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1
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Gu C, Tang Q, Li L, Chen Y. Optimization and Implication of Adipose-Derived Stem Cells in Craniofacial Bone Regeneration and Repair. Bioengineering (Basel) 2024; 11:1100. [PMID: 39593759 PMCID: PMC11592193 DOI: 10.3390/bioengineering11111100] [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: 09/14/2024] [Revised: 10/17/2024] [Accepted: 10/27/2024] [Indexed: 11/28/2024] Open
Abstract
Adipose-derived stem cells (ADSCs) have emerged as a promising resource for craniofacial bone regeneration due to their high abundance and easy accessibility, significant osteogenic potential, versatile applications, and potential for personalized medicine, which underscore their importance in this field. This article reviews the current progress of preclinical studies that describe the careful selection of specific ADSC subpopulations, key signaling pathways involved, and usage of various strategies to enhance the osteogenic potential of ADSCs. Additionally, clinical case reports regarding the application of ADSCs in the repair of calvarial defects, cranio-maxillofacial defects, and alveolar bone defects are also discussed.
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Affiliation(s)
- Cong Gu
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
| | - Qinghuang Tang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214, USA
| | - Liwen Li
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
- Department of Biological Sciences, University at Buffalo, Buffalo, NY 14260, USA
| | - YiPing Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA; (Q.T.); (L.L.); (Y.C.)
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2
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Singh M, Singh P, Singh B, Sharma K, Kumar N, Singh D, Mastana S. Molecular Signaling Pathways and MicroRNAs in Bone Remodeling: A Narrative Review. Diseases 2024; 12:252. [PMID: 39452495 PMCID: PMC11507001 DOI: 10.3390/diseases12100252] [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: 08/03/2024] [Revised: 10/02/2024] [Accepted: 10/06/2024] [Indexed: 10/26/2024] Open
Abstract
Bone remodeling is an intricate process executed throughout one's whole life via the cross-talk of several cellular events, progenitor cells and signaling pathways. It is an imperative mechanism for regaining bone loss, recovering damaged tissue and repairing fractures. To achieve this, molecular signaling pathways play a central role in regulating pathological and causal mechanisms in different diseases. Similarly, microRNAs (miRNAs) have shown promising results in disease management by mediating mRNA targeted gene expression and post-transcriptional gene function. However, the role and relevance of these miRNAs in signaling processes, which regulate the delicate balance between bone formation and bone resorption, are unclear. This review aims to summarize current knowledge of bone remodeling from two perspectives: firstly, we outline the modus operandi of five major molecular signaling pathways, i.e.,the receptor activator of nuclear factor kappa-B (RANK)-osteoprotegrin (OPG) and RANK ligand (RANK-OPG-RANKL), macrophage colony-stimulating factor (M-CSF), Wnt/β-catenin, Jagged/Notch and bone morphogenetic protein (BMP) pathways in regards to bone cell formation and function; and secondly, the miRNAs that participate in these pathways are introduced. Probing the miRNA-mediated regulation of these pathways may help in preparing the foundation for developing targeted strategies in bone remodeling, repair and regeneration.
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Affiliation(s)
- Monica Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Puneetpal Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Baani Singh
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Kirti Sharma
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Nitin Kumar
- Department of Human Genetics, Punjabi University, Patiala 147002, India; (M.S.); (B.S.); (K.S.); (N.K.)
| | - Deepinder Singh
- VardhmanMahavir Health Care, Urban Estate Ph-II, Patiala 147002, India;
| | - Sarabjit Mastana
- Human Genomics Laboratory, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK;
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3
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Ren Y, Wang S, Li H, Li J, Lan X, Wang Y. Low-energy red light-emitting diode irradiation enhances osteogenic differentiation of periodontal ligament stem cells by regulating miR-146a-5p. J Periodontal Res 2024; 59:1031-1041. [PMID: 38845170 DOI: 10.1111/jre.13276] [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: 09/27/2023] [Revised: 04/05/2024] [Accepted: 04/12/2024] [Indexed: 10/23/2024]
Abstract
AIMS The study aimed to investigate the role of miR-146a-5p in osteogenesis of hPDLSCs irradiated with low-energy red LEDs. METHODS After irradiation with 5 J/cm2 red LED, miR-146a-5p expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR), and osteogenic markers expression was determined by RT-qPCR and Western blotting. Alkaline phosphatase (ALP) activity was assessed by ALP staining, and mineralization was assessed by Alizarin Red staining, respectively. Lentiviral vectors were designed to regulate miR-146a-5p expression. Dual-luciferase reporter assay was performed to confirm the targeted relationship between miR-146a-5p and MAPK1. Short hairpin RNA (shRNA) was used to regulate MAPK1 expression. RESULTS RT-qPCR and western blotting revealed that 5 J/cm2 irradiation elevated the levels of the osteogenic markers osterix (OSX) and bone sialoprotein (BSP) in hPDLSCs. miR-146a-5p is downregulated in hPDLSCs under the low-energy red LED light irradiation. miR-146a-5p underexpression markedly promoted the osteogenic potential of hPDLSCs. miR-146a-5p targeted MAPK1. 5 J/cm2 red LED irradiation rescued the inhibitory effects of upregulated miR-146a-5p on osteogenic differentiation, and the positive influence of red LED irradiation could be reversed by downregulated MAPK1. CONCLUSION These findings confirm that miR-146a-5p is involved in the effect of LED irradiation on the osteogenic differentiation of hPDLSCs by targeting MAPK1. Red LED irradiation may be a potential clinical adjunct therapy for periodontal regeneration.
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Affiliation(s)
- Yajiao Ren
- Southwest Medical University, Luzhou, China
- The Department of Preventive Dentistry, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Southwest Medical University, Luzhou, China
| | - Shifen Wang
- Southwest Medical University, Luzhou, China
- The Department of Preventive Dentistry, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Southwest Medical University, Luzhou, China
| | - Hao Li
- Southwest Medical University, Luzhou, China
- The Department of Preventive Dentistry, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Southwest Medical University, Luzhou, China
| | - Jiaxin Li
- Southwest Medical University, Luzhou, China
- The Department of Preventive Dentistry, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Southwest Medical University, Luzhou, China
| | - Xiaorong Lan
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Southwest Medical University, Luzhou, China
| | - Yao Wang
- Southwest Medical University, Luzhou, China
- The Department of Preventive Dentistry, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Southwest Medical University, Luzhou, China
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4
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Jankowski M, Farzaneh M, Ghaedrahmati F, Shirvaliloo M, Moalemnia A, Kulus M, Ziemak H, Chwarzyński M, Dzięgiel P, Zabel M, Piotrowska-Kempisty H, Bukowska D, Antosik P, Mozdziak P, Kempisty B. Unveiling Mesenchymal Stem Cells' Regenerative Potential in Clinical Applications: Insights in miRNA and lncRNA Implications. Cells 2023; 12:2559. [PMID: 37947637 PMCID: PMC10649218 DOI: 10.3390/cells12212559] [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: 09/05/2023] [Revised: 10/20/2023] [Accepted: 10/28/2023] [Indexed: 11/12/2023] Open
Abstract
It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs.
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Affiliation(s)
- Maurycy Jankowski
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, 60-812 Poznan, Poland;
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Farhoodeh Ghaedrahmati
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Milad Shirvaliloo
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Future Science Group, Unitec House, 2 Albert Place, London N3 1QB, UK
| | - Arash Moalemnia
- Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Hanna Ziemak
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Mikołaj Chwarzyński
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Piotr Dzięgiel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Physiotherapy, Wroclaw University School of Physical Education, 50-038 Wroclaw, Poland
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 60-631 Poznan, Poland
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27607, USA
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27613, USA
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27613, USA
- Division of Anatomy, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 602 00 Brno, Czech Republic
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5
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Huang D, Liang J, Yang J, Yang C, Wang X, Dai T, Steinberg T, Li C, Wang F. Current Status of Tissue Regenerative Engineering for the Treatment of Uterine Infertility. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:558-573. [PMID: 37335062 DOI: 10.1089/ten.teb.2022.0226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2023]
Abstract
With the recent developments in tissue engineering, scientists have attempted to establish seed cells from different sources, create cell sheets through various technologies, implant them on scaffolds with various spatial structures, or load scaffolds with cytokines. These research results are very optimistic, bringing hope to the treatment of patients with uterine infertility. In this article, we reviewed articles related to the treatment of uterine infertility from the aspects of experimental treatment strategy, seed cells, scaffold application, and repair criteria so as to provide a basis for future research.
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Affiliation(s)
- Di Huang
- Shandong First Medical University, Jinan, China
| | - Junhui Liang
- Departments of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jie Yang
- The Affiliated Taian City Central Hospital of Qingdao University, Taian, China
| | - Chunrun Yang
- Departments of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xin Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Ultrasonography, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Tianyu Dai
- Shandong First Medical University, Jinan, China
| | - Thorsten Steinberg
- Division of Oral Biotechnology, Center for Dental Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Changzhong Li
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Fei Wang
- Departments of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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6
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Shams R, Behmanesh A, Mazhar FN, Vaghari AA, Hossein-Khannazer N, Agarwal T, Vosough M, Padrón JM. Developed Bone Biomaterials Incorporated with MicroRNAs to Promote Bone Regeneration: A Systematic Review, Bioinformatics, and Meta-analysis Study. ACS Biomater Sci Eng 2023; 9:5186-5204. [PMID: 37585807 DOI: 10.1021/acsbiomaterials.3c00178] [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] [Indexed: 08/18/2023]
Abstract
This systematic review and meta-analysis focused on the effectiveness of biomaterials integrated with specific microRNAs (miRNAs) for bone fracture repair treatment. We conducted a comprehensive search of the PubMed, Web of Science, and Scopus databases, identifying 42 relevant papers up to March 2022. Hydrogel-based scaffolds were the most commonly used, incorporating miRNAs like miR-26a, miR-21, and miR-222, with miR-26a being the most prevalent. The meta-analysis revealed significant benefits of incorporating miRNAs into scaffolds for bone repair, particularly in hydrogel scaffolds. However, some controversies were observed among studies, presenting challenges in selecting appropriate miRNAs for this purpose. The study concludes that incorporating specific miRNAs into bone biomaterials enhances bone regeneration, but further trials comparing different biomaterials and miRNAs are necessary to validate their potential applications for bone tissue regeneration.
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Affiliation(s)
- Roshanak Shams
- Bone and Joint Reconstruction Research Center, Department of Orthopedics, School of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Ali Behmanesh
- Bone and Joint Reconstruction Research Center, Department of Orthopedics, School of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Farid Najd Mazhar
- Bone and Joint Reconstruction Research Center, Department of Orthopedics, School of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Amir Ali Vaghari
- Bone and Joint Reconstruction Research Center, Department of Orthopedics, School of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran
| | - Tarun Agarwal
- Department of Bio-Technology, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Andhra Pradesh 522302, India
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, 171 77 Stockholm, Sweden
| | - José M Padrón
- BioLab, Instituto Universitario de Bio-Orgánica Antonio González (IUBO-AG), Universidad de La Laguna, P.O. Box 456, 38200 La Laguna, Spain
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7
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Su D, Swearson S, Krongbaramee T, Sun H, Hong L, Amendt BA. Exploring microRNAs in craniofacial regenerative medicine. Biochem Soc Trans 2023; 51:841-854. [PMID: 37073783 PMCID: PMC11244734 DOI: 10.1042/bst20221448] [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: 11/14/2022] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/20/2023]
Abstract
microRNAs (miRs) have been reported over the decades as important regulators in bone development and bone regeneration. They play important roles in maintaining the stem cell signature as well as regulating stem cell fate decisions. Thus, delivering miRs and miR inhibitors to the defect site is a potential treatment towards craniofacial bone defects. However, there are challenges in translation of basic research to clinics, including the efficiency, specificity, and efficacy of miR manipulation methods and the safety of miR delivery systems. In this review, we will compare miR oligonucleotides, mimics and antagomirs as therapeutic reagents to treat disease and regenerate tissues. Newer technology will be discussed as well as the efficiency and efficacy of using these technologies to express or inhibit miRs in treating and repairing oral tissues. Delivery of these molecules using extracellular vesicles and nanoparticles can achieve different results and depending on their composition will elicit specific effects. We will highlight the specificity, toxicity, stability, and effectiveness of several miR systems in regenerative medicine.
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Affiliation(s)
- Dan Su
- Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA, U.S.A
- Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, U.S.A
| | - Samuel Swearson
- Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA, U.S.A
| | - Tadkamol Krongbaramee
- Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA, U.S.A
- Division of Endodontics, Department of Restorative Dentistry & Periodontology, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Hongli Sun
- Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA, U.S.A
| | - Liu Hong
- Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, U.S.A
- Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA, U.S.A
| | - Brad A Amendt
- Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, IA, U.S.A
- Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, U.S.A
- Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA, U.S.A
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8
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Skeletal Muscle-Derived Exosomal miR-146a-5p Inhibits Adipogenesis by Mediating Muscle-Fat Axis and Targeting GDF5-PPARγ Signaling. Int J Mol Sci 2023; 24:ijms24054561. [PMID: 36901991 PMCID: PMC10003660 DOI: 10.3390/ijms24054561] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/13/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Skeletal muscle-fat interaction is essential for maintaining organismal energy homeostasis and managing obesity by secreting cytokines and exosomes, but the role of the latter as a new mediator in inter-tissue communication remains unclear. Recently, we discovered that miR-146a-5p was mainly enriched in skeletal muscle-derived exosomes (SKM-Exos), 50-fold higher than in fat exosomes. Here, we investigated the role of skeletal muscle-derived exosomes regulating lipid metabolism in adipose tissue by delivering miR-146a-5p. The results showed that skeletal muscle cell-derived exosomes significantly inhibited the differentiation of preadipocytes and their adipogenesis. When the skeletal muscle-derived exosomes co-treated adipocytes with miR-146a-5p inhibitor, this inhibition was reversed. Additionally, skeletal muscle-specific knockout miR-146a-5p (mKO) mice significantly increased body weight gain and decreased oxidative metabolism. On the other hand, the internalization of this miRNA into the mKO mice by injecting skeletal muscle-derived exosomes from the Flox mice (Flox-Exos) resulted in significant phenotypic reversion, including down-regulation of genes and proteins involved in adipogenesis. Mechanistically, miR-146a-5p has also been demonstrated to function as a negative regulator of peroxisome proliferator-activated receptor γ (PPARγ) signaling by directly targeting growth and differentiation factor 5 (GDF5) gene to mediate adipogenesis and fatty acid absorption. Taken together, these data provide new insights into the role of miR-146a-5p as a novel myokine involved in the regulation of adipogenesis and obesity via mediating the skeletal muscle-fat signaling axis, which may serve as a target for the development of therapies against metabolic diseases, such as obesity.
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9
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Zheng Z, Wu L, Li Z, Tang R, Li H, Huang Y, Wang T, Xu S, Cheng H, Ye Z, Xiao D, Lin X, Wu G, Jaspers RT, Pathak JL. Mir155 regulates osteogenesis and bone mass phenotype via targeting S1pr1 gene. eLife 2023; 12:77742. [PMID: 36598122 PMCID: PMC9839347 DOI: 10.7554/elife.77742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 01/03/2023] [Indexed: 01/05/2023] Open
Abstract
MicroRNA-155 (miR155) is overexpressed in various inflammatory diseases and cancer, in which bone resorption and osteolysis are frequently observed. However, the role of miR155 on osteogenesis and bone mass phenotype is still unknown. Here, we report a low bone mass phenotype in the long bone of Mir155-Tg mice compared with wild-type mice. In contrast, Mir155-KO mice showed a high bone mass phenotype and protective effect against inflammation-induced bone loss. Mir155-KO mice showed robust bone regeneration in the ectopic and orthotopic model, but Mir155-Tg mice showed compromised bone regeneration compared with the wild-type mice. Similarly, the osteogenic differentiation potential of bone marrow stromal stem cells (BMSCs) from Mir155-KO mice was robust and Mir155-Tg was compromised compared with that of wild-type mice. Moreover, Mir155 knockdown in BMSCs from wild-type mice showed higher osteogenic differentiation potential, supporting the results from Mir155-KO mice. TargetScan analysis predicted sphingosine 1-phosphate receptor-1 (S1pr1) as a target gene of Mir155, which was further confirmed by luciferase assay and Mir155 knockdown. S1pr1 overexpression in BMSCs robustly promoted osteogenic differentiation without affecting cell viability and proliferation. Furthermore, osteoclastogenic differentiation of Mir155-Tg bone marrow-derived macrophages was inhibited compared with that of wild-type mice. Thus, Mir155 showed a catabolic effect on osteogenesis and bone mass phenotype via interaction with the S1pr1 gene, suggesting inhibition of Mir155 as a potential strategy for bone regeneration and bone defect healing.
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Affiliation(s)
- Zhichao Zheng
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina,Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement SciencesAmsterdamNetherlands
| | - Lihong Wu
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
| | - Zhicong Li
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
| | - Ruoshu Tang
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
| | - Hongtao Li
- State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Yinyin Huang
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
| | - Tianqi Wang
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
| | - Shaofen Xu
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
| | - Haoyu Cheng
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
| | - Zhitong Ye
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
| | - Dong Xiao
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumour Immunology Research, Cancer Research Institute, School of Basic Medical Science, Southern Medical UniversityGuangzhouChina,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical UniversityGuangzhouChina
| | - Xiaolin Lin
- Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumour Immunology Research, Cancer Research Institute, School of Basic Medical Science, Southern Medical UniversityGuangzhouChina,Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical UniversityGuangzhouChina
| | - Gang Wu
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Center for Dentistry Amsterdam (ACTA), Amsterdam Movement Science, Vrije Universiteit AmsterdamAmsterdamNetherlands,Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit AmsterdamAmsterdamNetherlands
| | - Richard T Jaspers
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina,Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement SciencesAmsterdamNetherlands
| | - Janak L Pathak
- Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative MedicineGuangzhouChina
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10
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Zhang Q, Long Y, Jin L, Li C, Long J. Non-coding RNAs regulate the BMP/Smad pathway during osteogenic differentiation of stem cells. Acta Histochem 2023; 125:151998. [PMID: 36630753 DOI: 10.1016/j.acthis.2023.151998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 01/04/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023]
Abstract
MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are involved in the regulation of bone metabolism. The BMP/Smad pathway is a key signaling pathway for classical regulation of osteogenic differentiation. Non-coding RNAs (ncRNAs) and the BMP/Smad pathway both have important roles for osteogenic differentiation of stem cells, bone regeneration, and development of bone diseases. There is increasing evidence that ncRNAs interact with the BMP/Smad pathway to regulate not only osteogenic differentiation of stem cells but also progression of bone diseases, such as osteoporosis (OP), myeloma, and osteonecrosis of the femoral head (ONFH), by controlling the expression of bone disease-related genes. Therefore, ncRNAs that interact with BMP/Smad pathway molecules are potential targets for bone regeneration as well as bone disease diagnosis, prevention, and treatment. However, despite extensive studies on ncRNAs associated with the BMP/Smad pathway and osteogenic differentiation of stem cells, there is a lack of comparability. Moreover, some bone disease-associated ncRNAs with low abundance can be difficult to detect and there is a lack of mature delivery systems for their stable translocation to target sites, thus limiting their application. In this review, we summarize the research progress on interactions between ncRNAs and the BMP/Smad pathway during osteogenic differentiation of various stem cells and in the regulation of bone regeneration and bone diseases.
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Affiliation(s)
- Qiuling Zhang
- The State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Yifei Long
- The State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, PR China
| | - Liangyu Jin
- The State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Chenghao Li
- The State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu 610041, PR China.
| | - Jie Long
- The State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, PR China; Department of Oral and Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu 610041, PR China.
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11
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Deng M, Zou W. Noncoding RNAs: Novel Targets for Opioid Tolerance. Curr Neuropharmacol 2023; 21:1202-1213. [PMID: 36453497 PMCID: PMC10286586 DOI: 10.2174/1570159x21666221129122932] [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: 04/07/2022] [Revised: 10/12/2022] [Accepted: 11/11/2022] [Indexed: 12/03/2022] Open
Abstract
As a global health problem, chronic pain is one of the leading causes of disability, and it imposes a huge economic and public health burden on families and society. Opioids represent the cornerstone of analgesic drugs. However, opioid tolerance caused by long-term application of opioids is a major factor leading to drug withdrawal, serious side effects caused by dose increases, and even the death of patients, placing an increasing burden on individuals, medicine, and society. Despite efforts to develop methods to prevent and treat opioid tolerance, no effective treatment has yet been found. Therefore, understanding the mechanism underlying opioid tolerance is crucial for finding new prevention and treatment strategies. Noncoding RNAs (ncRNAs) are important parts of mammalian gene transcriptomes, and there are thousands of unique noncoding RNA sequences in cells. With the rapid development of high-throughput genome technology, research on ncRNAs has become a hot topic in biomedical research. In recent years, studies have shown that ncRNAs mediate physiological and pathological processes, including chromatin remodeling, transcription, posttranscriptional modification and signal transduction, which are key regulators of physiological processes in developmental and disease environments and have become biomarkers and potential therapeutic targets for various diseases. An increasing number of studies have found that ncRNAs are closely related to the development of opioid tolerance. In this review, we have summarized the evidence that ncRNAs play an important role in opioid tolerance and that ncRNAs may be novel targets for opioid tolerance.
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Affiliation(s)
- Meiling Deng
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wangyuan Zou
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
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12
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Ranjbarnejad F, Khazaei M, Shahryari A, Khazaei F, Rezakhani L. Recent advances in gene therapy for bone tissue engineering. J Tissue Eng Regen Med 2022; 16:1121-1137. [PMID: 36382408 DOI: 10.1002/term.3363] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 10/05/2022] [Accepted: 10/23/2022] [Indexed: 11/18/2022]
Abstract
Autografting, a major treatment for bone fractures, has potential risks related to the required surgery and disease transmission. Bone morphogenetic proteins (BMPs) are the most common osteogenic factors used for bone-healing applications. However, BMP delivery can have shortcomings such as a short half-life and the high cost of manufacturing the recombinant proteins. Gene delivery methods have demonstrated promising alternative strategies for producing BMPs or other osteogenic factors using engineered cells. These approaches can also enable temporal overexpression and local production of the therapeutic genes in the target tissues. This review addresses recent progress on engineered viral, non-viral, and RNA-mediated gene delivery systems that are being used for bone repair and regeneration. Advances in clustered regularly interspaced short palindromic repeats/Cas9 genome engineering for bone tissue regeneration also is discussed.
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Affiliation(s)
- Fatemeh Ranjbarnejad
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mozafar Khazaei
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Alireza Shahryari
- Tools for Bio-Imaging, Max-Planck-Institute for Biological Intelligence, Martinsried, Germany
| | - Fatemeh Khazaei
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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13
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Labusca L, Danceanu C, Minuti AE, Herea DD, Ghemes A, Rotarescu C, Dragos-Pinzaru O, Tibu M, Marian G, Chiriac H, Lupu N. Magnetic nanowires substrate increases adipose-derived mesenchymal cells osteogenesis. Sci Rep 2022; 12:16698. [PMID: 36202902 PMCID: PMC9537172 DOI: 10.1038/s41598-022-21145-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/22/2022] [Indexed: 11/08/2022] Open
Abstract
Magnetic nanomaterials are increasingly impacting the field of biology and medicine. Their versatility in terms of shape, structure, composition, coating, and magnetic responsivity make them attractive for drug delivery, cell targeting and imaging. Adipose derived-mesenchymal cells (ASCs) are intensely scrutinized for tissue engineering and regenerative medicine. However, differentiation into musculoskeletal lineages can be challenging. In this paper, we show that uncoated nickel nanowires (Ni NW) partially released from their alumina membrane offer a mechanically-responsive substrate with regular topography that can be used for the delivery of magneto-mechanical stimulation. We have used a tailored protocol for improving ASCs adherence to the substrate, and showed that cells retain their characteristic fibroblastic appearance, cytoskeletal fiber distribution and good viability. We report here for the first time significant increase in osteogenic but not adipogenic differentiation of ASCs on Ni NW exposed to 4 mT magnetic field compared to non-exposed. Moreover, magnetic actuation is shown to induce ASCs osteogenesis but not adipogenesis in the absence of external biochemical cues. While these findings need to be verified in vivo, the use of Ni NW substrate for inducing osteogenesis in the absence of specific differentiation factors is attractive for bone engineering. Implant coating with similar surfaces for orthopedic and dentistry could be as well envisaged as a modality to improve osteointegration.
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Affiliation(s)
- Luminita Labusca
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
- Orthopedics and Traumatology Clinic, County Emergency Hospital Saint Spiridon Iasi, 700111, Iasi, Romania
| | - Camelia Danceanu
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
| | - Anca Emanuela Minuti
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
- Alexandru Ioan Cuza University, Faculty of Physics, 700506, Iasi, Romania
| | - Dumitru-Daniel Herea
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania.
| | - Adrian Ghemes
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
| | - Cristian Rotarescu
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
| | - Oana Dragos-Pinzaru
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
| | - Mihai Tibu
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
| | - Grigoras Marian
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
| | - Horia Chiriac
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
| | - Nicoleta Lupu
- Department of Magnetic Devices and Materials, National Institute of Research and Development for Technical Physics, 700050, Iasi, Romania
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14
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Deng L, Lai S, Fan L, Li X, Huang H, Mu Y. miR-210-3p suppresses osteogenic differentiation of MC3T3-E1 by targeting brain derived neurotrophic factor (BDNF). J Orthop Surg Res 2022; 17:418. [PMID: 36104705 PMCID: PMC9476565 DOI: 10.1186/s13018-022-03315-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/31/2022] [Indexed: 12/01/2022] Open
Abstract
Background and objective As an important mediator of intercellular interaction and formation of extracellular bone matrix, porous scaffolds are widely used for bone regeneration. Accumulating evidences demonstrate that microRNA are involved in the regulation of scaffolds-induced bone regeneration. Recently, we revealed that miR-210-3p was highly expressed during osteogenesis induced by HAG. In present study, we further explored the molecular mechanism underlying the effect of miR-210-3p on osteogenic differentiation. Materials and methods In this study, miR-210-3p mimics and inhibitors were synthesized and transfected into MC3T3-E1 cells to explore their effects on osteogenic differentiation. The expression of osteogenic marker (Alp and Runx2) were detected by real-time quantitative PCR (qRT-PCR) and western blotting. After osteogenesis induction for 7 days, Alp staining were used to detected osteoblast differentiation of MC3T3-E1 cells. CCK8 and Transwell assays were performed to detected cell proliferation and migration. Then, top ranking list of target genes of miR-210-3p obtained from TargetScan and the expression of BDNF were detected by qRT-PCR and ELISA. The relationship between miR-210-3p and BDNF was verified by luciferase report assay. Furthermore, the effect of BDNF on osteoblast differentiation was verified by transfecting siRNA or adding BDNF to the culture medium. Results MiR-210-3p mimics markedly suppress osteogenic differentiation, cell migration and cell proliferation of MC3T3-E; nevertheless, silencing of miR-210-3p dramatically enhanced MC3T3-E1 osteogenesis, cell migration and proliferation. Furthermore, luciferase reporter assay verified that brain derived neurotrophic factor (BDNF) is a directly target of miR-210-3p. Moreover, BDNF siRNA significantly decreased the expression levels of ALP and cell migration. The addition of BDNF partially rescued the inhibition of osteogenesis by miR-210-3p. Conclusion miR-210-3p inhibited the osteogenic differentiation via targeting BDNF. Our Results provide a promising target for regulating osteogenic differentiation.
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15
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Zhang Z, Yang X, Cao X, Qin A, Zhao J. Current applications of adipose-derived mesenchymal stem cells in bone repair and regeneration: A review of cell experiments, animal models, and clinical trials. Front Bioeng Biotechnol 2022; 10:942128. [PMID: 36159705 PMCID: PMC9490047 DOI: 10.3389/fbioe.2022.942128] [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: 05/12/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
In the field of orthopaedics, bone defects caused by severe trauma, infection, tumor resection, and skeletal abnormalities are very common. However, due to the lengthy and painful process of related surgery, people intend to shorten the recovery period and reduce the risk of rejection; as a result, more attention is being paid to bone regeneration with mesenchymal stromal cells, one of which is the adipose-derived mesenchymal stem cells (ASCs) from adipose tissue. After continuous subculture and cryopreservation, ASCs still have the potential for multidirectional differentiation. They can be implanted in the human body to promote bone repair after induction in vitro, solve the problems of scarce sources and large damage, and are expected to be used in the treatment of bone defects and non-union fractures. However, the diversity of its differentiation lineage and the lack of bone formation potential limit its current applications in bone disease. Here, we concluded the current applications of ASCs in bone repair, especially with the combination and use of physical and biological methods. ASCs alone have been proved to contribute to the repair of bone damage in vivo and in vitro. Attaching to bone scaffolds or adding bioactive molecules can enhance the formation of the bone matrix. Moreover, we further evaluated the efficiency of ASC-committed differentiation in the bone in conditions of cell experiments, animal models, and clinical trials. The results show that ASCs in combination with synthetic bone grafts and biomaterials may affect the regeneration, augmentation, and vascularization of bone defects on bone healing. The specific conclusion of different materials applied with ASCs may vary. It has been confirmed to benefit osteogenesis by regulating osteogenic signaling pathways and gene transduction. Exosomes secreted by ASCs also play an important role in osteogenesis. This review will illustrate the understanding of scientists and clinicians of the enormous promise of ASCs’ current applications and future development in bone repair and regeneration, and provide an incentive for superior employment of such strategies.
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Affiliation(s)
- Zhengyue Zhang
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedics, Ninth People’s Hospital, Shanghai, China
| | - Xiao Yang
- Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiankun Cao
- Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - An Qin
- Shanghai Jiaotong University School of Medicine, Shanghai, China
- *Correspondence: An Qin, ; Jie Zhao,
| | - Jie Zhao
- Shanghai Jiaotong University School of Medicine, Shanghai, China
- *Correspondence: An Qin, ; Jie Zhao,
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16
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Regenerative mesenchymal stem c
ell‐derived
extracellular vesicles: A potential alternative to c
ell‐based
therapy in viral infection and disease damage control. WIREs Mech Dis 2022; 14:e1574. [DOI: 10.1002/wsbm.1574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 05/24/2022] [Indexed: 11/07/2022]
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17
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Labusca L. Adipose tissue in bone regeneration - stem cell source and beyond. World J Stem Cells 2022; 14:372-392. [PMID: 35949397 PMCID: PMC9244952 DOI: 10.4252/wjsc.v14.i6.372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/30/2021] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
Adipose tissue (AT) is recognized as a complex organ involved in major home-ostatic body functions, such as food intake, energy balance, immunomodulation, development and growth, and functioning of the reproductive organs. The role of AT in tissue and organ homeostasis, repair and regeneration is increasingly recognized. Different AT compartments (white AT, brown AT and bone marrow AT) and their interrelation with bone metabolism will be presented. AT-derived stem cell populations - adipose-derived mesenchymal stem cells and pluripotent-like stem cells. Multilineage differentiating stress-enduring and dedifferentiated fat cells can be obtained in relatively high quantities compared to other sources. Their role in different strategies of bone and fracture healing tissue engineering and cell therapy will be described. The current use of AT- or AT-derived stem cell populations for fracture healing and bone regenerative strategies will be presented, as well as major challenges in furthering bone regenerative strategies to clinical settings.
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Affiliation(s)
- Luminita Labusca
- Magnetic Materials and Sensors, National Institute of Research and Development for Technical Physics, Iasi 700050, Romania
- Orthopedics and Traumatology, County Emergency Hospital Saint Spiridon Iasi, Iasi 700050, Romania.
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18
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Shen H, Jiang W, Yu Y, Feng Y, Zhang T, Liu Y, Guo L, Zhou N, Huang X. microRNA-146a mediates distraction osteogenesis via bone mesenchymal stem cell inflammatory response. Acta Histochem 2022; 124:151913. [PMID: 35759812 DOI: 10.1016/j.acthis.2022.151913] [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: 02/14/2022] [Revised: 05/09/2022] [Accepted: 05/24/2022] [Indexed: 11/20/2022]
Abstract
Distraction osteogenesis (DO) is a widely used surgical technique to repair bone defects, partly owing to its high efficiency in inducing osteogenesis; however, the process of osteogenesis is complex, and the precise mechanism is still unclear. Among the factors identified for an effective DO procedure, well-controlled inflammation is essential. We aimed to explore how microRNA(miR)-146a, a negative regulator of inflammation, influences osteogenesis in DO. First, we established canine right mandibular DO and bone fracture models to evaluate the expression level of miR-146a in response to these procedures. Second, bone marrow mesenchymal stem cells (BMSCs) were isolated from healthy puppies and cultured with lipopolysaccharide (LPS) to observe how inflammation affects osteogenesis. Finally, the osteogenesis activity of BMSCs transfected with lentiviral vector either overexpressing (miR-146a-up) or inhibited for miR-146a expression was evaluated. miR-146a-up-transfected BMSCs were injected locally into the distraction gaps of the DO model canines. On days 42 and 56 post-surgery, the bone volume/tissue volume and bone mineral density values were evaluated via using micro-computed tomography, and newly formed tissues were harvested and evaluated via histological staining. The expression of miR-146a in both the DO canine model and LPS-stimulated BMSCs increased. Overexpression of miR-146a enhanced cell proliferation, migration, and osteogenic differentiation. Additionally, the newly formed callus was improved in canine mandibles injected with miR-146a-up-transfected BMSCs. In summary, miR-146a regulates mandibular DO by improving osteogenesis, and can serve as a potential target to shorten the therapy period of DO.
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Affiliation(s)
- Huijuan Shen
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Weidong Jiang
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Yangyang Yu
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Yuan Feng
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Tao Zhang
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Yan Liu
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Lina Guo
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China
| | - Nuo Zhou
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China.
| | - Xuanping Huang
- Departement of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, Nanning 530021, People's Republic of China; Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning 530021, People's Republic of China.
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Gao F, Wu X, Guo Z, Wang J, Gao W, Ma X, Li P. Teriparatide Promotes Bone Marrow Mesenchymal Stem Cells (BMSCs) Proliferation and Differentiation via Down-Regulating miR-298. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
This study explored whether teriparatide promotes BMSCs proliferation and differentiation via downregulating miR-298 and provided a basis for bone repair. Based on the microarray analysis after teriparatide treatment, qRT-PCR verified the differentially expressed miRNAs and the osteogenic
differentiation was assessed by transfection of miRNA overexpression plasmids and miRNA inhibitors. miRNA array analysis and qRT-PCR verification showed that miR-298 was significantly downregulated during teriparatide-induced BMSCs differentiation. miR-298 overexpression significantly inhibited
ALP and OPN expression which was promoted by transfection of miR-298 inhibitor. miR-298 is a negative regulator of BMSCs differentiation induced by teriparatide. Dlx5 is the target of miR-298. Inhibition of DLX5 expression by miR-298 was involved in the osteogenic differentiation of BMSCs.
In conclusion, miR-298 negatively regulates the differentiation of BMSCs induced by teriparatide by targeting DLX5, providing a possible therapeutic target for bone tissue repair and regeneration.
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Affiliation(s)
- Fei Gao
- Department of Orthopedics, Affiliated Hospital of Hebei University, Baoding, Hebei, 710000, China
| | - Xiaoming Wu
- Department of Orthopedics, Affiliated Hospital of Hebei University, Baoding, Hebei, 710000, China
| | - Zhao Guo
- Department of Orthopedics, Affiliated Hospital of Hebei University, Baoding, Hebei, 710000, China
| | - Jianzhong Wang
- Department of Orthopedics, Affiliated Hospital of Hebei University, Baoding, Hebei, 710000, China
| | - Wenshan Gao
- Department of Orthopedics, Affiliated Hospital of Hebei University, Baoding, Hebei, 710000, China
| | - Xiaoyong Ma
- Department of Orthopedics, Affiliated Hospital of Hebei University, Baoding, Hebei, 710000, China
| | - Panxiang Li
- Department of Orthopedics, Affiliated Hospital of Hebei University, Baoding, Hebei, 710000, China
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20
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Pan T, Song W, Xin H, Yu H, Wang H, Ma D, Cao X, Wang Y. MicroRNA-activated hydrogel scaffold generated by 3D printing accelerates bone regeneration. Bioact Mater 2022; 10:1-14. [PMID: 34901525 PMCID: PMC8637000 DOI: 10.1016/j.bioactmat.2021.08.034] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 01/09/2023] Open
Abstract
Bone defects remain a major threat to human health and bone tissue regeneration has become a prominent clinical demand worldwide. The combination of microRNA (miRNA) therapy with 3D printed scaffolds has always posed a challenge. It can mimic physiological bone healing processes, in which a biodegradable scaffold is gradually replaced by neo-tissue, and the sustained release of miRNA plays a vital role in creating an optimal osteogenic microenvironment, thus achieving promising bone repair outcomes. However, the balance between two key factors - scaffold degradation behavior and miRNA release profile - on osteogenesis and bone formation is still poorly understood. Herein, we construct a series of miRNA-activated hydrogel scaffolds (MAHSs) generated by 3D printing with different crosslinking degree to screened the interplay between scaffold degradation and miRNA release in the osteoinduction activity both in vitro and in vivo. Although MAHSs with a lower crosslinking degree (MAHS-0 and MAHS-0.25) released a higher amount of miR-29b in a sustained release profile, they degraded too fast to provide prolonged support for cell and tissue ingrowth. On the contrary, although the slow degradation of MAHSs with a higher crosslinking degree (MAHS-1 and MAHS-2.5) led to insufficient release of miR-29b, their adaptable degradation rate endowed them with more efficient osteoinductive behavior over the long term. MAHS-1 gave the most well-matched degradation rate and miR-29b release characteristics and was identified as the preferred MAHSs for accelerated bone regeneration. This study suggests that the bio-adaptable balance between scaffold degradation behavior and bioactive factors release profile plays a critical role in bone regeneration. These findings will provide a valuable reference about designing miRNAs as well as other bioactive molecules activated scaffold for tissue regeneration.
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Affiliation(s)
- Ting Pan
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, PR China
- Institute of Nanophotonics, Jinan University, Guangzhou, 511443, PR China
| | - Wenjing Song
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, PR China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
- Key Laboratory of Biomedical Engineering of Guangdong Province, And Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
| | - Hongbao Xin
- Institute of Nanophotonics, Jinan University, Guangzhou, 511443, PR China
| | - Haiyue Yu
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Oral Diagnosis, Digital Health and Health Services Research, Berlin, Germany
| | - He Wang
- Department of Endodontics, Stomatological Hospital, Southern Medical University, No. 366 South Jiangnan Avenue, Guangzhou, 510280, China
| | - Dandan Ma
- Department of Endodontics, Stomatological Hospital, Southern Medical University, No. 366 South Jiangnan Avenue, Guangzhou, 510280, China
| | - Xiaodong Cao
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, PR China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
- Key Laboratory of Biomedical Engineering of Guangdong Province, And Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
| | - Yingjun Wang
- School of Materials Science and Engineering, South China University of Technology, Guangzhou, 510006, PR China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
- Key Laboratory of Biomedical Engineering of Guangdong Province, And Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510006, China
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21
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Ding A, Li CH, Yu CY, Zhou HT, Zhang ZH. Long non-coding RNA MALAT1 enhances angiogenesis during bone regeneration by regulating the miR-494/SP1 axis. J Transl Med 2021; 101:1458-1466. [PMID: 34392309 DOI: 10.1038/s41374-021-00649-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 07/21/2021] [Accepted: 07/26/2021] [Indexed: 01/16/2023] Open
Abstract
Bone regeneration is a coordinated process involving connections between blood vessels and osteocytes. Angiogenesis and osteogenesis are tightly connected throughout the progression of bone regeneration. This study aimed to explore the underlying mechanism of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)-regulated angiogenesis during bone regeneration. Gene and protein expression was detected by quantitative real-time PCR and western blot assay. Vascular endothelial growth factor (VEGFA) secretion was assessed by enzyme-linked immunosorbent assay. To evaluate the effect of osteogenic differentiation, alkaline phosphatase (ALP) and alizarin red staining assays were performed. Proliferation was detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Migration and angiogenesis were measured using Transwell and tube formation assays. A dual luciferase reporter assay was performed to confirm the binding relationship among MALAT1, miR-494, and specificity protein 1 (SP1). Expression levels of MALAT1, SP1, and VEGFA were elevated and miR-494 was suppressed in MC3T3-E1 cells after culture in osteogenic medium. MALAT1 knockdown suppressed the osteogenic differentiation of MC3T3-E1, since ALP activity, mineralized nodules, and expression of the osteodifferentiated markers runt-related transcription factor 2 and osterix were restrained. In addition, MALAT1 silencing inhibited angiogenesis during bone regeneration, as the proliferation, migration, and capillary tube formation of human umbilical vein endothelial cells were blocked. Furthermore, miR-494 was directly targeted by MALAT1 and regulated the SP1/Toll-like receptor 2 (TLR2)/bone morphogenetic protein 2 (BMP2) axis by targeting SP1. Furthermore, miR-494 overexpression inhibited angiogenesis and osteogenic differentiation. Moreover, SP1 overexpression or miR-494 inhibition rescued the regulatory effect of sh-MALAT1 on angiogenesis and osteogenic differentiation. Taken together, these findings indicate that MALAT1 promotes angiogenesis and osteogenic differentiation by targeting miR-494 and activating the SP1/TLR2/BMP2 pathway, suggesting a novel target for bone regeneration therapy by promoting angiogenesis.
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Affiliation(s)
- Ao Ding
- Department of Stomatology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, P.R. China
| | - Cheng-Hua Li
- Department of Stomatology, Beidaihe Rihabilitation and Recuperation Center of PLA, Qinhuangdao, Hebei Province, P.R. China
| | - Chan-Yuan Yu
- Department of Stomatology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, P.R. China
| | - Hang-Tian Zhou
- Department of Stomatology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, P.R. China
| | - Zhi-Hong Zhang
- Department of Stomatology, The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, P.R. China.
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22
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Song YT, Liu PC, Tan J, Zou CY, Li QJ, Li-Ling J, Xie HQ. Stem cell-based therapy for ameliorating intrauterine adhesion and endometrium injury. Stem Cell Res Ther 2021; 12:556. [PMID: 34717746 PMCID: PMC8557001 DOI: 10.1186/s13287-021-02620-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/04/2021] [Indexed: 02/08/2023] Open
Abstract
Intrauterine adhesion refers to endometrial repair disorders which are usually caused by uterine injury and may lead to a series of complications such as abnormal menstrual bleeding, recurrent abortion and secondary infertility. At present, therapeutic approaches to intrauterine adhesion are limited due to the lack of effective methods to promote regeneration following severe endometrial injury. Therefore, to develop new methods to prevent endometrial injury and intrauterine adhesion has become an urgent need. For severely damaged endometrium, the loss of stem cells in the endometrium may affect its regeneration. This article aimed to discuss the characteristics of various stem cells and their applications for uterine tissue regeneration.
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Affiliation(s)
- Yu-Ting Song
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Peng-Cheng Liu
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jie Tan
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chen-Yu Zou
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qian-Jin Li
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jesse Li-Ling
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Medical Genetics, West China Second Hospital, Sichuan University, Chengdu, 610041, China
| | - Hui-Qi Xie
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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23
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Han X, Fan Z. MicroRNAs Regulation in Osteogenic Differentiation of Mesenchymal Stem Cells. FRONTIERS IN DENTAL MEDICINE 2021. [DOI: 10.3389/fdmed.2021.747068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cell with the potential of self-renewal and multidirectional differentiation. They can be obtained from a variety of tissues and can differentiate into a variety of cell types under different induction conditions, including osteoblasts. Because of this osteogenic property, MSCs have attracted much attention in the treatment of bone metabolism-related diseases. MicroRNAs (miRNAs), as an epigenetic factor, are thought to play an important regulatory role in the process of osteogenic differentiation of MSCs. In recent years, increasingly evidence shows that miRNAs imbalance is involved in the regulation of osteoporosis and fracture. In this review, miRNAs involved in osteogenic differentiation and their mechanisms for regulating the expression of target genes are reviewed. In addition, we also discuss the potential clinical applications and possible directions of this field in the future.
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24
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Ribeiro AO, de Oliveira AC, Costa JM, Nachtigall PG, Herkenhoff ME, Campos VF, Delella FK, Pinhal D. MicroRNA roles in regeneration: Multiple lessons from zebrafish. Dev Dyn 2021; 251:556-576. [PMID: 34547148 DOI: 10.1002/dvdy.421] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 08/23/2021] [Accepted: 09/07/2021] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs with pivotal roles in the control of gene expression. By comparing the miRNA profiles of uninjured vs. regenerating tissues and structures, several studies have found that miRNAs are potentially involved in the regenerative process. By inducing miRNA overexpression or inhibition, elegant experiments have directed regenerative responses validating relevant miRNA-to-target interactions. The zebrafish (Danio rerio) has been the epicenter of regenerative research because of its exceptional capability to self-repair damaged tissues and body structures. In this review, we discuss recent discoveries that have improved our understanding of the impact of gene regulation mediated by miRNAs in the context of the regeneration of fins, heart, retina, and nervous tissue in zebrafish. We compiled what is known about the miRNA control of regeneration in these tissues and investigated the links among up-regulated and down-regulated miRNAs, their putative or validated targets, and the regenerative process. Finally, we briefly discuss the forthcoming prospects, highlighting directions and the potential for further development of this field.
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Affiliation(s)
- Amanda Oliveira Ribeiro
- Laboratório Genômica e Evolução Molecular (LGEM), Departamento de Ciências Químicas e Biológicas, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Botucatu, SP, Brazil
| | - Arthur Casulli de Oliveira
- Laboratório Genômica e Evolução Molecular (LGEM), Departamento de Ciências Químicas e Biológicas, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Botucatu, SP, Brazil
| | - Juliana Mara Costa
- Laboratório Genômica e Evolução Molecular (LGEM), Departamento de Ciências Químicas e Biológicas, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Botucatu, SP, Brazil
| | - Pedro Gabriel Nachtigall
- Laboratório Genômica e Evolução Molecular (LGEM), Departamento de Ciências Químicas e Biológicas, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Botucatu, SP, Brazil.,Laboratório Especial de Toxicologia Aplicada (LETA), CeTICS, Instituto Butantan, São Paulo, SP, Brazil
| | - Marcos Edgar Herkenhoff
- Laboratório Genômica e Evolução Molecular (LGEM), Departamento de Ciências Químicas e Biológicas, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Botucatu, SP, Brazil.,Departamento de Tecnologia Bioquímico-Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Vinicius Farias Campos
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Flávia Karina Delella
- Departamento de Biologia Estrutural e Funcional, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Botucatu, SP, Brazil
| | - Danillo Pinhal
- Laboratório Genômica e Evolução Molecular (LGEM), Departamento de Ciências Químicas e Biológicas, Instituto de Biociências, Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Botucatu, SP, Brazil
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25
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Iwata T, Mizuno N, Nagahara T, Kaneda-Ikeda E, Kajiya M, Sasaki S, Takeda K, Kiyota M, Yagi R, Fujita T, Kurihara H. Cytokines regulate stemness of mesenchymal stem cells via miR-628-5p during periodontal regeneration. J Periodontol 2021; 93:269-286. [PMID: 34152611 DOI: 10.1002/jper.21-0064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 06/11/2021] [Accepted: 06/12/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND Cytokines play key roles in stimulating periodontal regeneration; however, their exact mechanisms of action remain unclear. Mesenchymal stem cells (MSCs) are multipotent cells that have self-renewal abilities and can differentiate into periodontal tissues such as bone, cementum, and periodontal ligaments following transplantation, like periodontal progenitor cells. Here, we used MSCs to identify the regulatory genes induced by periodontal regenerative cytokines. METHODS Human MSCs (hMSCs) were cultured under conditions of periodontal regenerative cytokine stimulation or silencing of undifferentiated hMSC transcription factors. To characterize the changes associated with periodontal regenerative cytokine-regulated microRNAs (miRNAs), miRNA, and mRNA expression was evaluated using miRNA arrays and quantitative real-time polymerase chain reaction, respectively. One of the identified miRNAs, miR-628-5p, was then overexpressed or suppressed in hMSCs during osteogenesis; the effect of these changes on osteogenesis was investigated. RESULTS Cytokine-stimulated MSCs showed characteristic miRNA profiles and mRNA levels of undifferentiated hMSC transcription factors ETV1, SOX11, and GATA6. Next, we silenced these transcription factors in MSCs and examined the miRNA profiles. The levels of miR-628-5p were decreased upon all cytokine treatments and were increased upon silencing of ETV1, SOX11, and GATA6. Overexpression of miR-628-5p suppressed osteogenesis; however, its inhibition enhanced OPN, ALP, OC, BMP2, and RUNX2 mRNA levels, and bone matrix mineralization, but not OSX mRNA or ALP activity. CONCLUSIONS miR-628-5p negatively regulates MSC stemness during periodontal regeneration. Periodontal regenerative cytokines act as miR-628-5p suppressors to support periodontal regeneration. Thus, selection of effective cytokines for different MSCs, based on miRNA profiling, is important for advancing regenerative therapies.
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Affiliation(s)
- Tomoyuki Iwata
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Noriyoshi Mizuno
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Takayoshi Nagahara
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Eri Kaneda-Ikeda
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Mikihito Kajiya
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Shinya Sasaki
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Katsuhiro Takeda
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.,Department of Biological Endodontics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Mari Kiyota
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Ryoichi Yagi
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Tsuyoshi Fujita
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Hidemi Kurihara
- Department of Periodontal Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
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26
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Shao X, Qin J, Wan C, Cheng J, Wang L, Ai G, Cheng Z, Tong X. ADSC Exosomes Mediate lncRNA-MIAT Alleviation of Endometrial Fibrosis by Regulating miR-150-5p. Front Genet 2021; 12:679643. [PMID: 34178037 PMCID: PMC8220143 DOI: 10.3389/fgene.2021.679643] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/22/2021] [Indexed: 12/23/2022] Open
Abstract
Background Secondary infertility remains a major complication of endometrial fibrosis in women. The use of exosomes from adipose-derived mesenchymal stem cells (ADSCs) has shown promising results for the treatment of endometrial fibrosis. However, the mechanisms of action of ADSC-exosome (ADSC-Exo) therapy remain unclear. Materials and Methods An endometrial fibrosis model was established in mice treated with alcohol and endometrial epithelial cells (ESCs) treated with TGF-β1. ADSCs were isolated from Sprague Dawley (SD) rats, and exosomes were isolated from ADSCs using ExoQuick reagent. Exosomes were identified by transmission electron microscopy (TEM), NanoSight, and Western blot analysis. The expression level of lncRNA-MIAT was detected by qPCR analysis. Western blot analysis was carried out to determine the protein levels of fibrosis markers (TGFβR1, α-SMA, and CK19). A dual-luciferase reporter gene assay was used to verify the relationship between target genes. The endometrial tissues of the endometrial fibrosis model were stained with HE and Masson’s trichrome. Results ADSCs and ADSC-Exos were successfully isolated, and the expression level of lncRNA-MIAT was significantly down-regulated in endometrial tissue and the TGF-β1-induced ESC injury model, whereas ADSC-Exos increased the expression of lncRNA-MIAT in the TGF-β1-induced ESC model. Functionally, ADSC-Exo treatment repressed endometrial fibrosis in vivo and in vitro by decreasing the expression of hepatic fibrosis markers (α-SMA and TGFβR1) and increasing the expression of CK19. Moreover, miR-150-5p expression was repressed by lncRNA-MIAT in the TGF-β1-induced ESC injury model. The miR-150-5p mimic promoted TGF-β1-induced ESC fibrosis. Conclusion ADSC-Exos mediate lncRNA-MIAT alleviation of endometrial fibrosis by regulating miR-150-5p, which suggests that lncRNA-MIAT from ADSC-Exos may be a viable treatment for endometrial fibrosis.
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Affiliation(s)
- Xiaowen Shao
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinlong Qin
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chendong Wan
- Department of Obstetrics and Gynecology, Fourth People's Hospital of Yixing City, Wuxi, China
| | - Jiajing Cheng
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lian Wang
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guihai Ai
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhongping Cheng
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaowen Tong
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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27
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Advances in the occurrence and biotherapy of osteoporosis. Biochem Soc Trans 2021; 48:1623-1636. [PMID: 32627832 DOI: 10.1042/bst20200005] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 12/17/2022]
Abstract
Osteoporosis (OP) is a bone metabolic disease, is characterized by degeneration of bone structure and decreased bone mass. It happens in more than 1/3 women and 1/5 men of over than 50 years old, which affects the health and lives of people. The main mechanism of OP is mainly that the dynamic balance between the bone formation and resorption is broken, so that bone resorption is more than bone formation. It is prone to result in bone metabolism disorder. There are many precipitating factor such as elder age, low hormone level, genetic factors and bad hobbies. At the same time, the occurrence of the OP and its complications has different degrees of impact on people's quality of life. Based on the current understanding of the OP, we summarized the etiology, current clinical drugs and potential targeting therapy for OP. Although the research have made many progress in explore what is the novel mechanism and how to improve the effect, there are still many problems in the treatment method that limit its application prospects and need to be solved. In this review, we mainly focus on the mechanism of OP and related research on the targeted treatment of OP. Hopefully, our summary will provide a reference to develop some novel strategies for the target therapy of OP.
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28
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Zhang S, Ding X, Miao H, Wang L, Xian L, Han S, Zhang D, Li J. The Effects of MiR-320 on the Proliferation and Differentiation of Human Alveolar Bone-Derived Mesenchymal Stem Cells. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Alveolar bone-derived mesenchymal stem cells (AB-BMSCs) have a biological morphology and antigen phenotype similar to those of BMSCs. However, the intrinsic characteristics of AB-BMSCs and their underlying mechanisms, in which the involvement of micro(mi)RNAs has been reported, remain
unknown. This study shows that miR-320c expression was significantly suppressed during osteoblastic differentiation of human AB-BMSCs. The overexpression of miR-320c markedly decreased cellular proliferation, intracellular activity of alkaline phosphatase (ALP) and formation of calcium nodules;
mRNA levels of osteogenesis-related genes were significantly reduced compared to those in control cells. Calcium nodule formation in miR-320c-knockdown cells was significantly increased, and HOXA10, Runx2, and BGP mRNA levels were significantly increased compared to those in
control cells. These results indicate that miR-320c suppresss the proliferation and osteogenic differentiation of AB-BMSCs, in part by decreasing ALP activity, cellular proliferation, mineralization, and expression of several osteogenesis-related genes. These results lay the basic foundation
for the elucidation of the molecular mechanisms of alveolar bone reconstruction.
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Affiliation(s)
- Shuyue Zhang
- Department of Stomatology, Tangshan People’s Hospital, Tangshan, 063001, China
| | - Xinguo Ding
- Xiamen Haicang Hospital, Xiamen, 361026, China
| | - Haixia Miao
- Department of Stomatology, Tangshan People’s Hospital, Tangshan, 063001, China
| | - Lei Wang
- Department of Pathology, Tangshan People’s Hospital, Tangshan, 063001, China
| | - Lige Xian
- Department of Pathology, Tangshan People’s Hospital, Tangshan, 063001, China
| | - Sugui Han
- ClinicalLaboratory, Tangshan People’s Hospital, Tangshan, 063001, China
| | - Di Zhang
- North China University of Science and Technology, Tangshan, 063000, China
| | - Jian Li
- Department of Stomatology, Xiang’an Hospital of Xiamen University, Xiamen, 361101, China
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29
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Iaquinta MR, Lanzillotti C, Mazziotta C, Bononi I, Frontini F, Mazzoni E, Oton-Gonzalez L, Rotondo JC, Torreggiani E, Tognon M, Martini F. The role of microRNAs in the osteogenic and chondrogenic differentiation of mesenchymal stem cells and bone pathologies. Theranostics 2021; 11:6573-6591. [PMID: 33995677 PMCID: PMC8120225 DOI: 10.7150/thno.55664] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/15/2021] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been identified in many adult tissues. MSCs can regenerate through cell division or differentiate into adipocytes, osteoblasts and chondrocytes. As a result, MSCs have become an important source of cells in tissue engineering and regenerative medicine for bone tissue and cartilage. Several epigenetic factors are believed to play a role in MSCs differentiation. Among these, microRNA (miRNA) regulation is involved in the fine modulation of gene expression during osteogenic/chondrogenic differentiation. It has been reported that miRNAs are involved in bone homeostasis by modulating osteoblast gene expression. In addition, countless evidence has demonstrated that miRNAs dysregulation is involved in the development of osteoporosis and bone fractures. The deregulation of miRNAs expression has also been associated with several malignancies including bone cancer. In this context, bone-associated circulating miRNAs may be useful biomarkers for determining the predisposition, onset and development of osteoporosis, as well as in clinical applications to improve the diagnosis, follow-up and treatment of cancer and metastases. Overall, this review will provide an overview of how miRNAs activities participate in osteogenic/chondrogenic differentiation, while addressing the role of miRNA regulatory effects on target genes. Finally, the role of miRNAs in pathologies and therapies will be presented.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Fernanda Martini
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara. Ferrara, Italy
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30
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Zheng M, Tan J, Liu X, Jin F, Lai R, Wang X. miR-146a-5p targets Sirt1 to regulate bone mass. Bone Rep 2021; 14:101013. [PMID: 33855130 PMCID: PMC8024884 DOI: 10.1016/j.bonr.2021.101013] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 02/08/2023] Open
Abstract
MicroRNAs (miRNAs) have been proven to serve as key post-transcriptional regulators, affecting diverse biological processes including osteogenic differentiation and bone formation. Recently, it has been reported that miR-146a-5p affects the activity of both osteoblasts and osteoclasts. However, the target genes of miR-146a-5p in these procedures remain unknown. Here we identify miR-146a-5p as a critical suppressor of osteoblastogenesis and bone formation. We found that miR-146a-5p knockout mice exhibit elevated bone formation and enhanced bone mass in vivo. Consistently, we also found that miR-146a-5p inhibited the osteoblast differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro. Importantly, we further demonstrated that miR-146a-5p directly targeted Sirt1 to inhibit osteoblast activity. Additionally, we showed that the expression of miR-146a-5p gradually increased in femurs with age not only in female mice but also in female patients, and miR-146a-5p deletion protected female mice from age-induced bone loss. These data suggested that miR-146a-5p has a crucial role in suppressing the bone formation and that inhibition of miR-146a-5p may be a strategy for ameliorating osteoporosis.
MiR-146a-5p inhibits osteoblast activity by targeting Sirt1. MiR-146a-5p deletion ameliorates age-induced bone loss in mice. MiR-146a-5p expression was increased in bone specimens from older females. MiR-146a-5p was a potential target for osteoporosis treatment.
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Affiliation(s)
- Mingxia Zheng
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, College of Stomatology, Jinan University, Guangdong 510632, China
| | - Junlong Tan
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, College of Stomatology, Jinan University, Guangdong 510632, China
| | - Xiangning Liu
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, College of Stomatology, Jinan University, Guangdong 510632, China
| | - Fujun Jin
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, College of Stomatology, Jinan University, Guangdong 510632, China.,Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing 100000, China
| | - Renfa Lai
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, College of Stomatology, Jinan University, Guangdong 510632, China
| | - Xiaogang Wang
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University & Department of Stomatology, College of Stomatology, Jinan University, Guangdong 510632, China.,Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing 100000, China
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31
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Wang Y, Zheng Y, Li W. Compression loading of osteoclasts attenuated microRNA-146a-5p expression, which promotes angiogenesis by targeting adiponectin. SCIENCE CHINA-LIFE SCIENCES 2021; 65:151-166. [PMID: 33677819 DOI: 10.1007/s11427-020-1869-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/06/2021] [Indexed: 11/24/2022]
Abstract
Osteoclastogenesis in alveolar bone induced by compression stress triggers orthodontic tooth movement. Compression stress also stimulates angiogenesis, which is essential for osteoclastogenesis. However, the effects of osteoclastogenesis induced by compression on angiogenesis are poorly understood. In vivo, we found the markers of angiogenesis increased during orthodontic bone remodeling. In vitro, osteoclast-derived exosomes increased proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs), as well as expression of vascular endothelial growth factor and CD31. The promotive effects of exosomes derived from compressed osteoclasts were greater than those derived from osteoclasts without compression. Next, we analyzed changes in the microRNA transcriptome after compression stress and focused on microRNA146a-5p (miR-146a), which was significantly decreased by compression. Transfection of an inhibitor of miR-146a stimulated angiogenesis of HUVECs while miR-146a mimics repressed angiogenesis. Adiponectin (ADP) was confirmed to be a target of miR-146a by dual luciferase reporter assay. In HUVECs treated with exosomes, we detected increased ADP which promoted angiogenesis. Knockdown of ADP in HUVECs reduced the promotive effects of exosomes. Our results demonstrate that the decreased miR-146a observed in osteoclasts after compression promotes angiogenesis by targeting ADP, suggesting a novel method to interfere with bone remodeling induced by compression stress.
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Affiliation(s)
- Yue Wang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China
| | - Yunfei Zheng
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
| | - Weiran Li
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
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32
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Hong L, Sun H, Amendt BA. MicroRNA function in craniofacial bone formation, regeneration and repair. Bone 2021; 144:115789. [PMID: 33309989 PMCID: PMC7869528 DOI: 10.1016/j.bone.2020.115789] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/25/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023]
Abstract
Bone formation in the craniofacial complex is regulated by cranial neural crest (CNC) and mesoderm-derived cells. Different elements of the developing skull, face, mandible, maxilla (jaws) and nasal bones are regulated by an array of transcription factors, signaling molecules and microRNAs (miRs). miRs are molecular modulators of these factors and act to restrict their expression in a temporal-spatial mechanism. miRs control the different genetic pathways that form the craniofacial complex. By understanding how miRs function in vivo during development they can be adapted to regenerate and repair craniofacial genetic anomalies as well as bone diseases and defects due to traumatic injuries. This review will highlight some of the new miR technologies and functions that form new bone or inhibit bone regeneration.
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Affiliation(s)
- Liu Hong
- Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA, USA
| | - Hongli Sun
- Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA, USA
| | - Brad A Amendt
- Iowa Institute for Oral Health Research, The University of Iowa, Iowa City, IA, USA; The University of Iowa, Department of Anatomy and Cell Biology, Iowa City, IA, USA; Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA, USA.
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33
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Shaik S, Martin E, Hayes D, Gimble J, Devireddy R. microRNA Sequencing of CD34+ Sorted Adipose Stem Cells Undergoing Endotheliogenesis. Stem Cells Dev 2021; 30:265-288. [PMID: 33397204 PMCID: PMC7994430 DOI: 10.1089/scd.2020.0173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/02/2021] [Indexed: 12/13/2022] Open
Abstract
While several microRNAs (miRNAs) that regulate the endotheliogenesis and further promote angiogenesis have been identified in various cancers, the identification of miRNAs that can drive the differentiation of adipose derived stromal/stem cells (ASCs) into the endothelial lineage has been largely unexplored. In this study, CD34+ ASCs sorted using magnetic bead separation were induced to differentiate along the endothelial pathway. miRNA sequencing of ASCs at day 3, 9, and 14 of endothelial differentiation was performed on Ion Proton sequencing system. The data obtained by this high-throughput method were aligned to the human genome HG38, and the differentially expressed miRNAs during endothelial differentiation at various time points (day 3, 9, and 14) were identified. The gene targets of the identified miRNAs were obtained through miRWalk database. The network-pathway analysis of miRNAs and their targets was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatic tools to determine the potential candidate miRNAs that promote endothelial differentiation. Based on these analyses, six upregulated miRNAs (miR-181a-5p, miR-330-5p, miR-335-3p, miR-15b-5p, miR-99a-5p, and miR-199a-5p) and six downregulated miRNAs (miR-145-5p, miR-155-5p, miR-193a-3p, miR-125a-5p, miR-221-5p, and miR-222-3p) were chosen for further studies. In vitro evaluation of these miRNAs to induce endothelial differentiation when transfected into CD34+ sorted ASCs was studied using Von Willebrand Factor (VWF) staining and quantitative real time-polymerase chain reaction (qRT-PCR). Our results suggest that miRNAs: 335-5p, 330-5p, 181a-5p and anti-miRNAs: 125a-5p, 145-5p can likely induce endothelial differentiation in CD34+ sorted ASCs. Further studies are clearly required to elucidate the specific mechanisms on how miRNAs or anti-miRNAs identified through bioinformatics approach can induce the endotheliogenesis in ASCs.
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Affiliation(s)
- Shahensha Shaik
- Bioengineering Laboratory, Department of Mechanical Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Elizabeth Martin
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Daniel Hayes
- Department of Biomedical Engineering, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Jeffrey Gimble
- La Cell, LLC and Obatala Sciences, Inc., New Orleans, Louisiana, USA
| | - Ram Devireddy
- Bioengineering Laboratory, Department of Mechanical Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
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Mazziotta C, Lanzillotti C, Iaquinta MR, Taraballi F, Torreggiani E, Rotondo JC, Otòn-Gonzalez L, Mazzoni E, Frontini F, Bononi I, De Mattei M, Tognon M, Martini F. MicroRNAs Modulate Signaling Pathways in Osteogenic Differentiation of Mesenchymal Stem Cells. Int J Mol Sci 2021; 22:2362. [PMID: 33673409 PMCID: PMC7956574 DOI: 10.3390/ijms22052362] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/18/2021] [Accepted: 02/24/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been identified in many adult tissues and they have been closely studied in recent years, especially in view of their potential use for treating diseases and damaged tissues and organs. MSCs are capable of self-replication and differentiation into osteoblasts and are considered an important source of cells in tissue engineering for bone regeneration. Several epigenetic factors are believed to play a role in the osteogenic differentiation of MSCs, including microRNAs (miRNAs). MiRNAs are small, single-stranded, non-coding RNAs of approximately 22 nucleotides that are able to regulate cell proliferation, differentiation and apoptosis by binding the 3' untranslated region (3'-UTR) of target mRNAs, which can be subsequently degraded or translationally silenced. MiRNAs control gene expression in osteogenic differentiation by regulating two crucial signaling cascades in osteogenesis: the transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) and the Wingless/Int-1(Wnt)/β-catenin signaling pathways. This review provides an overview of the miRNAs involved in osteogenic differentiation and how these miRNAs could regulate the expression of target genes.
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Affiliation(s)
- Chiara Mazziotta
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Carmen Lanzillotti
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Maria Rosa Iaquinta
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA;
- Orthopedics and Sports Medicine, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USA
| | - Elena Torreggiani
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - John Charles Rotondo
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Lucia Otòn-Gonzalez
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Elisa Mazzoni
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Francesca Frontini
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Ilaria Bononi
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Monica De Mattei
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Mauro Tognon
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
| | - Fernanda Martini
- Department of Medical Sciences, Section of Experimental Medicine, School of Medicine, University of Ferrara, 64b Fossato di Mortara Street, 44121 Ferrara, Italy; (C.M.); (C.L.); (M.R.I.); (E.T.); (J.C.R.); (L.O.-G.); (E.M.); (F.F.); (I.B.); (F.M.)
- Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 70, Eliporto Street, 44121 Ferrara, Italy
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35
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García-García P, Briffault E, Landin M, Evora C, Diaz-Rodriguez P, Delgado A. Tailor-made oligonucleotide-loaded lipid-polymer nanosystems designed for bone gene therapy. Drug Deliv Transl Res 2021; 11:598-607. [PMID: 33625680 DOI: 10.1007/s13346-021-00926-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2021] [Indexed: 12/17/2022]
Abstract
Gene therapy has emerged as a tool for the treatment of systemic metabolic disorders as osteoporosis (OP). However, the design of a suitable vehicle able to efficiently load and release the genetic material on the target cells is still a challenge. Moreover, the internalization pathway of nanosystems has been described to be dependent on their surface characteristics and the cell type evaluated. In this study, we aim at obtaining PEGylated lipid-PLGA nanoparticles (NPs) with variable surface charge able to incorporate GapmeRs (single-strand antisense oligonucleotides) for OP treatment. Nanoparticles showing negative, positive, and neutral surface charge were obtained by modulating the lipid composition. All formulations showed a remarkably low polydispersity index with adequate size. NPs were loaded with GapmeRs showing a high encapsulation efficiency and a surface charge-independent oligonucleotide loading. All the formulations were adequately internalized by MSCs. Future experiments will be devoted to use the developed formulations to clarify if the intracellular distribution of hybrid NPs on mesenchymal stem cells (MSCs) is dependent on surface charge. This portfolio of NPs will serve as a tool to analyze the effect of NP surface charge on gene therapy efficiency.
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Affiliation(s)
- Patricia García-García
- Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna, 38200, La Laguna, Spain
| | - Erik Briffault
- Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna, 38200, La Laguna, Spain
| | - Mariana Landin
- R+D Pharma Group (GI-1645); Strategic Grouping in Materials (AEMAT)Department of Pharmacology, Pharmacy and Pharmaceutical TechnologyFaculty of Pharmacy, Universidade de Santiago de Compostela-Campus Vida, 15782, Santiago de Compostela, Spain
| | - Carmen Evora
- Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna, 38200, La Laguna, Spain.,Institute of Biomedical Technologies (ITB), Center for Biomedical Research of the Canary Islands (CIBICAN), Universidad de La Laguna, 38200, La Laguna, Spain
| | - Patricia Diaz-Rodriguez
- Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna, 38200, La Laguna, Spain. .,Institute of Biomedical Technologies (ITB), Center for Biomedical Research of the Canary Islands (CIBICAN), Universidad de La Laguna, 38200, La Laguna, Spain.
| | - Araceli Delgado
- Department of Chemical Engineering and Pharmaceutical Technology, Universidad de La Laguna, 38200, La Laguna, Spain. .,Institute of Biomedical Technologies (ITB), Center for Biomedical Research of the Canary Islands (CIBICAN), Universidad de La Laguna, 38200, La Laguna, Spain.
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36
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Komatsu DE, Duque E, Hadjiargyrou M. MicroRNAs and fracture healing: Pre-clinical studies. Bone 2021; 143:115758. [PMID: 33212318 PMCID: PMC7769985 DOI: 10.1016/j.bone.2020.115758] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 11/13/2020] [Accepted: 11/13/2020] [Indexed: 12/28/2022]
Abstract
During the past several years, pre-clinical experiments have established that microRNAs (miRNAs), small non-coding RNAs, serve as key regulatory molecules of fracture healing. Their easy modulation with agonists and antagonists make them highly desirable targets for future therapeutic strategies, especially for pathophysiologic fractures that either do not heal (nonunions) or are delayed. It is now well documented that these problematic fractures lead to human suffering and impairment of life quality. Additionally, financial difficulties are also encountered as work productivity decreases and income is reduced. Moreover, targeting miRNAs may also be an avenue to enhancing normal physiological fracture healing. Herein we present the most current knowledge of the involvement of miRNAs during fracture healing in pre-clinical studies. Following a brief description on the nature of miRNAs and of the fracture healing process, we present data from studies focusing specifically, on miRNA regulation of osteoblast differentiation and osteogenesis (within the context of known signaling pathways), chondrocytes, angiogenesis, and apoptosis, all critical to successful bone repair. Further, we also discuss miRNAs and exosomes. We hope that this manuscript serves as a comprehensive review that will facilitate basic/translational scientists in the orthopaedic arena to realize and further decipher the biological and future therapeutic impact of these small regulatory RNA molecules, especially as they relate to the molecular events of each of the major phases of fracture healing.
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Affiliation(s)
- David E Komatsu
- Department of Orthopaedics and Rehabilitation, Stony Brook University, United States of America
| | - Edie Duque
- Department of Orthopaedics and Rehabilitation, Stony Brook University, United States of America
| | - Michael Hadjiargyrou
- Department of Biological and Chemical Sciences, New York Institute of Technology, United States of America.
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Chen M, Zhou M, Fu Y, Li J, Wang Z. Effects of miR-672 on the angiogenesis of adipose-derived mesenchymal stem cells during bone regeneration. Stem Cell Res Ther 2021; 12:85. [PMID: 33494825 PMCID: PMC7836178 DOI: 10.1186/s13287-021-02154-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 01/07/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Sufficient vascular network plays an important role in the repair of bone defects. Bone morphogenetic protein 2 (BMP2) being a key regulator of angiogenesis has attracted the attention of researchers. In addition, evidence has suggested that BMP2 coordinates with microRNAs (miRNAs) to form intracellular networks regulating mesenchymal stem cells (MSCs) angiogenesis. Elucidating the underlying mechanisms that are regulating adipose-derived mesenchymal stem cells (ADSCs) angiogenesis might provide more effective method to enhance bone regeneration. METHODS We identified the specific miRNA in rat ADSCs during BMP2-induced angiogenesis and chose the most significant differentially expressed miRNA, miR-672. Three lentiviral system named Lenti-miR-672, Lenti-as-miR-672, and Lenti-miR-NC were transduced into the ADSCs individually. Then, the quantitative real-time polymerase chain reaction (qPCR), western blotting, and blood vessel formation analysis were performed to investigate the effects of miR-672 on ADSCs angiogenesis. Bioinformation platforms were used to screen the potential target of miR-672. Small interfering RNA (siRNA) against TIMP2 (si-TIMP2) mRNA were obtained from GenePharma, and then si-TIMP2 miRNA and miR-672 were co-transfected into ADSCs to detect the effects of TIMP2 on angiogenesis. Calcium phosphate cement (CPC) scaffolds that seeded the lentiviral-modified ADSCs were constructed to test the vascularized bone regeneration in vivo. RESULTS Our data showed that after the angiogenesis of ADSCs induced by BMP2, miR-672 was the most significantly upregulated miRNA. Overexpression of miR-672 promoted the angiogenesis of ADSCs, while knockdown of miR-672 repressed the angiogenesis of ADSCs. The bioinformation prediction showed that TIMP2 might be the one of miR-672' potential targets. TIMP2 protein expression was gradually decreased in ADSCs with overexpressed miR-672. And the angiogenic factors were upregulated in the ADSCs which were transduced with si-TIMP2. Then, the CPC scaffolds coupled the miR-672-modified ADSCs and showed the good potential in vascularized bone regeneration. The overexpressed miR-672 could greatly enhance the blood vessel volume and Microfil-labeled blood vessel numbers in newly formed bone. CONCLUSION BMP2 could promote the angiogenesis of ADSCs through stimulating the expression of miR-672 in ADSCs. miR-672 acted as a positive regulator on the angiogenesis of ADSCs, and incorporating the miR-672-modified ADSCs in the CPC could significantly promote the vascularization and the bone regeneration.
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Affiliation(s)
- Mingjiao Chen
- grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 People’s Republic of China
| | - Meng Zhou
- grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 People’s Republic of China
| | - Yao Fu
- grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 People’s Republic of China
| | - Jin Li
- grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 People’s Republic of China
| | - Zi Wang
- grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Zhizaoju Road No. 639, Shanghai, 200011 People’s Republic of China
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Fittipaldi S, Visconti VV, Tarantino U, Novelli G, Botta A. Genetic variability in noncoding RNAs: involvement of miRNAs and long noncoding RNAs in osteoporosis pathogenesis. Epigenomics 2020; 12:2035-2049. [PMID: 33264054 DOI: 10.2217/epi-2020-0233] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The pathogenesis of osteoporosis is multifactorial and is the consequence of genetic, hormonal and lifestyle factors. Epigenetics, including noncoding RNA (ncRNA) deregulation, represents a link between susceptibility to develop the disease and environmental influences. The majority of studies investigated the expression of ncRNAs in osteoporosis patients; however, very little information is available on their genetic variability. In this review, we focus on two classes of ncRNAs: miRNAs and long noncoding RNAs (lncRNAs). We summarize recent findings on how polymorphisms in miRNAs and lncRNAs can perturb the lncRNA/miRNA/mRNA axis and may be involved in osteoporosis clinical outcome. We also provide a general overview on databases and bioinformatic tools useful for associating miRNAs and lncRNAs variability with complex genetic diseases.
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Affiliation(s)
- Simona Fittipaldi
- Department of Biomedicine & Prevention, Medical Genetics Section, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy
| | - Virginia Veronica Visconti
- Department of Biomedicine & Prevention, Medical Genetics Section, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.,Department of Orthopedics & Traumatology, PTV Foundation, 00133 Rome, Italy
| | - Umberto Tarantino
- Department of Orthopedics & Traumatology, PTV Foundation, 00133 Rome, Italy.,Department of Clinical Sciences & Translational Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Medical Genetics Section, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.,IRCCS Neuromed, Pozzilli, IS, Italy
| | - Annalisa Botta
- Department of Biomedicine & Prevention, Medical Genetics Section, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy
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Li R, Ruan Q, Yin F, Zhao K. MiR-23b-3p promotes postmenopausal osteoporosis by targeting MRC2 and regulating the Wnt/β-catenin signaling pathway. J Pharmacol Sci 2020; 145:69-78. [PMID: 33357782 DOI: 10.1016/j.jphs.2020.11.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/26/2020] [Accepted: 11/09/2020] [Indexed: 12/19/2022] Open
Abstract
Postmenopausal osteoporosis (PMOP) is one of the most common metabolic bone diseases in postmenopausal women. Increasing evidence has indicated that microRNAs (miRNAs) play vital regulatory roles during osteoporosis progression. This study aimed to investigate the potential function of miR-23b-3p in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). PMOP was induced in mice by bilateral ovariectomy. X-ray absorptiometry was applied to detect BMD and BMC in PMOP mice. Luciferase reporter assay and RIP assay were utilized to investigate the relationship between miR-23b-3p and MRC2. We found the upregulation of miR-23b-3p in bone tissues of PMOP mice. Silencing of miR-23b-3p relieved PMOP in mice. Moreover, miR-23b-3p knockdown facilitated the osteogenic differentiation of hMSCs by increasing the expression of Runx2, OCN, Osterix and promoting ALP activity. Mechanistically, MRC2 is a downstream target gene of miR-23b-3p. MRC2 knockdown significantly rescued the promoting effect of lenti-miR-23b-3p inhibitor on osteogenic differentiation of hMSCs. Furthermore, miR-23b-3p targeted MRC2 to inhibit the Wnt/β-catenin pathway during the osteogenic differentiation of hMSCs. In summary, inhibition of miR-23b-3p alleviates PMOP by targeting MRC2 to inhibit the Wnt/β-catenin signaling, which may provide a novel molecular insight for osteoporosis therapy.
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Affiliation(s)
- Ran Li
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China
| | - Qing Ruan
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China
| | - Fei Yin
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China
| | - Kunchi Zhao
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, China.
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40
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Saferding V, Hofmann M, Brunner JS, Niederreiter B, Timmen M, Magilnick N, Hayer S, Heller G, Steiner G, Stange R, Boldin M, Schabbauer G, Weigl M, Hackl M, Grillari J, Smolen JS, Blüml S. microRNA-146a controls age-related bone loss. Aging Cell 2020; 19:e13244. [PMID: 33085187 PMCID: PMC7681058 DOI: 10.1111/acel.13244] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/01/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
Bone loss is one of the consequences of aging, leading to diseases such as osteoporosis and increased susceptibility to fragility fractures and therefore considerable morbidity and mortality in humans. Here, we identify microRNA‐146a (miR‐146a) as an essential epigenetic switch controlling bone loss with age. Mice deficient in miR‐146a show regular development of their skeleton. However, while WT mice start to lose bone with age, animals deficient in miR‐146a continue to accrue bone throughout their life span. Increased bone mass is due to increased generation and activity of osteoblasts in miR‐146a‐deficient mice as a result of sustained activation of bone anabolic Wnt signaling during aging. Deregulation of the miR‐146a target genes Wnt1 and Wnt5a parallels bone accrual and osteoblast generation, which is accompanied by reduced development of bone marrow adiposity. Furthermore, miR‐146a‐deficient mice are protected from ovariectomy‐induced bone loss. In humans, the levels of miR‐146a are increased in patients suffering fragility fractures in comparison with those who do not. These data identify miR‐146a as a crucial epigenetic temporal regulator which essentially controls bone homeostasis during aging by regulating bone anabolic Wnt signaling. Therefore, miR‐146a might be a powerful therapeutic target to prevent age‐related bone dysfunctions such as the development of bone marrow adiposity and osteoporosis.
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Affiliation(s)
- Victoria Saferding
- Department of Rheumatology Medical University of Vienna Vienna Austria
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation Vienna Austria
| | - Melanie Hofmann
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation Vienna Austria
- Institute for Vascular Biology Centre for Physiology and Pharmacology Medical University of Vienna Vienna Austria
| | - Julia S. Brunner
- Institute for Vascular Biology Centre for Physiology and Pharmacology Medical University of Vienna Vienna Austria
| | | | - Melanie Timmen
- Department of Regenerative Musculoskeletal Medicine Institute of Musculoskeletal Medicine (IMM) University Hospital Münster Münster Germany
| | - Nathaniel Magilnick
- Department of Molecular and Cellular Biology Beckman Research Institute City of Hope Duarte California USA
| | - Silvia Hayer
- Department of Rheumatology Medical University of Vienna Vienna Austria
| | - Gerwin Heller
- Department of Medicine I Medical University of Vienna Vienna Austria
| | - Günter Steiner
- Department of Rheumatology Medical University of Vienna Vienna Austria
| | - Richard Stange
- Department of Regenerative Musculoskeletal Medicine Institute of Musculoskeletal Medicine (IMM) University Hospital Münster Münster Germany
| | - Mark Boldin
- Department of Molecular and Cellular Biology Beckman Research Institute City of Hope Duarte California USA
| | - Gernot Schabbauer
- Institute for Vascular Biology Centre for Physiology and Pharmacology Medical University of Vienna Vienna Austria
| | - Moritz Weigl
- TAmiRNA GmbH Vienna Austria
- Austrian Cluster for Tissue Regeneration Vienna Austria
| | - Matthias Hackl
- TAmiRNA GmbH Vienna Austria
- Austrian Cluster for Tissue Regeneration Vienna Austria
| | - Johannes Grillari
- Austrian Cluster for Tissue Regeneration Vienna Austria
- Department of Biotechnology Institute for Molecular Biotechnology BOKU – University of Natural Resources and Life Sciences Vienna Austria
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center Vienna Austria
| | - Josef S. Smolen
- Department of Rheumatology Medical University of Vienna Vienna Austria
| | - Stephan Blüml
- Department of Rheumatology Medical University of Vienna Vienna Austria
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Yan Y, Chang C, Su J, Venø MT, Kjems J. Osteoblastogenesis Alters Small RNA Profiles in EVs Derived from Bone Marrow Stem Cells (BMSCs) and Adipose Stem Cells (ASCs). Biomedicines 2020; 8:biomedicines8100387. [PMID: 32998458 PMCID: PMC7599808 DOI: 10.3390/biomedicines8100387] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022] Open
Abstract
Multipotent stem cells (MSCs) are used in various therapeutic applications based on their paracrine secretion activity. Here, we set out to identify and characterize the paracrine factors released during osteoblastogenesis, with a special focus on small non-coding RNAs released in extracellular vesicles (EVs). Bone marrow stem cells (BMSCs) and adipose stem cells (ASCs) from healthy human donors were used as representatives of MSCs. We isolated EVs secreted before and after induction of osteoblastic differentiation and found that the EVs contained a specific subset of microRNAs (miRNAs) and tRNA-derived small RNAs (tsRNA) compared to their parental cells. Osteoblastic differentiation had a larger effect on the small RNA profile of BMSC-EVs relative to ASC-EVs. Our data showed that EVs from different MSC origin exhibited distinct expression profiles of small RNA profiles when undergoing osteoblastogenesis, a factor that should be taken into consideration for stem cell therapy.
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Affiliation(s)
- Yan Yan
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (C.C.); (J.S.); (M.T.V.)
- Omiics ApS, Åbogade 15, 8200 Aarhus N, Denmark
| | - Clare Chang
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (C.C.); (J.S.); (M.T.V.)
| | - Junyi Su
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (C.C.); (J.S.); (M.T.V.)
| | - Morten T. Venø
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (C.C.); (J.S.); (M.T.V.)
- Omiics ApS, Åbogade 15, 8200 Aarhus N, Denmark
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark; (Y.Y.); (C.C.); (J.S.); (M.T.V.)
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark
- Correspondence: ; Tel.: +45-289-920-86
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Ko JH, Oh JY. The Effect of miR-146a on the Gene Expression of Immunoregulatory Cytokines in Human Mesenchymal Stromal Cells. Int J Mol Sci 2020; 21:ijms21186809. [PMID: 32948076 PMCID: PMC7554760 DOI: 10.3390/ijms21186809] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/12/2020] [Accepted: 09/16/2020] [Indexed: 12/02/2022] Open
Abstract
Mounting evidence indicates that microRNAs (miRNAs), including miR-146a, have an impact on the immunomodulatory activities of mesenchymal stem/stromal cells (MSCs). Suppression of inflammatory macrophage activation is one of the main immunomodulatory mechanisms of MSCs. Here, we investigated whether miR-146a in MSCs might play a role in the effects of MSCs on macrophage activation. A miRNA microarray revealed that miR-146a was the most highly upregulated miRNA in MSCs upon co-culture with activated macrophages. Inhibition of miR-146a in MSCs through miR-146a inhibitor transfection had a different effect on the expression of immunoregulatory factors secreted by MSCs. Pentraxin 3, tumor necrosis factor-inducible gene 6, and cyclooxygenase-2, which are well-known mediators of the immunomodulatory functions of MSCs, were significantly upregulated in MSCs after miR-146a knockdown. By contrast, hepatocyte growth factor and stanniocalcin 1, other immunoregulatory molecules expressed by MSCs, were downregulated by miR-146a knockdown. Consequently, the inhibition of miR-146a in MSCs did not change the overall effect of MSCs on the suppression of inflammatory macrophage activation or the induction of anti-inflammatory macrophage polarization.
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Affiliation(s)
- Jung Hwa Ko
- Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea;
| | - Joo Youn Oh
- Department of Ophthalmology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea;
- Department of Ophthalmology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea
- Correspondence: ; Tel.: +82-2-2072-0027; Fax: +82-2-741-3187
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Zhang D, Ni N, Wang Y, Tang Z, Gao H, Ju Y, Sun N, He X, Gu P, Fan X. CircRNA-vgll3 promotes osteogenic differentiation of adipose-derived mesenchymal stem cells via modulating miRNA-dependent integrin α5 expression. Cell Death Differ 2020; 28:283-302. [PMID: 32814879 PMCID: PMC7853044 DOI: 10.1038/s41418-020-0600-6] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/19/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023] Open
Abstract
Adipose-derived mesenchymal stem cells (ADSCs) are promising candidate for regenerative medicine to repair non-healing bone defects due to their high and easy availability. However, the limited osteogenic differentiation potential greatly hinders the clinical application of ADSCs in bone repair. Accumulating evidences demonstrate that circular RNAs (circRNAs) are involved in stem/progenitor cell fate determination, but their specific role in stem/progenitor cell osteogenesis, remains mostly undescribed. Here, we show that circRNA-vgll3 originating from the vgll3 locus markedly enhances osteogenic differentiation of ADSCs; nevertheless, silencing of circRNA-vgll3 dramatically attenuates ADSC osteogenesis. Furthermore, we validate that circRNA-vgll3 functions in ADSC osteogenesis through a circRNA-vgll3/miR-326-5p/integrin α5 (Itga5) pathway. Itga5 promotes ADSC osteogenic differentiation and miR-326-5p suppresses Itga5 translation. CircRNA-vgll3 directly sequesters miR-326-5p in the cytoplasm and inhibits its activity to promote osteogenic differentiation. Moreover, the therapeutic potential of circRNA-vgll3-modified ADSCs with calcium phosphate cement (CPC) scaffolds was systematically evaluated in a critical-sized defect model in rats. Our results demonstrate that circRNA-vgll3 markedly enhances new bone formation with upregulated bone mineral density, bone volume/tissue volume, trabeculae number, and increased new bone generation. This study reveals the important role of circRNA-vgll3 during new bone biogenesis. Thus, circRNA-vgll3 engineered ADSCs may be effective potential therapeutic targets for bone regenerative medicine.
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Affiliation(s)
- Dandan Zhang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Ni Ni
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Yuyao Wang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Zhimin Tang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Huiqin Gao
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Yahan Ju
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Na Sun
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Xiaoyu He
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China
| | - Ping Gu
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China.
| | - Xianqun Fan
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, P.R. China.
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He Y, Lin S, Ao Q, He X. The co-culture of ASCs and EPCs promotes vascularized bone regeneration in critical-sized bone defects of cranial bone in rats. Stem Cell Res Ther 2020; 11:338. [PMID: 32746906 PMCID: PMC7398348 DOI: 10.1186/s13287-020-01858-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 07/07/2020] [Accepted: 07/27/2020] [Indexed: 12/11/2022] Open
Abstract
Background The repair of critical-sized bone defect represents a challenging problem in bone tissue engineering. To address the most important problem in bone defect repair, namely insufficient blood supply, this study aimed to find a method that can promote the formation of vascularized bone tissue. Method The phenotypes of ASCs and EPCs were identified respectively, and ASCs/EPCs were co-cultured in vitro to detect the expression of osteogenic and angiogenic genes. Furthermore, the co-culture system combined with scaffold material was used to repair the critical-sized bone defects of the cranial bone in rats. Results The co-culture of ASCs/EPCs could increase osteogenesis and angiogenesis-related gene expression in vitro. The results of in vivo animal experiments demonstrated that the ASC/EPC group could promote bone regeneration and vascularization in the meantime and then significantly accelerate the repair of critical-sized bone defects. Conclusion It is feasible to replace traditional single seed cells with ASC/EPC co-culture system for vascularized bone regeneration. This system could ultimately enable clinicians to better repair the defect of craniofacial bone and avoid donor site morbidity.
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Affiliation(s)
- Yuanjia He
- Department of Stomatology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shuang Lin
- Department of Plastic Surgery, Shengjing Hospital affiliated to China Medical University, Shenyang, Liaoning, China
| | - Qiang Ao
- Department of Tissue Engineering, School of Fundamental Science, China Medical University, Shenyang, Liaoning, China
| | - Xiaoning He
- Department of Stomatology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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Liu Z, Deng Y, Li T, Zhu F, Zhou X, He Y. The opposite functions of miR-24 in the osteogenesis and adipogenesis of adipose-derived mesenchymal stem cells are mediated by the HOXB7/β-catenin complex. FASEB J 2020; 34:9034-9050. [PMID: 32413244 DOI: 10.1096/fj.202000006rr] [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: 01/05/2020] [Revised: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 12/28/2022]
Abstract
Adipose-derived mesenchymal stem cells (ADMSCs) used in combination with nanoparticles or scaffolds represent promising candidates for bone engineering. Compared to bone marrow-derived MSCs (BMMSCs), ADMSCs show a relatively low capacity for osteogenesis. In the current study, miR-24 was identified as an osteogenesis- and adipogenesis-related miRNA that performs opposing roles (inhibition in osteogenesis and promotion in adipogenesis) during these two differentiation processes. Through bioinformatics analysis and luciferase reporter assays, homeobox protein Hox-B7 (HOXB7) was identified as a potential novel downstream target of miR-24 that contains a miR-24 binding site in the 3'-UTR of its mRNA. Overexpression of HOXB7 could partly halt the inhibitory effect of miR-24 on osteogenesis, and downregulation of HOXB7 could also partly suppress the positive effect of miR-24 on adipogenesis. Furthermore, immunoprecipitation experiments found that HOXB7 and β-catenin formed a functional complex that acted as an essential modulator during osteogenesis and adipogenesis of ADMSCs. After transfecting ADMSCs with an MSNs-PEI-miR-24 agomir or antagomir and loading the cells onto gelatin-chitosan scaffolds, the compounds were assessed for their abilities to repair the critical-sized calvarial defects in rats. Comprehensive evaluation, including micro-CT, sequential fluorescent labeling, and immunohistochemistry analysis, revealed that silencing miR-24 distinctly promoted in vivo bone remolding, whereas overexpression of miR-24 significantly repressed bone formation. Taken together, our findings demonstrated opposite roles for the miR-24/HOXB7/β-catenin signaling pathway in the osteogenesis and adipogenesis of ADMSCs, which may provide a novel mechanism for determining the balance between these two biological processes.
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Affiliation(s)
- Zhonglong Liu
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital Affiliated to, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center of Stomatology, Shanghai, China
| | - Yiwen Deng
- Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, National Clinical Research Center of Stomatology, Shanghai, China
| | - Tao Li
- Department of Orthopedics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fengshuo Zhu
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital Affiliated to, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center of Stomatology, Shanghai, China
| | - Xiaojun Zhou
- Department of Orthopedics, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue He
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital Affiliated to, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center of Stomatology, Shanghai, China
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Tan J, Xu Y, Han F, Ye X. Genetical modification on adipose-derived stem cells facilitates facial nerve regeneration. Aging (Albany NY) 2020; 11:908-920. [PMID: 30728320 PMCID: PMC6382422 DOI: 10.18632/aging.101790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 01/17/2019] [Indexed: 12/20/2022]
Abstract
Adipose-derived stem cells (ASCs) have a demonstrative therapeutic potential in aging-associated facial nerve regeneration, in which ASCs work as a source of Schwann cells therapy as an alternative to autologous nerve grafts. However, the transplantation of ASCs may induce local fibrosis, which causes inferior outcome. Here, we aimed to use genetic modification approaches to reduce the fibrogenic properties of ASCs to improve their therapeutic effects on facial nerve regeneration. Since procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is essential for hydroxylation of lysine residues in collagen telopeptides and for collagen pyridinoline cross-link formation during fibrosis, and since we found that ASCs expressed high levels of PLOD1, we depleted PLOD1 in ASCs by expression of either a short-hair interfering RNA for PLOD1 (shPLOD1) or a microRNA-449 (miR-449), the latter of which targets PLOD1 mRNA to suppress protein translation. Transplantation of either ASCs-shPLOD1 or ASCs-miR-449 or ASCs-control to repair a 6mm-gap in rat facial nerve was compared. Either ASCs-shPLOD1 or ASCs-miR-449 exhibited a better facial nerve function. Mechanistically, ASCs-shPLOD1 or ASCs-miR-449 significantly and similarly reduced the fibrosis in the injured region, likely through suppression of reactive oxygen species (ROS) and activation of myofibroblasts.
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Affiliation(s)
- Jian Tan
- Department of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yipin Xu
- Department of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Fang Han
- Department of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Xinhai Ye
- Department of Plastic Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.,Department of Facial Plastic and Reconstructive Surgery, Eye and ENT Hospital of Fudan University, Shanghai 200031, China
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Wang Y, Jiang W, Xia B, Zhang M, Wang Y. MicroRNA-146a attenuates the development of morphine analgesic tolerance in a rat model. Neurol Res 2020; 42:415-421. [PMID: 32131713 DOI: 10.1080/01616412.2020.1735818] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Ying Wang
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Wei Jiang
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Bin Xia
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Mengyuan Zhang
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Yan Wang
- Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
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Peng Y, Li L, Yuan Q, Gu P, You Z, Zhuang A, Bi X. Effect of Bifunctional β Defensin 2-Modified Scaffold on Bone Defect Reconstruction. ACS OMEGA 2020; 5:4302-4312. [PMID: 32149260 PMCID: PMC7057706 DOI: 10.1021/acsomega.9b04249] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/07/2020] [Indexed: 05/05/2023]
Abstract
Bone tissue engineering has emerged as an effective alternative treatment to the problem of bone defect. To repair a bone defect, antibiosis and osteogenesis are two essential aspects of the repair process. By searching the literature and performing exploratory experiments, we found that β defensin 2 (BD2), with bifunctional properties of antibiosis and osteogenesis, was a feasible alternative for traditional growth factors. The antimicrobial ability of BD2 against Staphylococcus aureus and Escherichia coli was studied by the spread plate and live/dead staining methods (low effective concentration of 20 ng/mL). BD2 was also demonstrated to enhance osteogenesis, with higher messenger RNA (mRNA) and protein expression of the osteogenic markers collagen I (Col1), runt-related transcription factor 2 (Runx2), osteopontin (Opn), and osteocalcin (Ocn) in vitro (1.5-2.5-fold increase compared with the control group in the most effective concentration group), which was consistent with the alkaline phosphatase (ALP) and alizarin red S (ARS) staining results. We implanted poly(sebacoyl diglyceride) (PSeD) combined with BD2 and rat bone tissue-derived mesenchymal stem cells (rBMSCs) under the back skin of rats and found that the inflammatory response was significantly lower with this combination than with the PSeD/rBMSCs scaffold without BD2 and the pure PSeD group and was similar to the control group. Importantly, when assessed in a critical-sized in vivo rat 8 m diameter calvaria defect model, a scaffold we developed combining bifunctional BD2 with porous organic polymer displayed an osteogenic effect that was 160-200% greater than the control group. The in vivo study results revealed a significant osteogenic response and antimicrobial effect and were consistent with the in vitro results. In summary, BD2 displayed a great potential of simultaneously promoting bone regeneration and preventing infection and could provide a viable alternative to traditional growth factors applied in bone defect repair.
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Affiliation(s)
- Yiyu Peng
- Department of Ophthalmology,
Ninth People’s Hospital, Shanghai
Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, P. R. China
| | - Lunhao Li
- Department of Ophthalmology,
Ninth People’s Hospital, Shanghai
Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, P. R. China
| | - Qingyue Yuan
- Department of Ophthalmology,
Ninth People’s Hospital, Shanghai
Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, P. R. China
| | - Ping Gu
- Department of Ophthalmology,
Ninth People’s Hospital, Shanghai
Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, P. R. China
| | - Zhengwei You
- State Key Laboratory for Modification of
Chemical Fibers and Polymer Materials, Shanghai Belt and Road Joint
Laboratory of Advanced Fiber and Low-dimension Materials (Donghua
University), College of Materials Science and Engineering, Donghua University, Shanghai 201620, P. R. China
| | - Ai Zhuang
- Department of Ophthalmology,
Ninth People’s Hospital, Shanghai
Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, P. R. China
- E-mail: . Tel: 18930843344. Fax: +8621-63134218 (A.Z.)
| | - Xiaoping Bi
- Department of Ophthalmology,
Ninth People’s Hospital, Shanghai
Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, P. R. China
- Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, P. R. China
- E-mail: . Tel: +8621-63135606. Fax: +8621-63134218 (X.B.)
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Dong Y, Li Y, Zhang C, Chen H, Liu L, Chen S. Effects of SW033291 on the myogenesis of muscle-derived stem cells and muscle regeneration. Stem Cell Res Ther 2020; 11:76. [PMID: 32085799 PMCID: PMC7035785 DOI: 10.1186/s13287-020-1574-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 01/17/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022] Open
Abstract
Background The unmet medical needs in repairing large muscle defects promote the development of tissue regeneration strategy. The use of bioactive molecules in combination with biomaterial scaffold has become an area of great interest. SW033291, a small-molecule inhibitor targeting 15-hydroxyprostaglandin dehydrogenase (15-PDGH) and subsequently elevating the production of prostaglandin E2 (PGE2), has been proved to accelerate the recovery and potentiate the regeneration of multiple tissues including the bone, liver, and colon. The limited understanding of the potential therapeutic effects on myogenesis motivated us to investigate the role of SW033291 in regulating muscle-derived stem cell (MDSC) myogenic differentiation and MDSC-mediated muscle regeneration. Methods The characteristics of rat MDSCs, including cell-specific markers and myogenic differentiation potential, were determined. MDSCs were incubated with SW033291 to evaluate PGE2 production and cytotoxicity. The effects of SW033291 on MDSC myogenic differentiation were assessed by quantitative real-time polymerase chain reaction (qPCR), western blot, and immunocytochemistry. The fibrin gel containing MDSCs and SW033291 was used for muscle regeneration in a tibialis anterior muscle defect model. Results Our data demonstrated that MDSCs were well-tolerated to SW033291 and treatment with SW033291 significantly promoted the production of PGE2 by MDSCs. In vitro analysis showed that SW033291 enhanced the myogenic differentiation and myotube formation by upregulating a series of myogenic markers. Additionally, the activation of PI3K/Akt pathway was involved in the mechanism underlying these promotive effects. Then, in situ casting of fibrin gel containing MDSCs and SW033291 was used to repair the tibialis anterior muscle defect; the addition of SW033291 significantly promoted myofiber formation within the defect region with mild immune response, less fibrosis, and sufficient vascularization. Conclusion SW033291 acted as a positive regulator of MDSC myogenic differentiation, and incorporating the compound with MDSCs in fibrin gel could serve as an effective method to repair large skeletal muscle defects.
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Affiliation(s)
- Yuanqiang Dong
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Yuan Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Chuan Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Haibin Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China
| | - Lijia Liu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.
| | - Simeng Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, People's Republic of China.
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Feng Y, Ge Y, Wu M, Xie Y, Wang M, Chen Y, Shi X. Long Non‑Coding RNAs Regulate Inflammation in Diabetic Peripheral Neuropathy by Acting as ceRNAs Targeting miR-146a-5p. Diabetes Metab Syndr Obes 2020; 13:413-422. [PMID: 32110074 PMCID: PMC7035891 DOI: 10.2147/dmso.s242789] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 02/10/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs), as competing endogenous RNAs (ceRNAs), can regulate various pathophysiological processes by binding competitively to microRNAs at the post-transcription level. Our previous work demonstrated that miR-146a-5p was lowly expressed in diabetic peripheral neuropathy (DPN) rats. However, the ceRNA network in DPN mediated by lncRNAs and miR-146a-5p remains to be explored. METHODS Two groups of rats (n=4 per group), a type 2 diabetes (T2DM) group and a DPN group, were used in this study. Sciatic nerve conduction velocity (NCV) of each rat was determined at the 6th and the 12th week. LncRNA microarray analysis was performed in the sciatic nerve of DPN and T2DM rats. Based on the TargetScan algorithm and the miRanda database, we determined the differentially expressed (DE) lncRNAs bound to miR-146a-5p. Furthermore, we verified the DE lncRNAs potentially bound to miR-146a-5p by qRT-PCR. The genes targeted by miR-146a-5p were identified by bioinformatics prediction and experimental techniques. RESULTS We found 413 DE lncRNAs between DPN and T2DM rats (|log2FC| ≥ 2 and adjust P ≤ 0.05). Eight DE lncRNAs were predicted to bind to miR-146a-5p by both algorithms, of which four were verified by qRT-PCR. TRAF6, IRAK1, and SMAD4 were identified as miR-146a-5p targeted genes and were predominantly enriched in the inflammatory signaling pathway. CONCLUSION LncRNAs may contribute to the pathogenesis of DPN by regulating inflammation through functioning as ceRNAs of miR-146a-5p.
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Affiliation(s)
- Yonghao Feng
- Department of Endocrinology, Jinshan Hospital, Fudan University, Shanghai201508, People’s Republic of China
| | - Ying Ge
- Department of General Medicine, Community Health Service Center of Shanghai Jinshan Industrial Zone, Shanghai201506, People’s Republic of China
| | - Men Wu
- Department of Endocrinology, Jinshan Hospital, Fudan University, Shanghai201508, People’s Republic of China
| | - Yangmei Xie
- Department of Neurology, Jinshan Hospital, Fudan University, Shanghai201508, People’s Republic of China
| | - Ming Wang
- Department of Neurology, Jinshan Hospital, Fudan University, Shanghai201508, People’s Republic of China
| | - Yinghui Chen
- Department of Neurology, Jinshan Hospital, Fudan University, Shanghai201508, People’s Republic of China
| | - Xiaohong Shi
- Department of Endocrinology, Jinshan Hospital, Fudan University, Shanghai201508, People’s Republic of China
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