID: 21788829 DOI: 10.1097/prs.0b013e31821e6e49] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Given the diversity of species from which adipose-derived stromal cells are derived and studied, the authors set out to delineate the differences in the basic cell biology that may exist across species. Briefly, the authors found that significant differences exist with regard to proliferation and osteogenic potentials of adipose-derived stromal cells across species. METHODS Adipose-derived stromal cells were derived from human, mouse, and canine sources as previously described. Retinoic acid, insulin-like growth factor-1, and bone morphogenetic protein-2 were added to culture medium; proliferation and osteogenic differentiation were assessed by standardized assays. In vivo methods included seeding 150,000 adipose-derived stromal cells on a biomimetic scaffold and analyzing healing by micro-computed tomography and histology. RESULTS Adipose-derived stromal cells from all species had the capability to undergo osteogenic differentiation. Canine adipose-derived stromal cells were the most proliferative, whereas human adipose-derived stromal cells were the most osteogenic (p < 0.05). Human cells, however, had the most significant osteogenic response to osteogenic media. Retinoic acid stimulated osteogenesis in mouse and canine cells but not in human adipose-derived stromal cells. Insulin-like growth factor-1 enhanced osteogenesis across all species, most notably in human- and canine-derived cells. CONCLUSIONS Adipose-derived stromal cells derived from human, mouse, and canine all have the capacity to undergo osteogenic differentiation. Canine adipose-derived stromal cells appear to be the most proliferative, whereas human adipose-derived stromal cells appear to be the most osteogenic. Different cytokines and chemicals can be used to modulate this osteogenic response. These results are promising as attempts are made to optimize tissue-engineered bone using adipose-derived stromal cells.
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Osteogenic differentiation of adipose-derived stromal cells in mouse and human: in vitro and in vivo methods. J Craniofac Surg 2011; 22:388-91. [PMID: 21415625 DOI: 10.1097/scs.0b013e318207b72b] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
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Willems WF, Larsen M, Giusti G, Friedrich PF, Bishop AT. Revascularization and bone remodeling of frozen allografts stimulated by intramedullary sustained delivery of FGF-2 and VEGF. J Orthop Res 2011; 29:1431-6. [PMID: 21445997 DOI: 10.1002/jor.21338] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Accepted: 11/22/2010] [Indexed: 02/04/2023]
Abstract
Frozen bone allografts are susceptible to nonunion and fracture due to limited revascularization and incomplete bone remodeling. We aim to revascularize bone allografts by combining angiogenesis from implanted arteriovenous (AV) bundles with delivery of fibroblast growth factor (FGF-2) and/or vascular endothelial growth factor (VEGF) via biodegradable microspheres. Rat femoral diaphyseal allografts were frozen at -80°C, and heterotopically transplanted over a major histocompatibility mismatch. A saphenous AV bundle was inserted into the intramedullary canal. Growth factor was encapsulated into microspheres and inserted into the graft, providing localized and sustained drug release. Forty rats were included in four groups: (I) phosphate-buffered saline, (II) FGF-2, (III) VEGF, and (IV) FGF-2 + VEGF. At 4 weeks, angiogenesis was measured by the hydrogen washout method and microangiography. Bone remodeling was evaluated by quantitative histomorphometry and histology. Bone blood flow was significantly higher in groups III and IV compared to control (p < 0.05). Similarly, bone remodeling was higher in VEGF groups. FGF-2 had little effect on allograft revascularization. No synergistic effect was observed with use of both cytokines. Delivered in microspheres, VEGF proved to be a potent angiogenic cytokine, increasing cortical bone blood flow and new bone formation in frozen allografts revascularized with an implanted AV bundle.
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Affiliation(s)
- Wouter F Willems
- Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA
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Behr B, Sorkin M, Manu A, Lehnhardt M, Longaker MT, Quarto N. Fgf-18 is required for osteogenesis but not angiogenesis during long bone repair. Tissue Eng Part A 2011; 17:2061-9. [PMID: 21457097 PMCID: PMC3142654 DOI: 10.1089/ten.tea.2010.0719] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Accepted: 04/01/2011] [Indexed: 01/28/2023] Open
Abstract
Bone regeneration is a complex event that requires the interaction of numerous growth factors. Fibroblast growth factor (Fgf)-ligands have been previously described for their importance in osteogenesis during development. In the current study, we investigated the role of Fgf-18 during bone regeneration. By utilizing a unicortical tibial defect model, we revealed that mice haploinsufficient for Fgf-18 have a markedly reduced healing capacity as compared with wild-type mice. Reduced levels of Runx2 and Osteocalcin but not Vegfa accompanied the impaired bone regeneration. Interestingly, our data indicated that upon injury angiogenesis was not impaired in Fgf-18(+/-) mice. Moreover, other Fgf-ligands and Bmp-2 could not compensate for the loss of Fgf-18. Finally, application of FGF-18 protein was able to rescue the impaired healing in Fgf-18(+/-) mice. Thus, we identified Fgf-18 as an important mediator of bone regeneration, which is required during later stages of bone regeneration. This study provides hints on how to engineering efficiently programmed bony tissue for long bone repair.
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Affiliation(s)
- Björn Behr
- Hagey Laboratory, Department of Surgery, Stanford University School of Medicine, Stanford, California
- BG-Unfallklinik Ludwigshafen, Department of Plastic- and Handsurgery, University of Heidelberg, Heidelberg, Germany
| | - Michael Sorkin
- Hagey Laboratory, Department of Surgery, Stanford University School of Medicine, Stanford, California
| | - Alina Manu
- Hagey Laboratory, Department of Surgery, Stanford University School of Medicine, Stanford, California
| | - Marcus Lehnhardt
- BG-Unfallklinik Ludwigshafen, Department of Plastic- and Handsurgery, University of Heidelberg, Heidelberg, Germany
| | - Michael T. Longaker
- Hagey Laboratory, Department of Surgery, Stanford University School of Medicine, Stanford, California
| | - Natalina Quarto
- Hagey Laboratory, Department of Surgery, Stanford University School of Medicine, Stanford, California
- Department of Structural and Functional Biology, University of Naples Federico II, Complesso M. S. Angelo, Napoli, Italy
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