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Willbold E, Kalla K, Janning C, Bartsch I, Bobe K, Brauneis M, Haupt M, Reebmann M, Schwarze M, Remennik S, Shechtman D, Nellesen J, Tillmann W, Witte F. Dissolving magnesium hydroxide implants enhance mainly cancellous bone formation whereas degrading RS66 implants lead to prominent periosteal bone formation in rabbits. Acta Biomater 2024; 185:73-84. [PMID: 39053818 DOI: 10.1016/j.actbio.2024.07.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/20/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024]
Abstract
Bone fractures often require internal fixation using plates or screws. Normally, these devices are made of permanent metals like titanium providing necessary strength and biocompatibility. However, they can also cause long-term complications and may require removal. An interesting alternative are biocompatible degradable devices, which provide sufficient initial strength and then degrade gradually. Among other materials, biodegradable magnesium alloys have been developed for craniofacial and orthopaedic applications. Previously, we tested implants made of magnesium hydroxide and RS66, a strong and ductile ZK60-based alloy, with respect to biocompatibility and degradation behaviour. Here, we compare the effects of dissolving magnesium hydroxide and RS66 cylinders on bone regeneration and bone growth in rabbit condyles using microtomographical and histological analysis. Both magnesium hydroxide and RS66 induced a considerable osteoblastic activity leading to distinct but different spatio-temporal patterns of cancellous and periosteal bone growth. Dissolving RS66 implants induced a prominent periosteal bone formation on the medial surface of the original condyle whereas dissolving magnesium hydroxide implants enhance mainly cancellous bone formation. Especially periosteal bone formation was completed after 6 and 8 weeks, respectively. The observed bone promoting functions are in line with previous reports of magnesium stimulating cancellous and periosteal bone growth and possible underlying signalling mechanisms are discussed. STATEMENT OF SIGNIFICANCE: Biodegradable magnesium based implants are promising candidates for use in orthopedic and traumatic surgery. Although these implants are in the scientific focus for a long time, comparatively little is known about the interactions between degrading magnesium and the biological environment. In this work, we investigated the effects of two degrading cylindrical magnesium implants (MgOH2 and RS66) both on bone regeneration and on bone growth. Both MgOH2 and RS66 induce remarkable osteoblastic activities, however with different spatio-temporal patterns regarding cancellous and periosteal bone growth. We hypothesize that degradation products do not diffuse directionless away, but are transported by the restored blood flow in specific spatial patterns which is also dependent on the used surgical technique.
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Affiliation(s)
- Elmar Willbold
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany.
| | - Katharina Kalla
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany
| | - Carla Janning
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany
| | - Ivonne Bartsch
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany
| | - Katharina Bobe
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany
| | - Maria Brauneis
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany
| | - Maike Haupt
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany
| | - Mattias Reebmann
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany
| | - Michael Schwarze
- Laboratory for Biomechanics and Biomaterials, Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625 Hannover, Germany
| | - Sergei Remennik
- The Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel
| | - Dan Shechtman
- Department of Materials Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel
| | - Jens Nellesen
- Institute of Materials Engineering, Technische Universität Dortmund, Leonhard-Euler-Straße 2, 44227 Dortmund, Germany
| | - Wolfgang Tillmann
- Institute of Materials Engineering, Technische Universität Dortmund, Leonhard-Euler-Straße 2, 44227 Dortmund, Germany
| | - Frank Witte
- Charité - Universitätsmedizin Berlin, Department of Prosthodontics, Geriatric Dentistry and Craniomandibular Disorders, Aßmannshauser Straße 4-6, 14197, Berlin, Germany
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Tan J, Li S, Sun C, Bao G, Liu M, Jing Z, Fu H, Sun Y, Yang Q, Zheng Y, Wang X, Yang H. A Dose-Dependent Spatiotemporal Response of Angiogenesis Elicited by Zn Biodegradation during the Initial Stage of Bone Regeneration. Adv Healthc Mater 2024; 13:e2302305. [PMID: 37843190 DOI: 10.1002/adhm.202302305] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 10/09/2023] [Indexed: 10/17/2023]
Abstract
Zinc (Zn) plays a crucial role in bone metabolism and imbues biodegradable Zn-based materials with the ability to promote bone regeneration in bone trauma. However, the impact of Zn biodegradation on bone repair, particularly its influence on angiogenesis, remains unexplored. This study reveals that Zn biodegradation induces a consistent dose-dependent spatiotemporal response in angiogenesis,both in vivo and in vitro. In a critical bone defect model, an increase in Zn release intensity from day 3 to 10 post-surgery is observed. By day 10, the CD31-positive area around the Zn implant significantly surpasses that of the Ti implant, indicating enhanced angiogenesis. Furthermore,angiogenesis exhibits a distance-dependent pattern closely mirroring the distribution of Zn signals from the implant. In vitro experiments demonstrate that Zn extraction fosters the proliferation and migration of human umbilical vein endothelial cells and upregulates the key genes associated with tube formation, such as HIF-1α and VEGF-A, peaking at a concentration of 22.5 µM. Additionally, Zn concentrations within the range of 11.25-45 µM promote the polarization of M0-type macrophages toward the M2-type, while inhibiting polarization toward the M1-type. These findings provide essential insights into the biological effects of Zn on bone repair, shedding light on its potential applications.
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Affiliation(s)
- Junlong Tan
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 37 Xueyuan Rd, Beijing, 100191, China
| | - Shuang Li
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 37 Xueyuan Rd, Beijing, 100191, China
| | - Chaoyang Sun
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 37 Xueyuan Rd, Beijing, 100191, China
| | - Guo Bao
- Department of Reproduction and Physiology, National Research Institute for Family Planning, Beijing, 100081, China
| | - Meijing Liu
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 37 Xueyuan Rd, Beijing, 100191, China
| | - Zehao Jing
- Beijing Key Laboratory of Spinal Disease Research, Engineering Research Center of Bone and Joint Precision Medicine, Ministry of Education, Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, P. R. China
| | - Hanwei Fu
- School of Materials Science and Engineering, Beihang University, 37 Xueyuan Rd, Beijing, China
| | - Yanhua Sun
- Shandong Provincial Key Laboratory of Microparticles Drug Delivery Technology, Qilu Pharmaceutical Co. Ltd., Jinan, 250100, China
| | - Qingmin Yang
- Shandong Provincial Key Laboratory of Microparticles Drug Delivery Technology, Qilu Pharmaceutical Co. Ltd., Jinan, 250100, China
| | - Yufeng Zheng
- Beijing Advanced Innovation Center for Materials Genome Engineering and School of Materials Science and Engineering, Peking University, Beijing, 100871, China
| | - Xiaogang Wang
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 37 Xueyuan Rd, Beijing, 100191, China
| | - Hongtao Yang
- Key Laboratory of Big Data-Based Precision Medicine, School of Engineering Medicine, Beihang University, 37 Xueyuan Rd, Beijing, 100191, China
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Xu J, He S, Xia T, Shan Y, Wang L. Targeting type H vessels in bone-related diseases. J Cell Mol Med 2024; 28:e18123. [PMID: 38353470 PMCID: PMC10865918 DOI: 10.1111/jcmm.18123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 01/01/2024] [Accepted: 01/09/2024] [Indexed: 02/16/2024] Open
Abstract
Blood vessels are essential for bone development and metabolism. Type H vessels in bone, named after their high expression of CD31 and Endomucin (Emcn), have recently been reported to locate mainly in the metaphysis, exhibit different molecular properties and couple osteogenesis and angiogenesis. A strong correlation between type H vessels and bone metabolism is now well-recognized. The crosstalk between type H vessels and osteoprogenitor cells is also involved in bone metabolism-related diseases such as osteoporosis, osteoarthritis, fracture healing and bone defects. Targeting the type H vessel formation may become a new approach for managing a variety of bone diseases. This review highlighted the roles of type H vessels in bone-related diseases and summarized the research attempts to develop targeted intervention, which will help us gain a better understanding of their potential value in clinical application.
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Affiliation(s)
- Juan Xu
- Outpatient DepartmentChildren's Hospital of Soochow UniversitySuzhouChina
| | - Shuang‐jian He
- Department of OrthopaedicsSuzhou Hospital, Affiliated Hospital of Medical School, Nanjing UniversitySuzhouChina
| | - Ting‐ting Xia
- Clinical Research InstituteSuzhou Hospital, Affiliated Hospital of Medical School, Nanjing UniversitySuzhouChina
| | - Yu Shan
- Department of OrthopeadicsSuzhou Ninth Hospital Affiliated to Soochow UniversitySuzhouChina
| | - Liang Wang
- Department of OrthopaedicsSuzhou Hospital, Affiliated Hospital of Medical School, Nanjing UniversitySuzhouChina
- Department of OrthopeadicsThe Fourth Affiliated Hospital of Soochow UniversitySuzhouChina
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Wang Y, Xie Y, Wang X, Yang N, Wu Z, Zhang X. Tumor cells-derived extracellular vesicles carry circ_0064516 competitively inhibit microRNA-6805-3p and promote cervical cancer angiogenesis and tumor growth. Expert Opin Ther Targets 2024; 28:97-112. [PMID: 38270096 DOI: 10.1080/14728222.2024.2306353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 01/12/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer. RESEARCH DESIGN AND METHODS Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation. RESULTS In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice. CONCLUSIONS We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.
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Affiliation(s)
- Yujue Wang
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yao Xie
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xue Wang
- Department of Obstetrics and Gynecology, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, Sichuan, China
| | - Nian Yang
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhao Wu
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xun Zhang
- Department of Obstetrics and Gynecology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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Weng T, Yang M, Zhang W, Jin R, Xia S, Zhang M, Wu P, He X, Han C, Zhao X, Wang X. Dual gene-activated dermal scaffolds regulate angiogenesis and wound healing by mediating the coexpression of VEGF and angiopoietin-1. Bioeng Transl Med 2023; 8:e10562. [PMID: 37693053 PMCID: PMC10487340 DOI: 10.1002/btm2.10562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 05/22/2023] [Accepted: 06/01/2023] [Indexed: 09/12/2023] Open
Abstract
The vascularization of dermal substitutes is a key challenge in efforts to heal deep skin defects. In this study, dual gene-activated dermal scaffolds (DGADSs-1) were fabricated by loading nanocomposite particles of polyethylenimine (PEI)/multiple plasmid DNAs (pDNAs) encoding vascular endothelial growth factor and angiopoietin-1 at a ratio of 1:1. In a similar manner, DGADSs-2 were loaded with a chimeric plasmid encoding both VEGF and Ang-1. In vitro studies showed that both types of DGADSs released PEI/pDNA nanoparticles in a sustained manner; they demonstrated effective transfection ability, leading to upregulated expression of VEGF and Ang-1. Furthermore, both types of DGADSs promoted fibroblast proliferation and blood vessel formation, although DGADSs-1 showed a more obvious promotion effect. A rat full-thickness skin defect model showed that split-thickness skin transplanted using a one-step method could achieve full survival at the 12th day after surgery in both DGADSs-1 and DGADSs-2 groups, and the vascularization time of dermal substitutes was significantly shortened. Compared with the other three groups of scaffolds, the DGADSs-1 group had significantly greater cell infiltration, collagen deposition, neovascularization, and vascular maturation, all of which promoted wound healing. Thus, compared with single-gene-activated dermal scaffolds, DGADSs show greater potential for enhancing angiogenesis. DGADSs with different loading modes also exhibited differences in terms of angiogenesis; the effect of loading two genes (DGADSs-1) was better than the effect of loading a chimeric gene (DGADSs-2). In summary, DGADSs, which continuously upregulate VEGF and Ang-1 expression, offer a new functional tissue-engineered dermal substitute with the ability to activate vascularization.
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Affiliation(s)
- Tingting Weng
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
- Department of Burn and Plastic SurgeryChildren's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical CenterHangzhouChina
| | - Min Yang
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
| | - Wei Zhang
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
| | - Ronghua Jin
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
| | - Sizhan Xia
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
| | - Manjia Zhang
- The First Clinical Medical College, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Pan Wu
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
| | - Xiaojie He
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
| | - Chunmao Han
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
| | - Xiong Zhao
- Department of Burn and Plastic SurgeryChildren's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical CenterHangzhouChina
| | - Xingang Wang
- Department of Burns & Wound Care CentreSecond Affiliated Hospital of Zhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Severe Trauma and Burns of Zhejiang ProvinceHangzhouChina
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Dhumale P, Nielsen JV, Hansen ACS, Burton M, Beck HC, Jørgensen MG, Toyserkani NM, Haahr MK, Hansen ST, Lund L, Thomassen M, Sørensen JA, Andersen DC, Jensen CH, Sheikh SP. CD31 defines a subpopulation of human adipose-derived regenerative cells with potent angiogenic effects. Sci Rep 2023; 13:14401. [PMID: 37658225 PMCID: PMC10474028 DOI: 10.1038/s41598-023-41535-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 08/28/2023] [Indexed: 09/03/2023] Open
Abstract
Cellular heterogeneity represents a major challenge for regenerative treatment using freshly isolated Adipose Derived Regenerative Cells (ADRCs). Emerging data suggest superior efficacy of ADRCs as compared to the ex vivo expanded and more homogeneous ADRCs (= ASCs) for indications involving (micro)vascular deficiency, however, it remains unknown which ADRC cell subtypes account for the improvement. Surprisingly, we found regarding erectile dysfunction (ED) that the number of injected CD31+ ADRCs correlated positively with erectile function 12 months after one bolus of autologous ADRCs. Comprehensive in vitro and ex vivo analyses confirmed superior pro-angiogenic and paracrine effects of human CD31+ enriched ADRCs compared to the corresponding CD31- and parent ADRCs. When CD31+, CD31- and ADRCs were co-cultured in aortic ring- and corpus cavernous tube formation assays, the CD31+ ADRCs induced significantly higher tube development. This effect was corroborated using conditioned medium (CM), while quantitative mass spectrometric analysis suggested that this is likely explained by secretory pro-angiogenic proteins including DKK3, ANGPT2, ANAX2 and VIM, all enriched in CD31+ ADRC CM. Single-cell RNA sequencing showed that transcripts of the upregulated and secreted proteins were present in 9 endothelial ADRC subsets including endothelial progenitor cells in the heterogenous non-cultured ADRCs. Our data suggest that the vascular benefit of using ADRCs in regenerative medicine is dictated by CD31+ ADRCs.
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Affiliation(s)
- Pratibha Dhumale
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Department of Clinical Biochemistry, Odense University Hospital (OUH), Odense, Denmark
| | - Jakob Vennike Nielsen
- Department of Clinical Biochemistry, Odense University Hospital (OUH), Odense, Denmark
| | | | - Mark Burton
- Department of Clinical Genetics, OUH, Odense, Denmark
| | - Hans Christian Beck
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Department of Clinical Biochemistry, Odense University Hospital (OUH), Odense, Denmark
| | - Mads Gustaf Jørgensen
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Research Unit for Plastic Surgery, Department of Clinical Research, SDU, Odense, Denmark
| | - Navid Mohamadpour Toyserkani
- Department of Plastic Surgery, OUH, Odense, Denmark
- Research Unit for Plastic Surgery, Department of Clinical Research, SDU, Odense, Denmark
| | | | - Sabrina Toft Hansen
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Department of Urology, OUH, Odense, Denmark
| | - Lars Lund
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Department of Urology, OUH, Odense, Denmark
| | - Mads Thomassen
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Department of Clinical Genetics, OUH, Odense, Denmark
| | - Jens Ahm Sørensen
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Department of Plastic Surgery, OUH, Odense, Denmark
- Research Unit for Plastic Surgery, Department of Clinical Research, SDU, Odense, Denmark
| | - Ditte Caroline Andersen
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Department of Clinical Biochemistry, Odense University Hospital (OUH), Odense, Denmark
| | - Charlotte Harken Jensen
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark
- Department of Clinical Biochemistry, Odense University Hospital (OUH), Odense, Denmark
| | - Søren Paludan Sheikh
- Department of Clinical Research, University of Southern Denmark (SDU), Odense, Denmark.
- Department of Clinical Biochemistry, Odense University Hospital (OUH), Odense, Denmark.
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Löffler J, Noom A, Ellinghaus A, Dienelt A, Kempa S, Duda GN. A comprehensive molecular profiling approach reveals metabolic alterations that steer bone tissue regeneration. Commun Biol 2023; 6:327. [PMID: 36973478 PMCID: PMC10042875 DOI: 10.1038/s42003-023-04652-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/01/2023] [Indexed: 03/29/2023] Open
Abstract
Bone regeneration after fracture is a complex process with high and dynamic energy demands. The impact of metabolism on bone healing progression and outcome, however, is so far understudied. Our comprehensive molecular profiling reveals that central metabolic pathways, such as glycolysis and the citric acid cycle, are differentially activated between rats with successful or compromised bone regeneration (young versus aged female Sprague-Dawley rats) early in the inflammatory phase of bone healing. We also found that the citric acid cycle intermediate succinate mediates individual cellular responses and plays a central role in successful bone healing. Succinate induces IL-1β in macrophages, enhances vessel formation, increases mesenchymal stromal cell migration, and potentiates osteogenic differentiation and matrix formation in vitro. Taken together, metabolites-here particularly succinate-are shown to play central roles as signaling molecules during the onset of healing and in steering bone tissue regeneration.
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Affiliation(s)
- Julia Löffler
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 10115, Berlin, Germany
| | - Anne Noom
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Agnes Ellinghaus
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Anke Dienelt
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Stefan Kempa
- Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 10115, Berlin, Germany.
| | - Georg N Duda
- Julius Wolff Institute (JWI), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353, Berlin, Germany.
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8
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Bohlouli M, Bastami F, Nokhbatolfoghahei H, Khojasteh A. Tissue buccal fat pad-stromal vascular fraction as a safe source in maxillofacial bone regeneration: A clinical pilot study. J Plast Reconstr Aesthet Surg 2023; 79:111-121. [PMID: 36917913 DOI: 10.1016/j.bjps.2023.01.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 11/24/2022] [Accepted: 01/29/2023] [Indexed: 02/09/2023]
Abstract
AIM The purpose of this study was to examine the biological properties of the buccal fat pad (BFP)-derived tissue stromal vascular fraction (tSVF) in vitro and compare them with BFP-derived cellular SVF (cSVF). Furthermore, a clinical pilot study assessed the safety of using BFP-derived tSVF for maxillofacial bone regeneration. MATERIALS AND METHODS This study was performed in two sections: 1) experimental section: BFP tissue was harvested from three healthy donors, and then cSVF and tSVF were isolated by enzymatic and mechanical methods to assess their biological properties and 2) clinical section: Ten patients with maxillofacial bone defects were enrolled according to eligibility criteria and offered two options for surgery, including autologous BFP-tSVF (n = 5) and autologous bone grafting (n = 5), to evaluate safety after a year of follow-up. RESULTS The BFP-tSVF exhibited high cell viability and various cell surface markers, including CD45, CD31, and CD34. There was no population-doubling time and multilineage differentiation capacity compared with BFP-cSVF. BFP-tSVF is safe because of the lack of intervention-related adverse events reported in donor and surgery sites during a one-year period. In addition, cell therapy was feasible because it can be performed during surgery and requires little preparation time. Patients in the ABG group experienced pain and tenderness in the iliac crest, leading to dissatisfaction and complications. CONCLUSION The experimental results confirmed that the cells isolated from BFP-tSVF have stemness properties similar to BFP-cSVF. Clinical evaluation also indicated that this cellular product could be used safely to regenerate maxillofacial bone defects.
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Affiliation(s)
- Mahboubeh Bohlouli
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fashid Bastami
- Department of Oral-Maxillofacial Surgery, Dental Research Center, Research Institute of Dental Sciences Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hanieh Nokhbatolfoghahei
- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arash Khojasteh
- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Duda GN, Geissler S, Checa S, Tsitsilonis S, Petersen A, Schmidt-Bleek K. The decisive early phase of bone regeneration. Nat Rev Rheumatol 2023; 19:78-95. [PMID: 36624263 DOI: 10.1038/s41584-022-00887-0] [Citation(s) in RCA: 122] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2022] [Indexed: 01/11/2023]
Abstract
Bone has a remarkable endogenous regenerative capacity that enables scarless healing and restoration of its prior mechanical function, even under challenging conditions such as advanced age and metabolic or immunological degenerative diseases. However - despite much progress - a high number of bone injuries still heal with unsatisfactory outcomes. The mechanisms leading to impaired healing are heterogeneous, and involve exuberant and non-resolving immune reactions or overstrained mechanical conditions that affect the delicate regulation of the early initiation of scar-free healing. Every healing process begins phylogenetically with an inflammatory reaction, but its spatial and temporal intensity must be tightly controlled. Dysregulation of this inflammatory cascade directly affects the subsequent healing phases and hinders the healing progression. This Review discusses the complex processes underlying bone regeneration, focusing on the early healing phase and its highly dynamic environment, where vibrant changes in cellular and tissue composition alter the mechanical environment and thus affect the signalling pathways that orchestrate the healing process. Essential to scar-free healing is the interplay of various dynamic cascades that control timely resolution of local inflammation and tissue self-organization, while also providing sufficient local stability to initiate endogenous restoration. Various immunotherapy and mechanobiology-based therapy options are under investigation for promoting bone regeneration.
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Affiliation(s)
- Georg N Duda
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany. .,Berlin Institute of Health Centre for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
| | - Sven Geissler
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health Centre for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Sara Checa
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Serafeim Tsitsilonis
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health Centre for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.,Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ansgar Petersen
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health Centre for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health Centre for Regenerative Therapies (BCRT), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
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10
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Niemann M, Ort M, Lauterbach L, Streitz M, Wilhelm A, Grütz G, Fleckenstein FN, Graef F, Blankenstein A, Reinke S, Stöckle U, Perka C, Duda GN, Geißler S, Winkler T, Maleitzke T. Individual immune cell and cytokine profiles determine platelet-rich plasma composition. Arthritis Res Ther 2023; 25:6. [PMID: 36627721 PMCID: PMC9830842 DOI: 10.1186/s13075-022-02969-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 12/02/2022] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE Platelet-rich plasma (PRP) therapy is increasingly popular to treat musculoskeletal diseases, including tendinopathies and osteoarthritis (OA). To date, it remains unclear to which extent PRP compositions are determined by the immune cell and cytokine profile of individuals or by the preparation method. To investigate this, we compared leukocyte and cytokine distributions of different PRP products to donor blood samples and assessed the effect of pro-inflammatory cytokines on chondrocytes. DESIGN For each of three PRP preparations (ACP®, Angel™, and nSTRIDE® APS), products were derived using whole blood samples from twelve healthy donors. The cellular composition of PRP products was analyzed by flow cytometry using DURAClone antibody panels (DURAClone IM Phenotyping Basic and DURAClone IM T Cell Subsets). The MESO QuickPlex SQ 120 system was used to assess cytokine profiles (V-PLEX Proinflammatory Panel 1 Human Kit, Meso Scale Discovery). Primary human chondrocyte 2D and 3D in vitro cultures were exposed to recombinant IFN-γ and TNF-α. Proliferation and chondrogenic differentiation were quantitatively assessed. RESULTS All three PRP products showed elevated portions of leukocytes compared to baseline levels in donor blood. Furthermore, the pro-inflammatory cytokines IFN-γ and TNF-α were significantly increased in nSTRIDE® APS samples compared to donor blood and other PRP products. The characteristics of all other cytokines and immune cells from the donor blood, including pro-inflammatory T cell subsets, were maintained in all PRP products. Chondrocyte proliferation was impaired by IFN-γ and enhanced by TNF-α treatment. Differentiation and cartilage formation were compromised upon treatment with both cytokines, resulting in altered messenger ribonucleic acid (mRNA) expression of collagen type 1A1 (COL1A1), COL2A1, and aggrecan (ACAN) as well as reduced proteoglycan content. CONCLUSIONS Individuals with elevated levels of cells with pro-inflammatory properties maintain these in the final PRP products. The concentration of pro-inflammatory cytokines strongly varies between PRP products. These observations may help to unravel the previously described heterogeneous response to PRP in OA therapy, especially as IFN-γ and TNF-α impacted primary chondrocyte proliferation and their characteristic gene expression profile. Both the individual's immune profile and the concentration method appear to impact the final PRP product. TRIAL REGISTRATION This study was prospectively registered in the Deutsches Register Klinischer Studien (DRKS) on 4 November 2021 (registration number DRKS00026175).
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Affiliation(s)
- Marcel Niemann
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Melanie Ort
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany.
- Department of Biology, Chemistry and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195, Berlin, Germany.
| | - Luis Lauterbach
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Mathias Streitz
- Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Südufer 10, 17493, Greifswald, Insel Riems, Germany
| | - Andreas Wilhelm
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Gerald Grütz
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Florian N Fleckenstein
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Diagnostic and Interventional Radiology, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Frank Graef
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Antje Blankenstein
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Simon Reinke
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Ulrich Stöckle
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Carsten Perka
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Georg N Duda
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Sven Geißler
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Tobias Winkler
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Tazio Maleitzke
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Anna-Louisa-Karsch-Straße 2, 10178, Berlin, Germany
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11
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Kan T, He Z, Du J, Xu M, Cui J, Han X, Tong D, Li H, Yan M, Yu Z. Irisin promotes fracture healing by improving osteogenesis and angiogenesis. J Orthop Translat 2022; 37:37-45. [PMID: 36196152 PMCID: PMC9513699 DOI: 10.1016/j.jot.2022.07.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 06/27/2022] [Accepted: 07/15/2022] [Indexed: 11/08/2022] Open
Abstract
Background Osteogenesis and angiogenesis are important for bone fracture healing. Irisin is a muscle-derived monokine that is associated with bone formation. Methods To demonstrate the effect of irisin on bone fracture healing, closed mid-diaphyseal femur fractures were produced in 8-week-old C57BL/6 mice. Irisin was administrated intraperitoneally every other day after surgery, fracture healing was assessed by using X-rays. Bone morphometry of the fracture callus were assessed by using micro-computed tomography. Femurs of mice from each group were assessed by the three-point bending testing. Effect of irisin on osteogenic differentiation in mesenchymal stem cells in vitro was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), alkaline phosphatase staining and alizarin red staining. Angiogenesis of human umbilical vein endothelial cells (HUVECs) were evaluated by qRT-PCR, migration tests, and tube formation assays. Results Increased callus formation, mineralization and tougher fracture healing were observed in the irisin-treated group than in the control group, indicating the better fracture callus healing due to Irisin treatment. The vessel surface and vessel volume fraction of the callus also increased in the irisin-treated group. The expression of BMP2, CD31, and VEGF in callus were enhanced in the irisin-treated group. In mouse bone mesenchymal stem cells, irisin promoted ALP expression and mineralization, and increased the expression of osteogenic genes, including OSX, Runx2, OPG, ALP, OCN and BMP2. Irisin also promoted HUVEC migration and tube formation. Expression of angiogenic genes, including ANGPT1, ANGPT2, VEGFb, CD31, FGF2, and PDGFRB in HUVECs were increased by irisin. Conclusion All the results indicate irisin can promote fracture healing through osteogenesis and angiogenesis. These findings help in the understanding of muscle–bone interactions during fracture healing. The Translational Potential of this Article Irisin was one of the most important monokine secreted by skeletal muscle. Studies have found that irisin have anabolic effect one bone remodeling through affecting osteocyte and osteoblast. Based on our study, irisin could promote bone fracture healing by increasing bone mass and vascularization, which provide a potential usage of irisin to promote fracture healing and improve clinical outcomes.
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12
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Ji R, Ji Y, Ma L, Ge S, Chen J, Wu S, Huang T, Sheng Y, Wang L, Yi N, Liu Z. Keratin 17 upregulation promotes cell metastasis and angiogenesis in colon adenocarcinoma. Bioengineered 2021; 12:12598-12611. [PMID: 34935584 PMCID: PMC8809968 DOI: 10.1080/21655979.2021.2010393] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 01/05/2023] Open
Abstract
Colon adenocarcinoma (COAD), having high malignancy and poor prognosis, is the main pathological type of colon cancer. Previous studies show that Keratin 17 (KRT17) plays an important role in the development of many malignant tumors. However, its role and the molecular mechanism underlying COAD remain unclear. Using TCGA and ONCOMINE databases, as well as immunohistochemistry, we found that the expression of KRT17 was higher in COAD tissues as compared to that in the adjacent normal tissues. Cell- and animal-based experiments showed that overexpression of KRT17 promoted the invasion and metastasis of colon cancer cells while knocking down KRT17 reversed these processes both in vitro and in vivo. In addition, we also showed that KRT17 promoted the formation of new blood vessels. Mechanistically, KRT17 could regulate the WNT/β-catenin signaling pathway, and APC may be involved in this process by interacting with KRT17. In summary, these findings suggested that high expression of KRT17 could promote cell metastasis and angiogenesis of colon cancer cells by regulating the WNT/β-catenin signaling pathway. Thus, KRT17 could be a potential therapeutic target for COAD treatment.
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Affiliation(s)
- Ran Ji
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Yifei Ji
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Lin Ma
- Department of Gastroenterology, Affiliated Haian Hospital of Nantong University, Nantong, China
| | - Sijia Ge
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Jing Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Shuzhen Wu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Tianxin Huang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Yu Sheng
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Liyang Wang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Nan Yi
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhaoxiu Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
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13
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Monaco MCG, Maric D, Salvucci O, Passeri CAL, Accorsi P, Major EO, Berardi AC. Identification of circulating CD31 +CD45 + cell populations with the potential to differentiate into erythroid cells. Stem Cell Res Ther 2021; 12:236. [PMID: 33849659 PMCID: PMC8042691 DOI: 10.1186/s13287-021-02311-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/25/2021] [Indexed: 01/05/2023] Open
Abstract
Erythro-myeloid progenitors (EMP) are found in a population of cells expressing CD31 and CD45 markers (CD31+CD45+). A recent study indicated that EMPs persist until adulthood and can be a source of endothelial cells. We identified two sub-populations of EMP cells, CD31lowCD45low and CD31highCD45+, from peripheral blood that can differentiate into cells of erythroid lineage. Our novel findings add to the current knowledge of hematopoietic lineage commitment, and our sequential, dual-step, in vitro culture model provides a platform for the study of the molecular and cellular mechanisms underlying human hematopoiesis and erythroid differentiation.
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Affiliation(s)
- Maria Chiara G Monaco
- Viral Immunology Section, National Institute of Neurological, Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Dragan Maric
- NINDS Flow Cytometry Core Facility, National Institutes of Health, Bethesda, MD, USA
| | - Ombretta Salvucci
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - Patrizia Accorsi
- Department of Haematology, Transfusion Medicine and Biotechnologies, Santo Spirito Hospital, 65125, Pescara, Italy
| | - Eugene O Major
- Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Anna Concetta Berardi
- Department of Haematology, Laboratory of Stem Cells, Transfusion Medicine and Biotechnologies, Santo Spirito Hospital, Pescara, Italy.
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14
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Wang C, Xu H, Liu C, Peng Z, Min R, Zhang Z, Li J, Jin Y, Wang Y, Li Z, Guo J, Zhu L. CaO 2/gelatin oxygen slow-releasing microspheres facilitate tissue engineering efficiency for the osteonecrosis of femoral head by enhancing the angiogenesis and survival of grafted bone marrow mesenchymal stem cells. Biomater Sci 2021; 9:3005-3018. [PMID: 33651043 DOI: 10.1039/d0bm02071k] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The osteonecrosis of femoral head (ONFH), a common refractory disease, is still not fully understood today. Hypoxia caused by ischemia is not only an important pathogenic factor but also a critical challenge for the survival of seed cells in the tissue engineering therapy of ONFH. To explore an efficient strategy to treat ONFH by targeting hypoxia, newly designed CaO2/gelatin microspheres were composited with 3D printed polycaprolactone/nano-hydroxyapatite (PCL/nHA) porous scaffold, sodium alginate/gelatin hydrogel, and bone marrow mesenchymal stem cells (BMSCs) to develop a novel tissue engineering scaffold and then transplanted into the core depression area of the ONFH rabbit model. The current data demonstrated that CaO2/gelatin microspheres can constantly release oxygen for 19 days. In vitro assays with BMSCs illustrated that scaffolds have high biocompatibility and are favorable for cell proliferation in extreme hypoxia (1% O2). The in vivo study demonstrated that the transplanted scaffold with oxygen-generating microspheres significantly enhanced the osteogenic and angiogenic effects compared to the scaffold without microspheres. Further assessments revealed that microspheres in the scaffold can reduce the local cell apoptosis and enhance the survival of grafted cells in the host. Collectively, the present study developed a novel oxygen slow-releasing composite scaffold, which can facilitate tissue engineering efficiency for treating the osteonecrosis of the femoral head by enhancing the angiogenesis and survival of grafted stem cells.
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Affiliation(s)
- Chengqiang Wang
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Haixia Xu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Chun Liu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Ziyue Peng
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Ruoxing Min
- Department of Ultrasound Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
| | - Zhiming Zhang
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China. and Department of Orthopedics, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Jianjun Li
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Yanglei Jin
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Yihan Wang
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Zhihao Li
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
| | - Jiasong Guo
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China. and Department of Histology and Embryology, Southern Medical University, Guangzhou 510515, China and Key Laboratory of Tissue Construction and Detection of Guangdong Province, Guangzhou 510515, China and Institute of Bone Biology, Academy of Orthopedics, Guangzhou 510665, Guangdong Province, China and Key Laboratory of Mental Health of the Ministry of Education; Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou 510515, China and Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510530, China
| | - Lixin Zhu
- Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
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15
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Zeng B, Liao X, Liu L, Zhang C, Ruan H, Yang B. Thyroid hormone mediates cardioprotection against postinfarction remodeling and dysfunction through the IGF-1/PI3K/AKT signaling pathway. Life Sci 2020; 267:118977. [PMID: 33383053 DOI: 10.1016/j.lfs.2020.118977] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/14/2020] [Accepted: 12/20/2020] [Indexed: 12/29/2022]
Abstract
AIMS Severe cardiovascular diseases, such as myocardial infarction or heart failure, can alter thyroid hormone (TH) secretion and peripheral conversion, leading to low triiodothyronine (T3) syndrome. Accumulating evidence suggests that TH has protective properties against cardiovascular diseases and that treatment with TH can effectively reduce myocardial damage after myocardial infarction (MI). Our aim is to investigate the effect of T3 pretreatment on cardiac function and pathological changes in mice subjected to MI and the underlying mechanisms. MAIN METHODS Adult male C57BL/6 mice underwent surgical ligation of the left anterior descending coronary artery (LAD) (or sham operation) to establish MI model. T3, BMS-754807 (inhibitor of insulin-like growth factor-1 receptor (IGF-1R)) or vehicle was administered before surgery. KEY FINDINGS Compared with the MI group, the T3 pretreatment group exhibited significant attenuation of the myocardial infarct area, inhibition of cardiomyocyte apoptosis and fibrosis, and improved left ventricular function after MI. In addition, T3 exhibited an enhanced potency to stimulate angiogenesis and exert anti-inflammatory effects by reducing the levels of serum inflammatory cytokines after MI. However, all of these protective effects were inhibited by the IGF-1R inhibitor BMS-754807. Moreover, the protein expression of IGF-1/PI3K/AKT signaling-related proteins, such as IGF-1, IGF-1R, phosphorylated PI3K (p-PI3K) and p-AKT was significantly upregulated in MI mice that received T3 pretreatment, and BMS-754807 pretreatment blocked the upregulation of the expression of these signaling-related proteins. SIGNIFICANCE T3 pretreatment can protect the heart against dysfunction post-MI, which may be mediated by the activation of the IGF-1/PI3K/AKT signaling pathway.
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Affiliation(s)
- Bin Zeng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
| | - Xiaoting Liao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China; Department of Cardiology, Tianyou Hospital Affiliated to Wuhan University of Science & Technology, Wuhan 430060, PR China
| | - Lei Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China
| | - Caixia Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China
| | - Huaiyu Ruan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China
| | - Bo Yang
- Department of Cardiology, Xianfeng County People's Hospital, Enshi 445000, PR China
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Retrospective Analysis of the Clinical Outcome in a Matched Case-Control Cohort of Polytrauma Patients Following an Osteosynthetic Flail Chest Stabilization. J Clin Med 2020; 9:jcm9082379. [PMID: 32722527 PMCID: PMC7464248 DOI: 10.3390/jcm9082379] [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: 06/30/2020] [Revised: 07/24/2020] [Accepted: 07/24/2020] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND In polytrauma (PT) patients, osseous thoracic injuries are commonly observed. One of the most severe injuries is the flail chest where the rib cage is broken in such a way that leads to a partial functional detachment of the thoracic wall. Especially in PT patients, the integrity of the respiratory system and especially, of the respiratory muscles is essential to prevent respiratory failure. Besides conservative treatment options, flail chest injuries may be surgically stabilized. However, this treatment option is rarely carried out and evidence on the outcome of surgically treated flail chest patients is rare. OBJECTIVE This study intends to investigate the clinical outcome of PT patients with the diagnosis of a flail chest who received an osteosynthetic stabilization for that compared to the same group of patients without an operative treatment. The between-groups outcome was compared regarding the duration of the total hospital and the intensive care unit (ICU) stay, the total of the invasive ventilation days, the incidence of pneumonia, and the dosage of the pain medication at the hospital discharge. METHODS A retrospective analysis was conducted including all PT patients who received an osteosynthetic stabilization of a flail chest. Furthermore, another cohort of PT patients and the diagnosis of a flail chest but without operative treatment was determined. Both groups were case-control matched for the Injury Severity Score (ISS) and age. Further statistical analysis was performed using the Wilcoxon signed-rank test and the McNemar's test. RESULTS Out of eleven operatively and 59 conservatively treated patients, eleven patients per group were matched. Further analysis revealed no significant differences in the normal ward treatment duration (5.64 ± 6.62 and 6.20 ± 5.85 days), the invasive ventilation duration (was 6.25 ± 7.17 and 7.10 ± 6.14 days), the morphine equivalent dosage of the oral analgesia (61.36 ± 67.23 mg and 39.67 ± 65.65 mg), and the pneumonia incidence (36.4 and 54.5%) when conservatively and operatively treated patients were compared, respectively. However, surgically treated patients had a longer ICU (25.18 ± 14.48 and 15.27 ± 12.10 days, Z = -2.308, p = 0.021) and a longer total hospital treatment duration (30.10 ± 13.01 and 20.91 ± 10.34 days, Z = -2.807, p = 0.005) when compared to conservatively treated patients. CONCLUSION In the present study cohort, there was no outcome difference between conservatively and operatively treated patients with the diagnosis of a flail chest regarding the normal ward treatment duration, the invasive ventilation duration, the morphine equivalent dosage of the oral analgesia, and the pneumonia incidence while ICU treatment duration and hospital treatment duration was longer in operatively treated patients.
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Xu GP, Zhang XF, Sun L, Chen EM. Current and future uses of skeletal stem cells for bone regeneration. World J Stem Cells 2020; 12:339-350. [PMID: 32547682 PMCID: PMC7280866 DOI: 10.4252/wjsc.v12.i5.339] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/07/2020] [Accepted: 04/18/2020] [Indexed: 02/06/2023] Open
Abstract
The postnatal skeleton undergoes growth, modeling, and remodeling. The human skeleton is a composite of diverse tissue types, including bone, cartilage, fat, fibroblasts, nerves, blood vessels, and hematopoietic cells. Fracture nonunion and bone defects are among the most challenging clinical problems in orthopedic trauma. The incidence of nonunion or bone defects following fractures is increasing. Stem and progenitor cells mediate homeostasis and regeneration in postnatal tissue, including bone tissue. As multipotent stem cells, skeletal stem cells (SSCs) have a strong effect on the growth, differentiation, and repair of bone regeneration. In recent years, a number of important studies have characterized the hierarchy, differential potential, and bone formation of SSCs. Here, we describe studies on and applications of SSCs and/or mesenchymal stem cells for bone regeneration.
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Affiliation(s)
- Guo-Ping Xu
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xiang-Feng Zhang
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Lu Sun
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, MA 02115, United States
| | - Er-Man Chen
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
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18
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Löffler J, Sass FA, Filter S, Rose A, Ellinghaus A, Duda GN, Dienelt A. Compromised Bone Healing in Aged Rats Is Associated With Impaired M2 Macrophage Function. Front Immunol 2019; 10:2443. [PMID: 31681320 PMCID: PMC6813416 DOI: 10.3389/fimmu.2019.02443] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 10/01/2019] [Indexed: 12/12/2022] Open
Abstract
Fracture repair is initiated by a multitude of immune cells and induction of an inflammatory cascade. Alterations in the early healing response due to an aged adaptive immune system leads to impaired bone repair, delayed healing or even formation of non-union. However, immuno-senescence is not limited to the adaptive immunity, but is also described for macrophages, main effector cells from the innate immune system. Beside regulation of pro- and anti-inflammatory signaling, macrophages contribute to angiogenesis and granulation tissue maturation. Thus, it seems likely that an altered macrophage function due to aging may affect bone repair at various stages and contribute to age related deficiencies in bone regeneration. To prove this hypothesis, we analyzed the expression of macrophage markers and angiogenic factors in the early bone hematoma derived from young and aged osteotomized Spraque Dawley rats. We detected an overall reduced expression of the monocyte/pan-macrophage markers CD14 and CD68 in aged rats. Furthermore, the analysis revealed an impaired expression of anti-inflammatory M2 macrophage markers in hematoma from aged animals that was connected to a diminished revascularization of the bone callus. To verify that the age related disturbed bone regeneration was due to a compromised macrophage function, CD14+ macrophage precursors were transplanted locally into the osteotomy gap of aged rats. Transplantation rescued bone regeneration partially after 6 weeks, demonstrated by a significantly induced deposition of new bone tissue, reduced fibrosis and significantly improved callus vascularization.
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Affiliation(s)
- Julia Löffler
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany
| | - F Andrea Sass
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sebastian Filter
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alexander Rose
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Agnes Ellinghaus
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Georg N Duda
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anke Dienelt
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany
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19
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Qazi TH, Berkmann JC, Schoon J, Geißler S, Duda GN, Boccaccini AR, Lippens E. Dosage and composition of bioactive glasses differentially regulate angiogenic and osteogenic response of human MSCs. J Biomed Mater Res A 2018; 106:2827-2837. [PMID: 30281904 DOI: 10.1002/jbm.a.36470] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/03/2018] [Accepted: 05/24/2018] [Indexed: 12/14/2022]
Abstract
Vascularization of the fracture site and cell-mediated deposition of the mineralized matrix are crucial determinants for successful bone regeneration after injury. Ceramic biomaterials such as bioactive glasses (BAGs) that release bioactive ions have shown promising results in bone defect regeneration. However, it remains unclear how the dosage and composition of bioactive ions influence the angiogenic and osteogenic behavior of primary human mesenchymal stromal cells (MSCs). Here, we show that exposure to ionic dissolution products from 1393 and 45S5 BAGs can evoke distinct angiogenic and osteogenic responses from primary MSCs in a dose- and composition-dependent manner. Significantly higher concentrations of the pro-angiogenic factors VEGF, HGF, PIGF, angiopoietin, and angiogenin were detected in conditioned media (CM) from MSCs exposed to 45S5, but not 1393, BAGs. Application of this CM to human umbilical vein endothelial cells (HUVECs) resulted in robust 2D tube formation in vitro. Osteogenic differentiation of MSCs was assessed by gene expression analysis and mineralization assays. Low concentrations (0.1% w/v) of 1393 BAGs significantly enhanced the gene expression of RUNX2 and ALP and induced an earlier onset of matrix mineralization compared to all other groups. We further tested whether simultaneous exposure to both BAGs would improve both angiogenic secretion and osteogenic differentiation of MSCs, and did not find evidence to support this hypothesis. Our results provide evidence of BAG composition-dependent enhancement of primary human MSCs' regenerative function, besides also underlining the importance of an in vitro evaluation of the dose-response relationship to translate BAG based approaches into safe and effective clinical therapies. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2827-2837, 2018., 2018.
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Affiliation(s)
- Taimoor H Qazi
- Julius Wolff Institute, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies & Berlin-Brandenburg School for Regenerative Therapies, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Julia C Berkmann
- Julius Wolff Institute, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies & Berlin-Brandenburg School for Regenerative Therapies, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Janosch Schoon
- Julius Wolff Institute, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies & Berlin-Brandenburg School for Regenerative Therapies, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Sven Geißler
- Julius Wolff Institute, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies & Berlin-Brandenburg School for Regenerative Therapies, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Georg N Duda
- Julius Wolff Institute, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies & Berlin-Brandenburg School for Regenerative Therapies, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Aldo R Boccaccini
- Institute of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Cauerstrasse 6, 91058, Erlangen, Germany
| | - Evi Lippens
- Julius Wolff Institute, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies & Berlin-Brandenburg School for Regenerative Therapies, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
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20
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Zhang Y, Husch JFA, van den Beucken JJJP. Intraoperative Construct Preparation: A Practical Route for Cell-Based Bone Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:403-417. [PMID: 29631489 DOI: 10.1089/ten.teb.2018.0010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Stem cell-based bone tissue engineering based on the combination of a scaffold and expanded autologous mesenchymal stem cells (MSCs) represents the current state-of-the-art treatment for bone defects and fractures. However, the procedure of such construct preparation requires extensive ex vivo manipulation of patient's cells to achieve enough stem cells. Therefore, it is impractical and not cost-effective compared to other therapeutic interventions. For these reasons, a more practical strategy circumventing any ex vivo manipulation and an additional surgery for the patient would be advantageous. Intraoperative concept-based bone tissue engineering, where constructs are prepared with easily accessible autologous cells within the same surgical procedure, allows for such a simplification. In this study, we discuss the concept of intraoperative construct preparation for bone tissue engineering and summarize the available cellular options for intraoperative preparation. Furthermore, we propose methods to prepare intraoperative constructs, and review data of currently available preclinical and clinical studies using intraoperatively prepared constructs for bone regenerative applications. We identify several obstacles hampering the application of this emerging approach and highlight perspectives of technological innovations to advance the future developments of intraoperative construct preparation.
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Affiliation(s)
- Yang Zhang
- Department of Biomaterials, Radboudumc, Nijmegen, The Netherlands
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21
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Winkler T, Sass FA, Duda GN, Schmidt-Bleek K. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018; 7:232-243. [PMID: 29922441 PMCID: PMC5987690 DOI: 10.1302/2046-3758.73.bjr-2017-0270.r1] [Citation(s) in RCA: 256] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Despite its intrinsic ability to regenerate form and function after injury, bone tissue can be challenged by a multitude of pathological conditions. While innovative approaches have helped to unravel the cascades of bone healing, this knowledge has so far not improved the clinical outcomes of bone defect treatment. Recent findings have allowed us to gain in-depth knowledge about the physiological conditions and biological principles of bone regeneration. Now it is time to transfer the lessons learned from bone healing to the challenging scenarios in defects and employ innovative technologies to enable biomaterial-based strategies for bone defect healing. This review aims to provide an overview on endogenous cascades of bone material formation and how these are transferred to new perspectives in biomaterial-driven approaches in bone regeneration. Cite this article: T. Winkler, F. A. Sass, G. N. Duda, K. Schmidt-Bleek. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232–243. DOI: 10.1302/2046-3758.73.BJR-2017-0270.R1.
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Affiliation(s)
- T Winkler
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin and Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - F A Sass
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin and Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - G N Duda
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin and Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - K Schmidt-Bleek
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin and Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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22
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Abstract
Soft tissue trauma of skeletal muscle is one of the most common side effects in surgery. Muscle injuries are not only caused by accident-related injuries but can also be of an iatrogenic nature as they occur during surgical interventions when the anatomical region of interest is exposed. If the extent of trauma surpasses the intrinsic regenerative capacities, signs of fatty degeneration and formation of fibrotic scar tissue can occur, and, consequentially, muscle function deteriorates or is diminished. Despite research efforts to investigate the physiological healing cascade following trauma, our understanding of the early onset of healing and how it potentially determines success or failure is still only fragmentary. This review focuses on the initial physiological pathways following skeletal muscle trauma in comparison to bone and tendon trauma and what conclusions can be drawn from new scientific insights for the development of novel therapeutic strategies. Strategies to support regeneration of muscle tissue after injury are scarce, even though muscle trauma has a high incidence. Based on tissue specific differences, possible clinical treatment options such as local immune-modulatory and cell therapeutic approaches are suggested that aim to support the endogenous regenerative potential of injured muscle tissues.
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23
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Loeffler J, Duda GN, Sass FA, Dienelt A. The Metabolic Microenvironment Steers Bone Tissue Regeneration. Trends Endocrinol Metab 2018; 29:99-110. [PMID: 29290501 DOI: 10.1016/j.tem.2017.11.008] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/20/2017] [Accepted: 11/29/2017] [Indexed: 12/22/2022]
Abstract
Over the past years, basic findings in cancer research have revealed metabolic symbiosis between different cell types to cope with high energy demands under limited nutrient availability. Although this also applies to regenerating tissues with disrupted physiological nutrient and oxygen supply, the impact of this metabolic cooperation and metabolic reprogramming on cellular development, fate, and function during tissue regeneration has widely been neglected so far. With this review, we aim to provide a schematic overview on metabolic links that have a high potential to drive tissue regeneration. As bone is, aside from liver, the only tissue that can regenerate without excessive scar tissue formation, we will use bone healing as an exemplarily model system.
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Affiliation(s)
- Julia Loeffler
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany
| | - Georg N Duda
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - F Andrea Sass
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Anke Dienelt
- Julius Wolff Institute, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
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24
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Joly P, Schaus T, Sass A, Dienelt A, Cheung AS, Duda GN, Mooney DJ. Biophysical induction of cell release for minimally manipulative cell enrichment strategies. PLoS One 2017; 12:e0180568. [PMID: 28665971 PMCID: PMC5493423 DOI: 10.1371/journal.pone.0180568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 06/16/2017] [Indexed: 11/28/2022] Open
Abstract
The use of autologous cells harvested and subsequently transplanted in an intraoperative environment constitutes a new approach to promote regeneration. Usually cells are isolated by selection methods such as fluorescence- or magnetic- activated cell sorting with residual binding of the antibodies or beads. Thus, cell-based therapies would benefit from the development of new devices for cell isolation that minimally manipulate the target cell population. In the clinic, 5 to 10 percent of fractures do not heal properly and CD31+ cells have been identified as promising candidates to support bone regeneration. The aim of this project was to develop and prototype a simple system to facilitate the enrichment of CD31+ cells from whole blood. After validating the specificity of a commercially available aptamer for CD31, we combined this aptamer with traditional magnetic bead strategies, which led to enrichment of CD31+ cells with a purity of 91±10%. Subsequently, the aptamer was attached to agarose beads (Ø = 100–165 um) that were incorporated into a column-based system to enable capture and subsequent release of the CD31+ enriched cells. Different parameters were investigated to allow a biophysical-based cell release from beads, and a simple mixing was found sufficient to release initially bound cells from the optimized column without the need for any chemicals that promote disassociation. The system led to a significant enrichment of CD31+ cells (initial population: 63±9%, released: 87±3%) with excellent cell viability (released: 97±1%). The composition of the released CD31+ fraction indicated an enrichment of the monocyte population. The angiogenic and osteogenic potential of the released cell population were confirmed in vitro. These results and the simplicity of this system highlight the potential of such approach to enable cell enrichment strategies in intraoperative settings.
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Affiliation(s)
- Pascal Joly
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, United States of America.,Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Schaus
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, United States of America
| | - Andrea Sass
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies, Charité-University Medicine, Berlin, Germany
| | - Anke Dienelt
- Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies, Charité-University Medicine, Berlin, Germany
| | - Alexander S Cheung
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, United States of America.,School of Engineering and Applied Sciences, Harvard University, Cambridge, United States of America
| | - Georg N Duda
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, United States of America.,Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies, Charité-University Medicine, Berlin, Germany
| | - David J Mooney
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, United States of America.,School of Engineering and Applied Sciences, Harvard University, Cambridge, United States of America
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