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Mante N, Undale V, Sanap A, Bhonde R, Tambe P, Bansode M, Gupta RK. Disease microenvironment preconditioning: An evolving approach to improve therapeutic efficacy of human mesenchymal stromal cells. Int Immunopharmacol 2025; 157:114701. [PMID: 40300358 DOI: 10.1016/j.intimp.2025.114701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 04/10/2025] [Accepted: 04/18/2025] [Indexed: 05/01/2025]
Abstract
Despite the tremendous success in preclinical models, the translation of human mesenchymal stromal cells (hMSCs) as a therapy in the clinic is not up to the expectation. Intrinsic factors (age, sex, health status, life style of the donor, source, cellular senescence, and oxidative stress in hMSCs), extrinsic factors (culture system, batch-to-batch variations, choice of biomaterials, cell processing and preservation protocols), and host microenvironment (inflammatory milieu, oxidative stress, and hypoxia in the recipient) compromise the overall therapeutic efficacy of the transplanted hMSCs. In recent times, the approach of 'Disease Microenvironment Preconditioning (DMP)' has garnered attention to overcome the host-associated attributes involved in compromised hMSCs therapeutic potential. In this review, we discuss various approaches of DMP of hMSCs by employing serum and other body fluids obtained from diseased patients/animals and small molecules, including cytokines such as IFN-γ, IL-6, IL-10, IL- β, TGF-β1, IL-1α, IL-1β, TNF-α, HMGB1, IL-17 A, and IL-8 which are associated with disease conditions. DMP strengthens hMSCs ability to adapt/acclimatize and respond more efficiently to the hostile microenvironment they encounter upon transplantation. DMP modulate hMSCs to withstand inflammation, survive under hypoxic and nutrient-deprived conditions, and resist oxidative stress. Evidence from various disease models ranging from cardiovascular and neurodegenerative disorders to autoimmune diseases and tissue injuries supports the role of DMP in improving hMSC survival, integration, and functional efficacy. While the potential of DMP to revolutionize MSC-based therapies is evident, challenges such as standardizing/optimizing protocols for preconditioning is essential. This review synthesizes current advancements in the approach of DMP aiming to propel the area of regenerative medicine.
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Affiliation(s)
- Nishant Mante
- Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, India; Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune 411018, India; Department of Pharmacology, School of Pharmacy and Research, Dr. D. Y. Patil Dnyan Prasad University, Pimpri, Pune 411018, India
| | - Vaishali Undale
- Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, India; Department of Pharmacology, School of Pharmacy and Research, Dr. D. Y. Patil Dnyan Prasad University, Pimpri, Pune 411018, India.
| | - Avinash Sanap
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune 411018, India.
| | - Ramesh Bhonde
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune 411018, India
| | - Pratima Tambe
- Department of Pharmacology, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, India; Department of Pharmacology, School of Pharmacy and Research, Dr. D. Y. Patil Dnyan Prasad University, Pimpri, Pune 411018, India
| | - Manoj Bansode
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
| | - Rajesh Kumar Gupta
- Protein Biochemistry Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, Maharashtra, India
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Niazi V, Ghafouri-Fard S. Effect of hypoxia on extracellular vesicles in malignant and non-malignant conditions. Cancer Treat Res Commun 2025; 43:100924. [PMID: 40209539 DOI: 10.1016/j.ctarc.2025.100924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 03/21/2025] [Accepted: 04/04/2025] [Indexed: 04/12/2025]
Abstract
Extracellular vesicles (EVs) are produced by virtually all types of cells and can be detected in nearly all extracellular places. These particles mediate intercellular communication and transfer their cargo to the recipient cells, inducing a variety of processes in these cells through transmission of several biomolecules such as miRNAs, lncRNAs, other transcripts and a variety of proteins. It has been documented that size, quantity, and expression of biomolecules in the EVs are influenced by the level of oxygen. In fact, hypoxia can affect several cellular processes through modulation of the cargo of these vesicles. Hypoxic exosomes derived from tumor cells have several protumoral effects on the recipient cells, including enhancement of proliferation, migration, and invasion in other tumoral cells, induction of metastasis in distant organs, stimulation of angiogenesis in the endothelial cells, and modulation of macrophage polarization. Hypoxic EVs also contribute to several non-malignant diseases. This review summarizes the effect of hypoxia on EVs cargo in malignant and nonmalignant diseases of different organs.
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Affiliation(s)
- Vahid Niazi
- Stem Cell Research Center, Golestan University of Medical Science, Gorgan, Iran; School of Advanced Technologies in Medicine, Golestan University of Medical Science, Gorgan, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Hoseini SM, Montazeri F. Cell origin and microenvironment: The players of differentiation capacity in human mesenchymal stem cells. Tissue Cell 2025; 93:102709. [PMID: 39765135 DOI: 10.1016/j.tice.2024.102709] [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: 10/30/2024] [Revised: 12/12/2024] [Accepted: 12/26/2024] [Indexed: 03/05/2025]
Abstract
Mesenchymal stem cells (MSCs) have several important properties that make them desirable for regenerative medicine. These properties include immunomodulatory ability, growth factor production, and differentiation into various cell types. Despite extensive research and promising results in clinical trials, our understanding of MSC biology, their mechanism of action, and their targeted and routine use in clinics is limited. Differentiation of human MSCs (hMSCs) is a complex process influenced by various elements such as growth factors, pharmaceutical compounds, microRNAs, 3D scaffolds, and mechanical and electrical stimulation. Research has shown that different culture conditions can affect the differentiation potential of hMSCs obtained from multiple fetal and adult sources. Additionally, it seems that what affects the differentiation capacities of these cells is their secretory characteristics, which are influenced by the origin of the cells and the local microenvironment where the cells are located. The review can provide insights into the microenvironment-based mechanisms involved in MSC differentiation, which can be valuable for future therapeutic applications.
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Affiliation(s)
- Seyed Mehdi Hoseini
- Biotechnology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran; Hematology and Oncology Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Montazeri
- Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran.
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Su W, Liao C, Liu X. Angiogenic and neurogenic potential of dental-derived stem cells for functional pulp regeneration: A narrative review. Int Endod J 2025; 58:391-410. [PMID: 39660369 DOI: 10.1111/iej.14180] [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: 04/29/2024] [Revised: 10/26/2024] [Accepted: 11/22/2024] [Indexed: 12/12/2024]
Abstract
BACKGROUND Dental pulp tissue engineering is expected to become an ideal treatment for irreversible pulpitis and apical periodontitis. However, angiogenesis and neurogenesis for functional pulp regeneration have not yet met the standard for large-scale clinical application, and need further research. OBJECTIVE This review focused on the potential mechanisms of angiogenesis and neurogenesis in pulp regeneration, including stem cell types, upstream and downstream regulatory molecules and cascade signalling pathways, thereby providing a theoretical basis and inspiring new ideas to improve the effectiveness of dental pulp tissue engineering. METHODS An electronic literature search was carried out using the keywords of 'pulp regeneration', 'stem cell transplantation', 'dental pulp stem cells', 'angiogenesis' and 'neurogenesis'. The resulting literature was screened and reviewed. RESULTS Stem cells used in dental pulp tissue engineering can be classified as dental-derived and non-dental-derived stem cells, amongst which dental pulp stem cells (DPSC) have achieved promising results in animal experiments and clinical trials. Multiple molecules and signalling pathways are involved in the process of DPSC-mediated angiogenic and neurogenetic regeneration. In order to promote angiogenesis and neurogenesis in pulp regeneration, feasible measures include the addition of growth factors, the modulation of transcription factors and signalling pathways, the use of extracellular vesicles and the modification of bioscaffold materials. CONCLUSION Dental pulp tissue engineering has had breakthroughs in preclinical and clinical studies in vivo. Overcoming difficulties in pulpal angiogenesis and neurogenesis, and achieving functional pulp regeneration will lead to a significant impact in endodontics.
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Affiliation(s)
- Wanting Su
- School of Stomatology, Jinan University, Guangzhou, China
| | - Chufang Liao
- School of Stomatology, Jinan University, Guangzhou, China
- Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou, China
- Hospital of stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiangning Liu
- School of Stomatology, Jinan University, Guangzhou, China
- Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou, China
- Hospital of stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
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Kavakebian F, Rezapour A, Seyedebrahimi R, Eslami Farsani M, Jabbari Fakhr M, Zare Jalise S, Ababzadeh S. Intrinsic and extrinsic modulators of human dental pulp stem cells: advancing strategies for tissue engineering applications. Mol Biol Rep 2025; 52:190. [PMID: 39899148 DOI: 10.1007/s11033-025-10281-0] [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: 09/26/2024] [Accepted: 01/21/2025] [Indexed: 02/04/2025]
Abstract
This review focuses on dental pulp stem cells (DPSCs) which are mesenchymal stem cells (MSCs) and originating from the neural crest. These cells possess a high capacity for self-renewal and multilineage differentiation. Because of these traits, they represent promising sources for tissue engineering, regenerative medicine, and clinical applications. The objective of this study was to assess the extrinsic and intrinsic factors influencing DPSC characteristics and their potential in tissue engineering. This review discusses the external and internal factors affecting DPSC properties, including proliferation, migration, differentiation, and gene expression post extraction. Additionally, it explores the impact of the microenvironment-its composition and physical properties-and genetic and epigenetic regulation on DPSC behavior. Variations in the microenvironment and genetic regulation play pivotal roles in modulating DPSC functions, including their proliferation and differentiation potential. Intrinsic and extrinsic factors are key barriers to realizing the full therapeutic potential of DPSCs. A deeper understanding of the extrinsic and intrinsic factors affecting DPSC behavior is critical for optimizing their use in regenerative medicine, particularly for dental and craniofacial applications. Although DPSCs hold significant promise, challenges remain, and this review provides insights into the current limitations and future directions for DPSC-based therapies. Researchers and clinicians are offered a comprehensive resource for advancing the field.
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Affiliation(s)
- Fatemeh Kavakebian
- Tissue Engineering and Applied Cell Sciences Department, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Alireza Rezapour
- Tissue Engineering and Applied Cell Sciences Department, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Reihaneh Seyedebrahimi
- Anatomy Department, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Mohsen Eslami Farsani
- Anatomy Department, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Massoumeh Jabbari Fakhr
- Tissue Engineering and Applied Cell Sciences Department, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Saeedeh Zare Jalise
- Tissue Engineering and Applied Cell Sciences Department, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Shima Ababzadeh
- Tissue Engineering and Applied Cell Sciences Department, School of Medicine, Qom University of Medical Sciences, Qom, Iran.
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
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Liu Y, Ren L, Li M, Zheng B, Liu Y. The Effects of Hypoxia-Preconditioned Dental Stem Cell-Derived Secretome on Tissue Regeneration. TISSUE ENGINEERING. PART B, REVIEWS 2025; 31:44-60. [PMID: 38613806 DOI: 10.1089/ten.teb.2024.0054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/15/2024]
Abstract
Mesenchymal stroma cells derived from oral tissues are known as dental stem cells (DSCs). Owing to their unique therapeutic niche and clinical accessibility, DSCs serve as a promising treatment option for bone defects and oral tissue regeneration. DSCs exist in a hypoxic microenvironment in vivo, which is far lower than the current 20% oxygen concentration used in in vitro culture. It has been widely reported that the application of an oxygen concentration less than 5% in the culture of DSCs is beneficial for preserving stemness and promoting proliferation, migration, and paracrine activity. The paracrine function of DSCs involves the secretome, which includes conditioned media (CM) and soluble bioactive molecules, as well as extracellular vesicles extracted from CM. Hypoxia can play a role in immunomodulation and angiogenesis by altering the protein or nucleic acid components in the secretory group, which enhances the therapeutic potential of DSCs. This review summarizes the biological characteristics of DSCs, the influence of hypoxia on DSCs, the impact of hypoxia on the secretory group of DSCs, and the latest progress on the use of DSCs secretory group in tissue regeneration based on hypoxia pretreatment. We highlighted the multifunctional biological effect of hypoxia culture on tissue regeneration and provided a summary of the current mechanism of hypoxia in the pretreatment of DSCs.
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Affiliation(s)
- Yi Liu
- Department of Orthodontics, School and Hospital of Stomatology, Shenyang Clinical Medical Research Center of Orthodontic Disease, China Medical University, Shenyang, China
| | - Ling Ren
- Department of Orthodontics, School and Hospital of Stomatology, Shenyang Clinical Medical Research Center of Orthodontic Disease, China Medical University, Shenyang, China
| | - Mengyao Li
- Department of Orthodontics, School and Hospital of Stomatology, Shenyang Clinical Medical Research Center of Orthodontic Disease, China Medical University, Shenyang, China
| | - Bowen Zheng
- Department of Orthodontics, School and Hospital of Stomatology, Shenyang Clinical Medical Research Center of Orthodontic Disease, China Medical University, Shenyang, China
| | - Yi Liu
- Department of Orthodontics, School and Hospital of Stomatology, Shenyang Clinical Medical Research Center of Orthodontic Disease, China Medical University, Shenyang, China
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Dunbar H, Hawthorne IJ, Tunstead C, Dunlop M, Volkova E, Weiss DJ, dos Santos CC, Armstrong ME, Donnelly SC, English K. The VEGF-Mediated Cytoprotective Ability of MIF-Licensed Mesenchymal Stromal Cells in House Dust Mite-Induced Epithelial Damage. Eur J Immunol 2025; 55:e202451205. [PMID: 39502000 PMCID: PMC11739667 DOI: 10.1002/eji.202451205] [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: 04/18/2024] [Revised: 10/16/2024] [Accepted: 10/23/2024] [Indexed: 01/06/2025]
Abstract
Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)-licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)-driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow-derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT7 bone marrow-derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT7-MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or the use of mitomycin C abrogated this effect. Furthermore, CATT7-MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF-dependent, as the use of anti-human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF-licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium.
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Affiliation(s)
- Hazel Dunbar
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Ian J. Hawthorne
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Courteney Tunstead
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Molly Dunlop
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Evelina Volkova
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
| | - Daniel J. Weiss
- Department of Medicine, 226 Health Sciences Research Facility, Larner College of MedicineUniversity of VermontBurlingtonVermontUSA
| | - Claudia C. dos Santos
- The Keenan Research Centre for Biomedical Science of St. Michael's HospitalTorontoOntarioCanada
- Institute of Medical Sciences and Interdepartmental Division of Critical CareFaculty of MedicineUniversity of TorontoTorontoOntarioCanada
| | | | - Seamas C. Donnelly
- Department of MedicineTrinity College Dublin and Tallaght HospitalDublinIreland
| | - Karen English
- Kathleen Lonsdale Institute for Human Health ResearchMaynooth UniversityMaynooth, Co. KildareIreland
- Department of BiologyMaynooth UniversityMaynooth, Co. KildareIreland
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Chatzopoulou E, Bousaidi N, Guilbert T, Rucher G, Rose J, Germain S, Rouzet F, Chaussain C, Muller L, Gorin C. Multiscale Imaging to Monitor Functional SHED-Supported Engineered Vessels. J Dent Res 2024; 103:1392-1402. [PMID: 39290146 DOI: 10.1177/00220345241271122] [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: 09/19/2024] Open
Abstract
Regeneration of orofacial tissues is hampered by the lack of adequate vascular supply. Implantation of in vitro engineered, prevascularized constructs has emerged as a strategy to allow the rapid vascularization of the entire graft. Given the angiogenic properties of dental pulp stem cells, we hereby established a preclinical model of prevascularized constructs loaded with stem cells from human exfoliating deciduous teeth (SHED) in a 3-dimensional-printed material and provided a functional analysis of their in vivo angiogenesis, vascular perfusion, and permeability. Three different cell-loaded collagen hydrogels (SHED-human umbilical vein endothelial cell [HUVEC], HUVEC with SHED-conditioned medium, and SHED alone) were cast in polylactic acid (PLA) grids and ectopically implanted in athymic mice. At day 10, in vivo positron emission tomography (PETscan) revealed a significantly increased uptake of radiotracer targeting activated endothelial cells in the SHED-HUVEC group compared to the other groups. At day 30, ex vivo micro-computed tomography imaging confirmed that SHED-HUVEC constructs had a significantly increased vascular volume compared to the other ones. Injection of species-specific lectins analyzed by 2-photon microscopy demonstrated blood perfusion of the engineered human vessels in both prevascularized groups. However, in vivo quantification showed increased vessel density in the SHED-HUVEC group. In addition, coinjection of fluorescent lectin and dextran revealed that prevascularization with SHED prevented vascular leakage, demonstrating the active role of SHED in the maturation of human-engineered microvascular networks. This preclinical study introduces a novel PLA prevascularized and implantable construct, along with an array of imaging techniques, to validate the ability of SHED to promote functional human-engineered vessels, further highlighting the interest of SHED for orofacial tissue engineering. Furthermore, this study validates the use of PETscan for the early detection of in vivo angiogenesis, which may be applied in the clinic to monitor the performance of prevascularized grafts.
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Affiliation(s)
- E Chatzopoulou
- Université Paris Cité, URP2496 Pathologies, Imagerie et Biothérapies Orofaciales et Plateforme Imagerie du Vivant, Montrouge, France
- AP-HP, Services de médecine bucco-dentaire, FHU DDS-Net, GH Paris Nord et Paris Est, France
| | - N Bousaidi
- Université Paris Cité, URP2496 Pathologies, Imagerie et Biothérapies Orofaciales et Plateforme Imagerie du Vivant, Montrouge, France
| | - T Guilbert
- Université Paris Cité, CNRS, INSERM U1016, Institut Cochin, Paris, France
| | - G Rucher
- Université Paris Cité, LVTS, INSERM U1148, France
- Université Paris Cité, UMS 34-FRIM, France
| | - J Rose
- AP-HP, Département de médecine nucléaire, Hôpital Bichat, Paris, France
| | - S Germain
- Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Université PSL, Paris, France
| | - F Rouzet
- Université Paris Cité, LVTS, INSERM U1148, France
- AP-HP, Département de médecine nucléaire, Hôpital Bichat, Paris, France
| | - C Chaussain
- Université Paris Cité, URP2496 Pathologies, Imagerie et Biothérapies Orofaciales et Plateforme Imagerie du Vivant, Montrouge, France
- AP-HP, Services de médecine bucco-dentaire, FHU DDS-Net, GH Paris Nord et Paris Est, France
| | - L Muller
- Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Université PSL, Paris, France
| | - C Gorin
- Université Paris Cité, URP2496 Pathologies, Imagerie et Biothérapies Orofaciales et Plateforme Imagerie du Vivant, Montrouge, France
- AP-HP, Services de médecine bucco-dentaire, FHU DDS-Net, GH Paris Nord et Paris Est, France
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9
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Xing Y, Kang L, Chen L, Li Y, Lu D. Research progress of exosomes in pathogenesis and treatment of preeclampsia. J Obstet Gynaecol Res 2024; 50:2183-2194. [PMID: 39434205 DOI: 10.1111/jog.16106] [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: 07/02/2024] [Accepted: 09/16/2024] [Indexed: 10/23/2024]
Abstract
AIM Preeclampsia (PE) is a critical and severe disease in obstetrics, which seriously affects maternal and neonatal life safety and long-term prognosis. However, the etiology and pathogenesis of PE are complex, and no unified conclusion has been reached. The types and number of exosomes and their transport substances in PE patients changed. The study of exosomes in PE patients helps clarify the etiology, diagnosis, effective treatment, accurate monitoring, and prognosis. METHOD The published articles were reviewed. RESULTS Exosomes may affect endothelial and vascular production and function, participate in maternal-fetal immune regulation, and transport substances such as miRNAs, lncRNAs, and proteins involved in the development of PE. Detection of the contents of exosomes can help in the early diagnosis of PE, and can help to improve PE by inhibiting the action of exosomes or preventing their binding to target organs. CONCLUSION Exosomes may be involved in the development of PE, and exosomes can be used as markers for predicting the onset of PE and tracking the disease process and determining the prognosis, and exosomes have great potential in the treatment of PE.
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Affiliation(s)
- Yue Xing
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Luyao Kang
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Lu Chen
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Youyou Li
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
| | - Dan Lu
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China
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10
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Zhang J. Non-coding RNAs and angiogenesis in cardiovascular diseases: a comprehensive review. Mol Cell Biochem 2024; 479:2921-2953. [PMID: 38306012 DOI: 10.1007/s11010-023-04919-5] [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: 10/27/2023] [Accepted: 12/18/2023] [Indexed: 02/03/2024]
Abstract
Non-coding RNAs (ncRNAs) have key roles in the etiology of many illnesses, including heart failure, myocardial infarction, stroke, and in physiological processes like angiogenesis. In transcriptional regulatory circuits that control heart growth, signaling, and stress response, as well as remodeling in cardiac disease, ncRNAs have become important players. Studies on ncRNAs and cardiovascular disease have made great progress recently. Here, we go through the functions of non-coding RNAs (ncRNAs) like circular RNAs (circRNAs), and microRNAs (miRNAs) as well as long non-coding RNAs (lncRNAs) in modulating cardiovascular disorders.
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Affiliation(s)
- Jie Zhang
- Medical School, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
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11
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García-Guerrero CA, Fuentes P, Araya MJ, Djouad F, Luz-Crawford P, Vega-Letter AM, Altamirano C. How to enhance MSCs therapeutic properties? An insight on potentiation methods. Stem Cell Res Ther 2024; 15:331. [PMID: 39334487 PMCID: PMC11438163 DOI: 10.1186/s13287-024-03935-6] [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: 08/06/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) have emerged as a promising tool in the field of regenerative medicine due to their unique therapeutic properties as they can differentiate into multiple cell types and exert paracrine effects. However, despite encouraging results obtained in preclinical studies, clinical trials have not achieved the same levels of efficacy. To improve the therapeutic properties of MSCs, several strategies have been explored. Therefore, in this review, the therapeutic properties of MSCs will be analyzed, and an update and overview of the most prominent approaches used to enhance their therapeutic capabilities will be provided. These approaches include using drugs, molecules, strategies based on biomaterials, and modification parameters in culture. The strategy described shows several common factors among those affected by these strategies that lead to an enhancement of the MSCs therapeutic properties such as the activation of the PI3K/AKT pathway and the increased expression of Heat Shock Proteins and Hypoxia-Inducible Factor. The combined effect of these elements shift MSCs towards a glycolytic state, suggesting this shift is essential for their enhancement.
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Affiliation(s)
- Cynthia Aylín García-Guerrero
- Doctorado en Biomedicina, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Paloma Fuentes
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - María Jesús Araya
- Doctorado en Biomedicina, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de La Santé Et de La Recherche Médicale, Montpellier, France
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile.
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
| | - Ana María Vega-Letter
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
| | - Claudia Altamirano
- IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile.
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
- Centro Regional de Estudios en Alimentos Saludables, Av. Universidad 330, Curauma-Placilla, Valparaíso, Chile.
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12
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Lim JJ, Vining KH, Mooney DJ, Blencowe BJ. Matrix stiffness-dependent regulation of immunomodulatory genes in human MSCs is associated with the lncRNA CYTOR. Proc Natl Acad Sci U S A 2024; 121:e2404146121. [PMID: 39074278 PMCID: PMC11317610 DOI: 10.1073/pnas.2404146121] [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: 02/29/2024] [Accepted: 06/17/2024] [Indexed: 07/31/2024] Open
Abstract
Cell-matrix interactions in 3D environments significantly differ from those in 2D cultures. As such, mechanisms of mechanotransduction in 2D cultures are not necessarily applicable to cell-encapsulating hydrogels that resemble features of tissue architecture. Accordingly, the characterization of molecular pathways in 3D matrices is expected to uncover insights into how cells respond to their mechanical environment in physiological contexts, and potentially also inform hydrogel-based strategies in cell therapies. In this study, a bone marrow-mimetic hydrogel was employed to systematically investigate the stiffness-responsive transcriptome of mesenchymal stromal cells. High matrix rigidity impeded integrin-collagen adhesion, resulting in changes in cell morphology characterized by a contractile network of actin proximal to the cell membrane. This resulted in a suppression of extracellular matrix-regulatory genes involved in the remodeling of collagen fibrils, as well as the upregulation of secreted immunomodulatory factors. Moreover, an investigation of long noncoding RNAs revealed that the cytoskeleton regulator RNA (CYTOR) contributes to these 3D stiffness-driven changes in gene expression. Knockdown of CYTOR using antisense oligonucleotides enhanced the expression of numerous mechanoresponsive cytokines and chemokines to levels exceeding those achievable by modulating matrix stiffness alone. Taken together, our findings further our understanding of mechanisms of mechanotransduction that are distinct from canonical mechanotransductive pathways observed in 2D cultures.
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Affiliation(s)
- Justin J. Lim
- Donnelly Centre, University of Toronto, Toronto, ONM5S3E1, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S1A8, Canada
| | - Kyle H. Vining
- Department of Preventative and Restorative Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA19104
- Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA19104
| | - David J. Mooney
- Department of Bioengineering, John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA02138
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA02138
| | - Benjamin J. Blencowe
- Donnelly Centre, University of Toronto, Toronto, ONM5S3E1, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S1A8, Canada
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13
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Zhang H, Li L, Sun X, Hou B, Luo C. Research and development of microenvironment's influence on stem cells from the apical papilla - construction of novel research microdevices: tooth-on-a-chip. Biomed Microdevices 2024; 26:33. [PMID: 39023652 DOI: 10.1007/s10544-024-00715-0] [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] [Accepted: 06/29/2024] [Indexed: 07/20/2024]
Abstract
Stem cells are crucial in tissue engineering, and their microenvironment greatly influences their behavior. Among the various dental stem cell types, stem cells from the apical papilla (SCAPs) have shown great potential for regenerating the pulp-dentin complex. Microenvironmental cues that affect SCAPs include physical and biochemical factors. To research optimal pulp-dentin complex regeneration, researchers have developed several models of controlled biomimetic microenvironments, ranging from in vivo animal models to in vitro models, including two-dimensional cultures and three-dimensional devices. Among these models, the most powerful tool is a microfluidic microdevice, a tooth-on-a-chip with high spatial resolution of microstructures and precise microenvironment control. In this review, we start with the SCAP microenvironment in the regeneration of pulp-dentin complexes and discuss research models and studies related to the biological process.
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Affiliation(s)
- Hexuan Zhang
- Center for Microscope Enhanced Dentistry, School of Stomatology, Capital Medical University, Beijing, China
- Department of Endodontics and Operative Dentistry, School of Stomatology, Capital Medical University, Beijing, China
| | - Lingjun Li
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Xiaoqiang Sun
- Department of Endodontics and Operative Dentistry, School of Stomatology, Capital Medical University, Beijing, China.
| | - Benxiang Hou
- Center for Microscope Enhanced Dentistry, School of Stomatology, Capital Medical University, Beijing, China.
| | - Chunxiong Luo
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
- The State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing, China.
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14
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Hezam K, Fu E, Zhang J, Li Z. Therapeutic trends of priming mesenchymal stem cells: A bibliometric analysis. Biochem Biophys Rep 2024; 38:101708. [PMID: 38623536 PMCID: PMC11016583 DOI: 10.1016/j.bbrep.2024.101708] [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: 01/23/2024] [Revised: 03/22/2024] [Accepted: 04/05/2024] [Indexed: 04/17/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have gained substantial attention in regenerative medicine due to their multilineage differentiation potential and immunomodulatory capabilities. MSCs have demonstrated therapeutic promise in numerous preclinical and clinical studies across a variety of diseases, including neurodegenerative disorders, cardiovascular diseases, and autoimmune conditions. Recently, priming MSCs has emerged as a novel strategy to enhance their therapeutic efficacy by preconditioning them for optimal survival and function in challenging in vivo environments. This study presented a comprehensive bibliometric analysis of research activity in the field of priming mesenchymal stem cells (MSCs) from 2003 to 2023. Utilizing a dataset of 585 documents, we explored research trends, leading authors and countries, productive journals, and frequently used keywords. We also explored priming strategies to augment the therapeutic efficacy of MSCs. Our findings show increasing research productivity with a peak in 2019, identified the United States as the leading contributor, and highlighted WANG JA as the most prolific author. The most published journal was Stem Cell Research & Therapy. Keyword analysis revealed core research areas emerging hotspots, while coword and cited sources visualizations elucidated the conceptual framework and key information sources. Further studies are crucial to advance the translation of primed MSCs from bench to bedside, potentially revolutionizing the landscape of regenerative medicine.
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Affiliation(s)
- Kamal Hezam
- Nankai University School of Medicine, Tianjin, 300071, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, Tianjin, 300052, China
| | - Enze Fu
- Nankai University School of Medicine, Tianjin, 300071, China
| | - Jun Zhang
- Department of Anesthesiology and Pain Medical Center, Tianjin Union Medical Center, Nankai University, Tianjin, 300121, China
| | - Zongjin Li
- Nankai University School of Medicine, Tianjin, 300071, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, Tianjin, 300052, China
- National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, 100853, China
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15
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Shekatkar M, Kheur S, Deshpande S, Sanap A, Kharat A, Navalakha S, Gupta A, Kheur M, Bhonde R, Merchant YP. Angiogenic Potential of Various Oral Cavity-Derived Mesenchymal Stem Cells and Cell-Derived Secretome: A Systematic Review and Meta-Analysis. Eur J Dent 2024; 18:712-742. [PMID: 37995732 PMCID: PMC11290931 DOI: 10.1055/s-0043-1776315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2023] Open
Abstract
Recent evidence suggests the immense potential of human mesenchymal stem cell (hMSC) secretome conditioned medium-mediated augmentation of angiogenesis. However, angiogenesis potential varies from source and origin. The hMSCs derived from the oral cavity share an exceptional quality due to their origin from a hypoxic environment. Our systematic review aimed to compare the mesenchymal stem cells (MSCs) derived from various oral cavity sources and cell-derived secretomes, and evaluate their angiogenic potential. A literature search was conducted using PubMed and Scopus from January 2000 to September 2020. Source-wise outcomes were systematically analyzed using in vitro, in vivo, and in ovo studies, emphasizing endothelial cell migration, tube formation, and blood vessel formation. Ninety-four studies were included in the systematic review, out of which 4 studies were subsequently included in the meta-analysis. Prominent growth factors and other bioactive components implicated in improving angiogenesis were included in the respective studies. The findings suggest that oral tissues are a rich source of hMSCs. The meta-analysis revealed a positive correlation between dental pulp-derived MSCs (DPMSCs) and stem cells derived from apical papilla (SCAP) compared to human umbilical cord-derived endothelial cell lines as a control. It shows a statistically significant positive correlation between the co-culture of human umbilical vein endothelial cells (HUVECs) and DPMSCs with tubule length formation and total branching points. Our meta-analysis revealed that oral-derived MSCs (dental pulp stem cells and SCAP) carry a better angiogenic potential in vitro than endothelial cell lines alone. The reviewed literature illustrates that oral cavity-derived MSCs (OC-MSCs) increased angiogenesis. The present literature reveals a dearth of investigations involving sources other than dental pulp. Even though OC-MSCs have revealed more significant potential than other MSCs, more comprehensive, target-oriented interinstitutional prospective studies are warranted to determine whether oral cavity-derived stem cells are the most excellent sources of significant angiogenic potential.
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Affiliation(s)
- Madhura Shekatkar
- Department of Oral Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, India
| | - Supriya Kheur
- Department of Oral Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, India
| | - Shantanu Deshpande
- Department of Pediatric and Preventive Dentistry, Bharati Vidyapeeth (Deemed to be) University Dental College and Hospital, Navi Mumbai, India
| | - Avinash Sanap
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, India
| | - Avinash Kharat
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, India
| | - Shivani Navalakha
- Regenerative Medicine Laboratory, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, India
| | - Archana Gupta
- Department of Oral Pathology and Microbiology, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, India
| | - Mohit Kheur
- Department of Prosthodontics, M.A. Rangoonwala College of Dental Sciences and Research Centre, Pune, India
| | | | - Yash P. Merchant
- Department of Oral and Maxillofacial Surgery, Dr. D. Y. Patil Dental College, and Hospital, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, India
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16
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Ma M. Role of Hypoxia in Mesenchymal Stem Cells from Dental Pulp: Influence, Mechanism and Application. Cell Biochem Biophys 2024; 82:535-547. [PMID: 38713403 PMCID: PMC11344735 DOI: 10.1007/s12013-024-01274-0] [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] [Accepted: 04/08/2024] [Indexed: 05/08/2024]
Abstract
Mesenchymal stem cells (MSCs) from dental pulp (DP-MSCs), which include dental pulp stem cells (DPSCs) isolated from permanent teeth and stem cells from human exfoliated deciduous teeth (SHED), have emerged as highly promising cell sources for tissue regeneration, due to their high proliferative rate, multi-lineage differentiation capability and non-invasive accessibility. DP-MSCs also exert extensive paracrine effects through the release of extracellular vesicles (EVs) and multiple trophic factors. To be noted, the microenvironment, commonly referred to as the stem cell niche, plays a crucial role in shaping the functionality and therapeutic effects of DP-MSCs, within which hypoxia has garnered considerable attention. Extensive research has demonstrated that hypoxic conditions profoundly impact DP-MSCs. Specifically, hypoxia promotes DP-MSC proliferation, survival, stemness, migration, and pro-angiogenic potential while modulating their multi-lineage differentiation capacity. Furthermore, hypoxia stimulates the paracrine activities of DP-MSCs, leading to an increased production of EVs and soluble factors. Considering these findings, hypoxia preconditioning has emerged as a promising approach to enhance the therapeutic potential of DP-MSCs. In this comprehensive review, we provide a systematic overview of the influence of hypoxia on DP-MSCs, shedding light on the underlying mechanisms involved. Moreover, we also discuss the potential applications of hypoxia-preconditioned DP-MSCs or their secretome in tissue regeneration. Additionally, we delve into the methodologies employed to simulate hypoxic environments. This review aims to promote a comprehensive and systematic understanding of the hypoxia-induced effects on DP-MSCs and facilitate the refinement of regenerative therapeutic strategies based on DP-MSCs.
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Affiliation(s)
- Muyuan Ma
- School of Medicine, South China University of Technology, Guangzhou, China.
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17
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He H, Yang YH, Yang X, Huang Y. The growth factor multimodality on treating human dental mesenchymal stem cells: a systematic review. BMC Oral Health 2024; 24:290. [PMID: 38429689 PMCID: PMC10905837 DOI: 10.1186/s12903-024-04013-2] [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: 11/09/2023] [Accepted: 02/12/2024] [Indexed: 03/03/2024] Open
Abstract
BACKGROUND Ensuring the quantity, quality, and efficacy of human dental mesenchymal stem cells (MSCs) has become an urgent problem as their applications increase. Growth factors (GFs) have low toxicity, good biocompatibility, and regulate stem cell survival and differentiation. They bind to specific receptors on target cells, initiating signal transduction and triggering biological functions. So far, relatively few studies have been conducted to summarize the effect of different GFs on the application of dental MSCs. We have reviewed the literature from the past decade to examine the effectiveness and mechanism of applying one or multiple GFs to human dental MSCs. Our review is based on the premise that a single dental MSC cannot fulfill all applications and that different dental MSCs react differently to GFs. METHODS A search for published articles was carried out using the Web of Science core collection and PubMed. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines. This review considered studies from 2014 to 2023 that examined the effects of GFs on human dental MSCs. The final selection of articles was made on the 15th of July 2023. RESULTS Three thousand eight hundred sixty-seven pieces of literature were gathered for this systematic review initially, only 56 of them were selected based on their focus on the effects of GFs during the application of human dental MSCs. Out of the 56, 32 literature pieces were focused on a single growth factor while 24 were focused on multiple growth factors. This study shows that GFs can regulate human dental MSCs through a multi-way processing manner. CONCLUSION Multimodal treatment of GFs can effectively regulate human dental MSCs, ensuring stem cell quality, quantity, and curative effects.
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Affiliation(s)
- Huiying He
- School of Stomatology, Jinan University, Guangzhou, 510632, China
| | - Yun-Hsuan Yang
- School of Stomatology, Jinan University, Guangzhou, 510632, China
| | - Xuesong Yang
- Clinical Research Center, Clifford Hospital, Guangzhou, 511495, China.
| | - Yue Huang
- School of Stomatology, Jinan University, Guangzhou, 510632, China.
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18
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Mauroux A, Joncour P, Brassard-Jollive N, Bacar H, Gillet B, Hughes S, Ardidie-Robouant C, Marchand L, Liabotis A, Mailly P, Monnot C, Germain S, Bordes S, Closs B, Ruggiero F, Muller L. Papillary and reticular fibroblasts generate distinct microenvironments that differentially impact angiogenesis. Acta Biomater 2023; 168:210-222. [PMID: 37406716 DOI: 10.1016/j.actbio.2023.06.040] [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: 12/16/2022] [Revised: 06/20/2023] [Accepted: 06/27/2023] [Indexed: 07/07/2023]
Abstract
Papillary and reticular dermis show distinct extracellular matrix (ECM) and vascularization corresponding to their specific functions. These characteristics are associated with gene expression patterns of fibroblasts freshly isolated from their native microenvironment. In order to assess the relevance of these fibroblast subpopulations in a tissue engineering context, we investigated their contribution to matrix production and vascularization using cell sheet culture conditions. We first performed RNA-seq differential expression analysis to determine whether several rounds of cell amplification and high-density culture affected their gene expression profile. Bioinformatics analysis revealed that expression of angiogenesis-related and matrisome gene signatures were maintained, resulting in papillary and reticular ECMs that differ in composition and structure. The impact of secreted or ECM-associated factors was then assessed using two independent 3D angiogenesis assays: -1/ a fibrin hydrogel-based assay allowing investigation of diffusible secreted factors, -2/ a scaffold-free cell-sheet based assay for investigation of fibroblast-produced microenvironment. These analyses revealed that papillary fibroblasts secrete highly angiogenic factors and produce a microenvironment characterised by ECM remodelling capacity and dense and branched microvascular network, whereas reticular fibroblasts produced more structural core components of the ECM associated with less branched and larger vessels. These features mimick the characteristics of both the ECM and the vasculature of dermis subcompartments. In addition to showing that skin fibroblast populations differentially regulate angiogenesis via both secreted and ECM factors, our work emphasizes the importance of papillary and reticular fibroblasts for engineering and modelling dermis microenvironment and vascularization. STATEMENT OF SIGNIFICANCE: Recent advances have brought to the forefront the central role of microenvironment and vascularization in tissue engineering for regenerative medicine and microtissue modelling. We have investigated the role of papillary and reticular fibroblast subpopulations using scaffold-free cell sheet culture. This approach provides differentiated cells conditions allowing the production of their own microenvironment. Analysis of gene expression profiles and characterisation of the matrix produced revealed strong and specific angiogenic properties that we functionally characterized using 3D angiogenesis models targeting the respective role of either secreted or matrix-bound factors. This study demonstrates the importance of cell-generated extracellular matrix and questions the importance of cell source and the relevance of hydrogels for developing physio-pathologically relevant tissue engineered substitutes.
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Affiliation(s)
- Adèle Mauroux
- Center for Interdisciplinary Research in Biology (CIRB), College de France - CNRS, INSERM, Université PSL, 11 Place Marcelin Berthelot, Paris 75005, France; Institut de Génomique Fonctionnelle de Lyon (IGFL), ENS de Lyon, CNRS, Univ Lyon 1, 32-34 Avenue Tony Garnier, Lyon 69007, France; R&D Department, SILAB, ZI de la Nau, Saint Viance 19240, France; Sorbonne Université, Collège Doctoral, 15 rue de l'Ecole de Médecine, Paris 75006, France
| | - Pauline Joncour
- Institut de Génomique Fonctionnelle de Lyon (IGFL), ENS de Lyon, CNRS, Univ Lyon 1, 32-34 Avenue Tony Garnier, Lyon 69007, France
| | - Noémie Brassard-Jollive
- Center for Interdisciplinary Research in Biology (CIRB), College de France - CNRS, INSERM, Université PSL, 11 Place Marcelin Berthelot, Paris 75005, France; Sorbonne Université, Collège Doctoral, 15 rue de l'Ecole de Médecine, Paris 75006, France
| | - Hisoilat Bacar
- Institut de Génomique Fonctionnelle de Lyon (IGFL), ENS de Lyon, CNRS, Univ Lyon 1, 32-34 Avenue Tony Garnier, Lyon 69007, France
| | - Benjamin Gillet
- Institut de Génomique Fonctionnelle de Lyon (IGFL), ENS de Lyon, CNRS, Univ Lyon 1, 32-34 Avenue Tony Garnier, Lyon 69007, France
| | - Sandrine Hughes
- Institut de Génomique Fonctionnelle de Lyon (IGFL), ENS de Lyon, CNRS, Univ Lyon 1, 32-34 Avenue Tony Garnier, Lyon 69007, France
| | - Corinne Ardidie-Robouant
- Center for Interdisciplinary Research in Biology (CIRB), College de France - CNRS, INSERM, Université PSL, 11 Place Marcelin Berthelot, Paris 75005, France
| | | | - Athanasia Liabotis
- Center for Interdisciplinary Research in Biology (CIRB), College de France - CNRS, INSERM, Université PSL, 11 Place Marcelin Berthelot, Paris 75005, France; Sorbonne Université, Collège Doctoral, 15 rue de l'Ecole de Médecine, Paris 75006, France
| | - Philippe Mailly
- Center for Interdisciplinary Research in Biology (CIRB), College de France - CNRS, INSERM, Université PSL, 11 Place Marcelin Berthelot, Paris 75005, France
| | - Catherine Monnot
- Center for Interdisciplinary Research in Biology (CIRB), College de France - CNRS, INSERM, Université PSL, 11 Place Marcelin Berthelot, Paris 75005, France
| | - Stéphane Germain
- Center for Interdisciplinary Research in Biology (CIRB), College de France - CNRS, INSERM, Université PSL, 11 Place Marcelin Berthelot, Paris 75005, France
| | - Sylvie Bordes
- R&D Department, SILAB, ZI de la Nau, Saint Viance 19240, France
| | - Brigitte Closs
- R&D Department, SILAB, ZI de la Nau, Saint Viance 19240, France
| | - Florence Ruggiero
- Institut de Génomique Fonctionnelle de Lyon (IGFL), ENS de Lyon, CNRS, Univ Lyon 1, 32-34 Avenue Tony Garnier, Lyon 69007, France.
| | - Laurent Muller
- Center for Interdisciplinary Research in Biology (CIRB), College de France - CNRS, INSERM, Université PSL, 11 Place Marcelin Berthelot, Paris 75005, France.
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Koch DW, Schnabel LV. Mesenchymal stem cell licensing: enhancing MSC function as a translational approach for the treatment of tendon injury. Am J Vet Res 2023; 84:1-8. [PMID: 37669745 PMCID: PMC11027115 DOI: 10.2460/ajvr.23.07.0154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/14/2023] [Indexed: 09/07/2023]
Abstract
Tendon injuries are common in both veterinary and human clinical patients and result in morbidity, pain, and lost athletic performance. Consequently, utilizing naturally occurring injuries in veterinary patients as a comparative model could inform the development of novel therapies and increase translation for the treatment of human tendon injuries. Mesenchymal stem cells (MSCs) have shown considerable efficacy for the treatment of experimental and clinical superficial digital flexor tendon injury in the horse; however, the reinjury rate following treatment can remain high and MSC efficacy in treating other tendons is less well known. Additionally, the translation of MSC therapy to human tendon injury has remained poor. Recent evidence indicates that naïve MSC function can be enhanced through exogenous stimulation or manipulation of their environment. This stimulation or activation, herein termed MSC licensing, markedly alters MSC functions associated with immunomodulation, extracellular matrix remodeling, vascular development, bioactive factor production, and endogenous stromal/progenitor cell support. Additionally, a variety of licensing strategies has proven to influence MSC-secreted factors that have positively influenced outcome parameters in both in vitro and in vivo disease models separate from musculoskeletal tissues. Therefore, identifying the optimal licensing strategy for MSCs could ultimately provide an avenue for reliable and repeatable treatment of a broad range of tendon injuries of both veterinary and human clinical patients. This article details current evidence on the effects of licensed MSCs in both in vitro and in vivo disease models of different species and provides commentary on how those effector functions identified may be translated to the treatment of tendon injuries.
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Affiliation(s)
- Drew W. Koch
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC
| | - Lauren V. Schnabel
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC
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Jakl V, Popp T, Haupt J, Port M, Roesler R, Wiese S, Friemert B, Rojewski MT, Schrezenmeier H. Effect of Expansion Media on Functional Characteristics of Bone Marrow-Derived Mesenchymal Stromal Cells. Cells 2023; 12:2105. [PMID: 37626914 PMCID: PMC10453497 DOI: 10.3390/cells12162105] [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: 07/19/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The therapeutic efficacy of mesenchymal stromal cells (MSCs) has been shown to rely on their immunomodulatory and regenerative properties. In order to obtain sufficient numbers of cells for clinical applications, MSCs have to be expanded ex vivo. Expansion media with xenogeneic-free (XF) growth-promoting supplements like human platelet lysate (PL) or serum- and xenogeneic-free (SF/XF) formulations have been established as safe and efficient, and both groups provide different beneficial qualities. In this study, MSCs were expanded in XF or SF/XF media as well as in mixtures thereof. MSCs cultured in these media were analyzed for phenotypic and functional properties. MSC expansion was optimal with SF/XF conditions when PL was present. Metabolic patterns, consumption of growth factors, and secretome of MSCs differed depending on the type and concentration of supplement. The lactate per glucose yield increased along with a higher proportion of PL. Many factors in the supernatant of cultured MSCs showed distinct patterns depending on the supplement (e.g., FGF-2, TGFβ, and insulin only in PL-expanded MSC, and leptin, sCD40L PDGF-AA only in SF/XF-expanded MSC). This also resulted in changes in cell characteristics like migratory potential. These findings support current approaches where growth media may be utilized for priming MSCs for specific therapeutic applications.
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Affiliation(s)
- Viktoria Jakl
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
| | - Tanja Popp
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Julian Haupt
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Matthias Port
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Reinhild Roesler
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Sebastian Wiese
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Benedikt Friemert
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Markus T. Rojewski
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
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21
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Wang H, Zhang P, Lu P, Cai X, Wang G, Xu X, Liu Y, Huang T, Li M, Qian T, Zhu H, Xue C. Neural tissue-engineered prevascularization in vivo enhances peripheral neuroregeneration via rapid vascular inosculation. Mater Today Bio 2023; 21:100718. [PMID: 37455820 PMCID: PMC10339252 DOI: 10.1016/j.mtbio.2023.100718] [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: 03/22/2023] [Revised: 06/01/2023] [Accepted: 06/21/2023] [Indexed: 07/18/2023] Open
Abstract
Neural tissue engineering techniques typically face a significant challenge, simulating complex natural vascular systems that hinder the clinical application of tissue-engineered nerve grafts (TENGs). Here, we report a subcutaneously pre-vascularized TENG consisting of a vascular endothelial growth factor-induced host vascular network, chitosan nerve conduit, and inserted silk fibroin fibers. Contrast agent perfusion, tissue clearing, microCT scan, and blood vessel 3D reconstruction were carried out continuously to prove whether the regenerated blood vessels were functional. Moreover, histological and electrophysiological evaluations were also applied to investigate the efficacy of repairing peripheral nerve defects with pre-vascularized TENG. Rapid vascular inosculation of TENG pre-vascularized blood vessels with the host vascular system was observed at 4 d bridging the 10 mm sciatic nerve defect in rats. Transplantation of pre-vascularized TENG in vivo suppressed proliferation of vascular endothelial cells (VECs) while promoting their migration within 14 d post bridging surgery. More importantly, the early vascularization of TENG drives axonal regrowth by facilitating bidirectional migration of Schwann cells (SCs) and the bands of Büngner formation. This pre-vascularized TENG increased remyelination, promoted recovery of electrophysiological function, and prevented atrophy of the target muscles when observed 12 weeks post neural transplantation. The neural tissue-engineered pre-vascularization technique provides a potential approach to discover an individualized TENG and explore the innovative neural regenerative process.
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Affiliation(s)
- Hongkui Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
| | - Ping Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
| | - Panjian Lu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
| | - Xiaodong Cai
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
| | - Gang Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
| | - Xi Xu
- Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, JS, 226001, PR China
| | - Ying Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, JS, 226001, PR China
| | - Tianyi Huang
- Medical School of Nantong University, Nantong, JS, 226001, PR China
| | - Meiyuan Li
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
| | - Tianmei Qian
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
| | - Hui Zhu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
| | - Chengbin Xue
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong University, Nantong, JS, 226001, PR China
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22
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Schönherr-Hellec S, Chatzopoulou E, Barnier JP, Atlas Y, Dupichaud S, Guilbert T, Dupraz Y, Meyer J, Chaussain C, Gorin C, Nassif X, Germain S, Muller L, Coureuil M. Implantation of engineered human microvasculature to study human infectious diseases in mouse models. iScience 2023; 26:106286. [PMID: 36942053 PMCID: PMC10024136 DOI: 10.1016/j.isci.2023.106286] [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: 09/30/2022] [Revised: 01/10/2023] [Accepted: 02/21/2023] [Indexed: 03/03/2023] Open
Abstract
Animal models for studying human pathogens are crucially lacking. We describe the implantation in mice of engineered human mature microvasculature consisting of endothelial and perivascular cells embedded in collagen hydrogel that allows investigation of pathogen interactions with the endothelium, including in vivo functional studies. Using Neisseria meningitidis as a paradigm of human-restricted infection, we demonstrated the strength and opportunities associated with the use of this approach.
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Affiliation(s)
- Sophia Schönherr-Hellec
- Université Paris Cité, UFR de Médecine, Paris, France
- Institut Necker Enfants-Malades, Inserm U1151, CNRS UMR 8253, Paris, France
| | - Eirini Chatzopoulou
- Université Paris Cité, UPR2496 Pathologies, Imagerie et Biothérapies Orofaciales et Plateforme Imagerie du Vivant, UFR Odontologie, Paris, France
| | - Jean-Philippe Barnier
- Université Paris Cité, UFR de Médecine, Paris, France
- Institut Necker Enfants-Malades, Inserm U1151, CNRS UMR 8253, Paris, France
| | - Yoann Atlas
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France
- Sorbonne Université, Collège doctoral, Paris, France
| | - Sébastien Dupichaud
- Cell Imaging Platform, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, Paris, France
| | - Thomas Guilbert
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Cité, Paris, France
| | - Yves Dupraz
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France
| | - Julie Meyer
- Université Paris Cité, UFR de Médecine, Paris, France
- Institut Necker Enfants-Malades, Inserm U1151, CNRS UMR 8253, Paris, France
| | - Catherine Chaussain
- Université Paris Cité, UPR2496 Pathologies, Imagerie et Biothérapies Orofaciales et Plateforme Imagerie du Vivant, UFR Odontologie, Paris, France
- AP-HP, Services Médecines bucco-dentaire (GH Paris Sud-Sorbonne Université, Paris Nord-Université Paris Cité), Paris, France
| | - Caroline Gorin
- Université Paris Cité, UPR2496 Pathologies, Imagerie et Biothérapies Orofaciales et Plateforme Imagerie du Vivant, UFR Odontologie, Paris, France
- AP-HP, Services Médecines bucco-dentaire (GH Paris Sud-Sorbonne Université, Paris Nord-Université Paris Cité), Paris, France
| | - Xavier Nassif
- Université Paris Cité, UFR de Médecine, Paris, France
- Institut Necker Enfants-Malades, Inserm U1151, CNRS UMR 8253, Paris, France
| | - Stephane Germain
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France
| | - Laurent Muller
- Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France
- Corresponding author
| | - Mathieu Coureuil
- Université Paris Cité, UFR de Médecine, Paris, France
- Institut Necker Enfants-Malades, Inserm U1151, CNRS UMR 8253, Paris, France
- Corresponding author
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23
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Hezam K, Wang C, Fu E, Zhou M, Liu Y, Wang H, Zhu L, Han Z, Han ZC, Chang Y, Li Z. Superior protective effects of PGE2 priming mesenchymal stem cells against LPS-induced acute lung injury (ALI) through macrophage immunomodulation. Stem Cell Res Ther 2023; 14:48. [PMID: 36949464 PMCID: PMC10032272 DOI: 10.1186/s13287-023-03277-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 03/13/2023] [Indexed: 03/24/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have demonstrated remarkable therapeutic promise for acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS). MSC secretomes contain various immunoregulatory mediators that modulate both innate and adaptive immune responses. Priming MSCs has been widely considered to boost their therapeutic efficacy for a variety of diseases. Prostaglandin E2 (PGE2) plays a vital role in physiological processes that mediate the regeneration of injured organs. METHODS This work utilized PGE2 to prime MSCs and investigated their therapeutic potential in ALI models. MSCs were obtained from human placental tissue. MSCs were transduced with firefly luciferase (Fluc)/eGFP fusion protein for real-time monitoring of MSC migration. Comprehensive genomic analyses explored the therapeutic effects and molecular mechanisms of PGE2-primed MSCs in LPS-induced ALI models. RESULTS Our results demonstrated that PGE2-MSCs effectively ameliorated lung injury and decreased total cell numbers, neutrophils, macrophages, and protein levels in bronchoalveolar lavage fluid (BALF). Meanwhile, treating ALI mice with PGE2-MSCs dramatically reduced histopathological changes and proinflammatory cytokines while increasing anti-inflammatory cytokines. Furthermore, our findings supported that PGE2 priming improved the therapeutic efficacy of MSCs through M2 macrophage polarization. CONCLUSION PGE2-MSC therapy significantly reduced the severity of LPS-induced ALI in mice by modulating macrophage polarization and cytokine production. This strategy boosts the therapeutic efficacy of MSCs in cell-based ALI therapy.
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Affiliation(s)
- Kamal Hezam
- Nankai University School of Medicine, Tianjin, 300071, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, Tianjin, 300052, China
- The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, College of Life Sciences, Tianjin, 300071, China
| | - Chen Wang
- Nankai University School of Medicine, Tianjin, 300071, China
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, Tianjin, 300052, China
- The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, College of Life Sciences, Tianjin, 300071, China
| | - Enze Fu
- Nankai University School of Medicine, Tianjin, 300071, China
| | - Manqian Zhou
- Department of Radiation Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, 300120, China
| | - Yue Liu
- Nankai University School of Medicine, Tianjin, 300071, China
| | - Hui Wang
- Department of Radiation Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, 300120, China
| | - Lihong Zhu
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Zhibo Han
- Jiangxi Engineering Research Center for Stem Cells, Shangrao, 334109, Jiangxi, China
- Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceuticals, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd, Tianjin, 300457, China
- Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health & Biotech Co., 100176, Beijing, China
| | - Zhong-Chao Han
- Jiangxi Engineering Research Center for Stem Cells, Shangrao, 334109, Jiangxi, China
- Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceuticals, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd, Tianjin, 300457, China
- Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health & Biotech Co., 100176, Beijing, China
| | - Ying Chang
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, Tianjin, 300052, China.
| | - Zongjin Li
- Nankai University School of Medicine, Tianjin, 300071, China.
- Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, Tianjin, 300052, China.
- The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, College of Life Sciences, Tianjin, 300071, China.
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, 100853, China.
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24
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Lopes-Pacheco M, Rocco PRM. Functional enhancement strategies to potentiate the therapeutic properties of mesenchymal stromal cells for respiratory diseases. Front Pharmacol 2023; 14:1067422. [PMID: 37007034 PMCID: PMC10062457 DOI: 10.3389/fphar.2023.1067422] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Respiratory diseases remain a major health concern worldwide because they subject patients to considerable financial and psychosocial burdens and result in a high rate of morbidity and mortality. Although significant progress has been made in understanding the underlying pathologic mechanisms of severe respiratory diseases, most therapies are supportive, aiming to mitigate symptoms and slow down their progressive course but cannot improve lung function or reverse tissue remodeling. Mesenchymal stromal cells (MSCs) are at the forefront of the regenerative medicine field due to their unique biomedical potential in promoting immunomodulation, anti-inflammatory, anti-apoptotic and antimicrobial activities, and tissue repair in various experimental models. However, despite several years of preclinical research on MSCs, therapeutic outcomes have fallen far short in early-stage clinical trials for respiratory diseases. This limited efficacy has been associated with several factors, such as reduced MSC homing, survival, and infusion in the late course of lung disease. Accordingly, genetic engineering and preconditioning methods have emerged as functional enhancement strategies to potentiate the therapeutic actions of MSCs and thus achieve better clinical outcomes. This narrative review describes various strategies that have been investigated in the experimental setting to functionally potentiate the therapeutic properties of MSCs for respiratory diseases. These include changes in culture conditions, exposure of MSCs to inflammatory environments, pharmacological agents or other substances, and genetic manipulation for enhanced and sustained expression of genes of interest. Future directions and challenges in efficiently translating MSC research into clinical practice are discussed.
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Affiliation(s)
- Miquéias Lopes-Pacheco
- Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- *Correspondence: Miquéias Lopes-Pacheco, ; Patricia R. M. Rocco,
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25
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Gornostaeva AN, Buravkova LB. Changes Induced by Inflammatory-Activated Immune Cell Microenvironment in the Paracrine Profile of MSC. Bull Exp Biol Med 2023; 174:544-548. [PMID: 36894814 DOI: 10.1007/s10517-023-05745-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Indexed: 03/11/2023]
Abstract
We studied the influence of activated innate and adaptive immune cells on the production of growth factors by human adipose tissue multipotent mesenchymal stromal cells (MSC). MSC showed immunosuppressive properties in vitro: decreased activation and proliferation of stimulated immune cells. T-cell interaction with MSC resulted with increased secretion of EGF, PDGF-AB/BB, FGF-2, and VEGF growth factors. Co-culturing with natural killer cells also stimulated TGFα production. The intensity of the effect varied depending on the type of immune cells. Natural killer caused a more significant increase in PDGF-AB/BB and FGF-2 secretion, while VEGF secretion increased stronger after co-culturing with T cells. The obtained data indicate the possibility of increasing reparative potential of MSC under the influence of inflammatory microenvironment.
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Affiliation(s)
- A N Gornostaeva
- Institute of Biomedical Problems, State Research Center, Russian Academy of Sciences, Moscow, Russia.
| | - L B Buravkova
- Institute of Biomedical Problems, State Research Center, Russian Academy of Sciences, Moscow, Russia
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26
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Mavinga M, Palmier M, Rémy M, Jeannière C, Lenoir S, Rey S, Saint-Marc M, Alonso F, Génot E, Thébaud N, Chevret E, Mournetas V, Rousseau B, Boiziau C, Boeuf H. The Journey of SCAPs (Stem Cells from Apical Papilla), from Their Native Tissue to Grafting: Impact of Oxygen Concentration. Cells 2022; 11:cells11244098. [PMID: 36552862 PMCID: PMC9776846 DOI: 10.3390/cells11244098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/30/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022] Open
Abstract
Tissue engineering strategies aim at characterizing and at optimizing the cellular component that is combined with biomaterials, for improved tissue regeneration. Here, we present the immunoMap of apical papilla, the native tissue from which SCAPs are derived. We characterized stem cell niches that correspond to a minority population of cells expressing Mesenchymal stromal/Stem Cell (CD90, CD105, CD146) and stemness (SSEA4 and CD49f) markers as well as endothelial cell markers (VWF, CD31). Based on the colocalization of TKS5 and cortactin markers, we detected migration-associated organelles, podosomes-like structures, in specific regions and, for the first time, in association with stem cell niches in normal tissue. From six healthy teenager volunteers, each with two teeth, we derived twelve cell banks, isolated and amplified under 21 or 3% O2. We confirmed a proliferative advantage of all banks when cultured under 3% versus 21% O2. Interestingly, telomerase activity was similar to that of the highly proliferative hiPSC cell line, but unrelated to O2 concentration. Finally, SCAPs embedded in a thixotropic hydrogel and implanted subcutaneously in immunodeficient mice were protected from cell death with a slightly greater advantage for cells preconditioned at 3% O2.
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Affiliation(s)
- Marine Mavinga
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France
| | | | - Murielle Rémy
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France
| | | | - Solène Lenoir
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France
| | - Sylvie Rey
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France
| | | | - Florian Alonso
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France
| | - Elisabeth Génot
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France
| | - Noélie Thébaud
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France
| | - Edith Chevret
- Univ. Bordeaux, INSERM, BRIC, U1312, F-33000 Bordeaux, France
| | | | - Benoit Rousseau
- Univ. Bordeaux, Animal Facility A2, Service Commun des Animaleries, F-33000 Bordeaux, France
| | | | - Helene Boeuf
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France
- Correspondence:
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27
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Nadine S, Fernandes IJ, Correia CR, Mano JF. Close-to-native bone repair via tissue-engineered endochondral ossification approaches. iScience 2022; 25:105370. [PMID: 36339269 PMCID: PMC9626746 DOI: 10.1016/j.isci.2022.105370] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
In order to solve the clinical challenges related to bone grafting, several tissue engineering (TE) strategies have been proposed to repair critical-sized defects. Generally, the classical TE approaches are designed to promote bone repair via intramembranous ossification. Although promising, strategies that direct the osteogenic differentiation of mesenchymal stem/stromal cells are usually characterized by a lack of functional vascular supply, often resulting in necrotic cores. A less explored alternative is engineering bone constructs through a cartilage-mediated approach, resembling the embryological process of endochondral ossification. The remodeling of an intermediary hypertrophic cartilaginous template triggers vascular invasion and bone tissue deposition. Thus, employing this knowledge can be a promising direction for the next generation of bone TE constructs. This review highlights the most recent biomimetic strategies for applying endochondral ossification in bone TE while discussing the plethora of cell types, culture conditions, and biomaterials essential to promote a successful bone regeneration process.
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28
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Franca CM, Balbinot GDS, Cunha D, Saboia VDPA, Ferracane J, Bertassoni LE. In-vitro models of biocompatibility testing for restorative dental materials: From 2D cultures to organs on-a-chip. Acta Biomater 2022; 150:58-66. [PMID: 35933103 PMCID: PMC9814917 DOI: 10.1016/j.actbio.2022.07.060] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 07/13/2022] [Accepted: 07/28/2022] [Indexed: 02/08/2023]
Abstract
Dental caries is a biofilm-mediated, diet-modulated, multifactorial and dynamic disease that affects more than 90% of adults in Western countries. The current treatment for decayed tissue is based on using materials to replace the lost enamel or dentin. More than 500 million dental restorations are placed annually worldwide, and materials used for these purposes either directly or indirectly interact with dentin and pulp tissues. The development and understanding of the effects of restorative dental materials are based on different in-vitro and in-vivo tests, which have been evolving with time. In this review, we first discuss the characteristics of the tooth and the dentin-pulp interface that are unique for materials testing. Subsequently, we discuss frequently used in-vitro tests to evaluate the biocompatibility of dental materials commonly used for restorative procedures. Finally, we present our perspective on the future directions for biological research on dental materials using tissue engineering and organs on-a-chip approaches. STATEMENT OF SIGNIFICANCE: Dental caries is still the most prevalent infectious disease globally, requiring more than 500 million restorations to be placed every year. Regrettably, the failure rates of such restorations are still high. Those rates are partially based on the fact that current platforms to test dental materials are somewhat inaccurate in reproducing critical components of the complex oral microenvironment. Thus, there is a collective effort to develop new materials while evolving the platforms to test them. In this context, the present review critically discusses in-vitro models used to evaluate the biocompatibility of restorative dental materials and brings a perspective on future directions for tissue-engineered and organs-on-a-chip platforms for testing new dental materials.
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Affiliation(s)
- Cristiane Miranda Franca
- Department of Restorative Dentistry, School of Dentistry, Oregon Health & Science University, Portland, OR, United States
| | - Gabriela de Souza Balbinot
- Dental Materials Laboratory, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Diana Cunha
- Post-Graduation Program in Dentistry, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | | | - Jack Ferracane
- Department of Restorative Dentistry, School of Dentistry, Oregon Health & Science University, Portland, OR, United States
| | - Luiz E Bertassoni
- Department of Restorative Dentistry, School of Dentistry, Oregon Health & Science University, Portland, OR, United States; Center for Regenerative Medicine, School of Medicine, Oregon Health & Science University, Portland, OR, United States; Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR, United States; Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Portland, OR, United States.
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29
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Barisón MJ, Nogoceke R, Josino R, Horinouchi CDDS, Marcon BH, Correa A, Stimamiglio MA, Robert AW. Functionalized Hydrogels for Cartilage Repair: The Value of Secretome-Instructive Signaling. Int J Mol Sci 2022; 23:ijms23116010. [PMID: 35682690 PMCID: PMC9181449 DOI: 10.3390/ijms23116010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 02/07/2023] Open
Abstract
Cartilage repair has been a challenge in the medical field for many years. Although treatments that alleviate pain and injury are available, none can effectively regenerate the cartilage. Currently, regenerative medicine and tissue engineering are among the developed strategies to treat cartilage injury. The use of stem cells, associated or not with scaffolds, has shown potential in cartilage regeneration. However, it is currently known that the effect of stem cells occurs mainly through the secretion of paracrine factors that act on local cells. In this review, we will address the use of the secretome—a set of bioactive factors (soluble factors and extracellular vesicles) secreted by the cells—of mesenchymal stem cells as a treatment for cartilage regeneration. We will also discuss methodologies for priming the secretome to enhance the chondroregenerative potential. In addition, considering the difficulty of delivering therapies to the injured cartilage site, we will address works that use hydrogels functionalized with growth factors and secretome components. We aim to show that secretome-functionalized hydrogels can be an exciting approach to cell-free cartilage repair therapy.
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30
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Olmedo-Moreno L, Aguilera Y, Baliña-Sánchez C, Martín-Montalvo A, Capilla-González V. Heterogeneity of In Vitro Expanded Mesenchymal Stromal Cells and Strategies to Improve Their Therapeutic Actions. Pharmaceutics 2022; 14:1112. [PMID: 35631698 PMCID: PMC9146397 DOI: 10.3390/pharmaceutics14051112] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 12/12/2022] Open
Abstract
Beneficial properties of mesenchymal stromal cells (MSCs) have prompted their use in preclinical and clinical research. Accumulating evidence has been provided for the therapeutic effects of MSCs in several pathologies, including neurodegenerative diseases, myocardial infarction, skin problems, liver disorders and cancer, among others. Although MSCs are found in multiple tissues, the number of MSCs is low, making in vitro expansion a required step before MSC application. However, culture-expanded MSCs exhibit notable differences in terms of cell morphology, physiology and function, which decisively contribute to MSC heterogeneity. The changes induced in MSCs during in vitro expansion may account for the variability in the results obtained in different MSC-based therapy studies, including those using MSCs as living drug delivery systems. This review dissects the different changes that occur in culture-expanded MSCs and how these modifications alter their therapeutic properties after transplantation. Furthermore, we discuss the current strategies developed to improve the beneficial effects of MSCs for successful clinical implementation, as well as potential therapeutic alternatives.
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Affiliation(s)
| | | | | | | | - Vivian Capilla-González
- Department of Regeneration and Cell Therapy, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-CSIC-US-UPO, 41092 Seville, Spain; (L.O.-M.); (Y.A.); (C.B.-S.); (A.M.-M.)
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Yong Z, Kuang G, Fengying S, Shoumei X, Duohong Z, Jiacai H, Xuyan T. Comparison of the Angiogenic Ability between SHED and DPSC in a Mice Model with Critical Limb Ischemic. Tissue Eng Regen Med 2022; 19:861-870. [PMID: 35474506 PMCID: PMC9294125 DOI: 10.1007/s13770-022-00452-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/14/2022] [Accepted: 03/09/2022] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND Regenerative medicine by using stem cells from dental pulp is promising for treating patients with critical limb ischemic (CLI). Here, we investigated the difference in the angiogenetic ability of stem cells from human exfoliated deciduous teeth (SHED) and human dental pulp stem cells (DPSC). METHODS SHED and DPSC were harvested from dental pulp and analyzed in flow- cytometry for detecting the expression of surface markers. Levels of angiogenetic marker were examined by RT-PCR and Western-blot. Eighteen immunodeficient mice of critical limb ischemic model were divided into three groups: SHED, DPSC and saline, which was administered with SHED, DPSC or saline intramuscularly. Histological examination was performed to detect the regenerative results. RESULTS A highly expression of CD146 was detected in SHED. Moreover, cells with negative expression of both CD146 and CD31 in SHED were more in comparison with those in DPSC. Expression of angiogenesis factors including CXCL12, CXCR4, Hif-1a, CD31, VEGF and bFGF were significant higher in SHED than DPSC by the RT-PCR and Western-Blot results. SHED induced more CD31 expression and less fibrous tissue formation in the critical limb ischemic model as compare with DPSC and saline. CONCLUSION Both SHED and DPSC possessed the ability of repairing CLI. With expressing more proangiogenesis factors, SHED may have the advantage of repairing CLI.
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Affiliation(s)
- Zhou Yong
- College & Hospital of Stomatology, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, 230032, China.,Department of Dental Implantology, College & Hospital of Stomatology, Anhui Medical University, Hefei, 230032, China.,Periodontal Department College & Hospital of Stomatology, Anhui Medical University, Hefei, 230032, China
| | - Gu Kuang
- College & Hospital of Stomatology, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, 230032, China.,Periodontal Department College & Hospital of Stomatology, Anhui Medical University, Hefei, 230032, China
| | - Sun Fengying
- College & Hospital of Stomatology, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, 230032, China.,Periodontal Department College & Hospital of Stomatology, Anhui Medical University, Hefei, 230032, China
| | - Xuan Shoumei
- College & Hospital of Stomatology, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, 230032, China.,Periodontal Department College & Hospital of Stomatology, Anhui Medical University, Hefei, 230032, China
| | - Zou Duohong
- Department of Oral Surgery, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, School of Medicine, Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai, 200011, China.,Periodontal Department College & Hospital of Stomatology, Anhui Medical University, Hefei, 230032, China
| | - He Jiacai
- College & Hospital of Stomatology, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, 230032, China.,Department of Dental Implantology, College & Hospital of Stomatology, Anhui Medical University, Hefei, 230032, China.,Periodontal Department College & Hospital of Stomatology, Anhui Medical University, Hefei, 230032, China
| | - Tang Xuyan
- College & Hospital of Stomatology, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei, 230032, China.
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Li M, Jiang Y, Hou Q, Zhao Y, Zhong L, Fu X. Potential pre-activation strategies for improving therapeutic efficacy of mesenchymal stem cells: current status and future prospects. Stem Cell Res Ther 2022; 13:146. [PMID: 35379361 PMCID: PMC8981790 DOI: 10.1186/s13287-022-02822-2] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/20/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cell (MSC)-based therapy has been considered as a promising approach targeting a variety of intractable diseases due to remarkable multiple effect of MSCs, such as multilineage differentiation, immunomodulatory property, and pro-regenerative capacity. However, poor engraftment, low survival rate of transplanted MSC, and impaired donor-MSC potency under host age/disease result in unsatisfactory therapeutic outcomes. Enhancement strategies, including genetic manipulation, pre-activation, and modification of culture method, have been investigated to generate highly functional MSC, and approaches for MSC pre-activation are highlighted. In this review, we summarized the current approaches of MSC pre-activation and further classified, analysed the scientific principles and main characteristics of these manipulations, and described the pros and cons of individual pre-activation strategies. We also discuss the specialized tactics to solve the challenges in this promising field so that it improves MSC therapeutic functions to serve patients better.
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Affiliation(s)
- Meirong Li
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China. .,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China. .,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China.
| | - Yufeng Jiang
- Wound Repairing Department, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, China
| | - Qian Hou
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China.,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China.,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China
| | - Yali Zhao
- Central Laboratory, Trauma Treatment Center, Chinese PLA General Hospital, Hainan Hospital, Sanya, China
| | - Lingzhi Zhong
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China.,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China.,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China
| | - Xiaobing Fu
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical College, Beijing, China. .,PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Beijing, China. .,Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences 2019RU051, Beijing, China.
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Tracy EP, Stielberg V, Rowe G, Benson D, Nunes SS, Hoying JB, Murfee WL, LeBlanc AJ. State of the field: cellular and exosomal therapeutic approaches in vascular regeneration. Am J Physiol Heart Circ Physiol 2022; 322:H647-H680. [PMID: 35179976 PMCID: PMC8957327 DOI: 10.1152/ajpheart.00674.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/19/2023]
Abstract
Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis. In many clinical settings, current pharmacologic strategies use a single or narrow targeted approach to address symptoms of pathology rather than a comprehensive and multifaceted approach to address their root cause. To address this, efforts have been heavily focused on cellular therapies and cell-free therapies (e.g., exosomes) that can tackle the multifaceted etiology of vascular and microvascular dysfunction. In this review, we discuss 1) the state of the field in terms of common therapeutic cell population isolation techniques, their unique characteristics, and their advantages and disadvantages, 2) common molecular mechanisms of cell therapies to restore vascularization and/or vascular function, 3) arguments for and against allogeneic versus autologous applications of cell therapies, 4) emerging strategies to optimize and enhance cell therapies through priming and preconditioning, and, finally, 5) emerging strategies to bolster therapeutic effect. Relevant and recent clinical and animal studies using cellular therapies to restore vascular function or pathologic tissue health by way of improved vascularization are highlighted throughout these sections.
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Affiliation(s)
- Evan Paul Tracy
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Virginia Stielberg
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Gabrielle Rowe
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Daniel Benson
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
- Department of Bioengineering, University of Louisville, Louisville, Kentucky
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - James B Hoying
- Advanced Solutions Life Sciences, Manchester, New Hampshire
| | - Walter Lee Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Amanda Jo LeBlanc
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
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Dynamics of Endothelial Engagement and Filopodia Formation in Complex 3D Microscaffolds. Int J Mol Sci 2022; 23:ijms23052415. [PMID: 35269558 PMCID: PMC8910162 DOI: 10.3390/ijms23052415] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/08/2022] [Accepted: 02/16/2022] [Indexed: 11/28/2022] Open
Abstract
The understanding of endothelium–extracellular matrix interactions during the initiation of new blood vessels is of great medical importance; however, the mechanobiological principles governing endothelial protrusive behaviours in 3D microtopographies remain imperfectly understood. In blood capillaries submitted to angiogenic factors (such as vascular endothelial growth factor, VEGF), endothelial cells can transiently transdifferentiate in filopodia-rich cells, named tip cells, from which angiogenesis processes are locally initiated. This protrusive state based on filopodia dynamics contrasts with the lamellipodia-based endothelial cell migration on 2D substrates. Using two-photon polymerization, we generated 3D microstructures triggering endothelial phenotypes evocative of tip cell behaviour. Hexagonal lattices on pillars (“open”), but not “closed” hexagonal lattices, induced engagement from the endothelial monolayer with the generation of numerous filopodia. The development of image analysis tools for filopodia tracking allowed to probe the influence of the microtopography (pore size, regular vs. elongated structures, role of the pillars) on orientations, engagement and filopodia dynamics, and to identify MLCK (myosin light-chain kinase) as a key player for filopodia-based protrusive mode. Importantly, these events occurred independently of VEGF treatment, suggesting that the observed phenotype was induced through microtopography. These microstructures are proposed as a model research tool for understanding endothelial cell behaviour in 3D fibrillary networks.
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Towards Induction of Angiogenesis in Dental Pulp Stem Cells Using Chitosan-Based Hydrogels Releasing Basic Fibroblast Growth Factor. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5401461. [PMID: 35198635 PMCID: PMC8860569 DOI: 10.1155/2022/5401461] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 11/26/2021] [Accepted: 01/19/2022] [Indexed: 11/17/2022]
Abstract
Introduction. Chitosan is a natural biopolymer that attracted enormous attention in biomedical fields. The main components of regenerative endodontic procedures (REPs), as well as tissue engineering, are scaffolds, stem cells, and growth factors. As one of the basic factors in the REPs is maintaining vascularization, this study was aimed at developing basic fibroblast growth factor- (bFGF-) loaded scaffolds and investigating their effects on the angiogenic induction in human dental pulp stem cells (hDPSCs). Methods. Poly (ε-caprolactone) (PCL)/chitosan- (CS-) based highly porous scaffold (PCL/CS) was prepared and evaluated by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) analyses. The adhesion and survival potency of seeded cells were assessed by SEM and MTT assays, respectively. The amount of angiogenic markers was investigated in gene and protein levels by real-time PCR and western blotting assays, respectively. Results. Based on our findings, the SEM and FTIR tests confirmed the appropriate structure of synthesized scaffolds. Besides, the adhesion and survival rate of cells and the levels of VEGFR-2, Tie2, and Angiopoietin-1 genes were increased significantly in the PCL/CS/bFGF group. Also, the western blotting results showed the upregulation of these markers at protein levels, which were considerably higher at the PCL/CS/bFGF group (
). Conclusions. On a more general note, this study demonstrates that the bFGF-loaded PCL/CS scaffolds have the potential to promote angiogenesis of hDPSCs, which could provide vitality of dentin-pulp complex as the initial required factor for regenerative endodontic procedures.
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Colin-Pierre C, Berthélémy N, Belloy N, Danoux L, Bardey V, Rivet R, Mine S, Jeanmaire C, Maquart FX, Ramont L, Brézillon S. The Glypican-1/HGF/C-Met and Glypican-1/VEGF/VEGFR2 Ternary Complexes Regulate Hair Follicle Angiogenesis. Front Cell Dev Biol 2021; 9:781172. [PMID: 34957110 PMCID: PMC8692797 DOI: 10.3389/fcell.2021.781172] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/16/2021] [Indexed: 12/30/2022] Open
Abstract
The hair renewal involves changes in the morphology of the hair follicle and its micro-vascularization. In alopecia, the hair cycle is accelerated, resulting in the formation of thinner and shorter hair. In addition, alopecia is associated with a decrease in the micro-vascularization of the hair follicles. In this study, the role of glypicans (GPCs) was analyzed in the regulation of the angiogenesis of human dermal microvascular endothelial cells (HDMEC). The analysis of glypican gene expression showed that GPC1 is the major glypican expressed by human keratinocytes of outer root sheath (KORS), human hair follicle dermal papilla cells (HHFDPC) and HDMEC. KORS were demonstrated to secrete VEGF and HGF. The HDMEC pseudotube formation was induced by KORS conditioned media (KORSCM). It was totally abrogated after GPC1 siRNA transfection of HDMEC. Moreover, when cleaved by phospholipase C (PLC), GPC1 promotes the proliferation of HDMEC. Finally, GPC1 was shown to interact directly with VEGFR2 or c-Met to regulate angiogenesis induced by the activation of these receptors. Altogether, these results showed that GPC1 is a key regulator of microvascular endothelial cell angiogenesis induced by VEGF and HGF secreted by KORS. Thus, GPC1 might constitute an interesting target to tackle alopecia in dermatology research.
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Affiliation(s)
- Charlie Colin-Pierre
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, Reims, France.,BASF Beauty Care Solutions France SAS, Pulnoy, France
| | | | - Nicolas Belloy
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, Reims, France.,P3M, Multiscale Molecular Modeling Platform, Université de Reims Champagne-Ardenne, Reims, France
| | - Louis Danoux
- BASF Beauty Care Solutions France SAS, Pulnoy, France
| | | | - Romain Rivet
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, Reims, France
| | - Solène Mine
- BASF Beauty Care Solutions France SAS, Pulnoy, France
| | | | - François-Xavier Maquart
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France
| | - Laurent Ramont
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, Reims, France.,CHU de Reims, Service Biochimie-Pharmacologie-Toxicologie, Reims, France
| | - Stéphane Brézillon
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, Reims, France
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Zhang Q, Yang T, Zhang R, Liang X, Wang G, Tian Y, Xie L, Tian W. Platelet lysate functionalized gelatin methacrylate microspheres for improving angiogenesis in endodontic regeneration. Acta Biomater 2021; 136:441-455. [PMID: 34551330 DOI: 10.1016/j.actbio.2021.09.024] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023]
Abstract
Rapid angiogenesis is one of the challenges in endodontic regeneration. Recently, tailored polymeric microsphere system that loaded pro-angiogenic growth factors (GFs) is promising in facilitating vascularization in dental pulp regeneration. In addition, the synergistic effect of multiple GFs is considered more beneficial, but combination usage of them is rather complex and costly. Herein, we aimed to incorporate human platelet lysate (PL), a natural-derived pool of multiple GFs, into gelatin methacrylate (GelMA) microsphere system (GP), which was further modified by Laponite (GPL), a nanoclay with efficient drug delivery ability. These hybrid microspheres were successfully fabricated by electrostatic microdroplet technique with suitable size range (180∼380 µm). After incorporation of the PL and Laponite with GelMA, the Young's modulus of the hybrid hydrogel increased up to about 3-fold and the swelling and degradation rate decreased simultaneously. The PL-derived GFs continued to release up to 28 days from both the GP and GPL microspheres, while the latter released relatively more slowly. What's more, the released GFs could effectively induce tubule formation of human umbilical endothelial cells (HUVECs) and also promote human dental pulp stem cells (hDPSCs) migration. Additionally, the PL component in the GelMA microspheres significantly improved the proliferation, spreading, and odontogenic differentiation of the encapsulated hDPSCs. As further verified by the subcutaneous implantation results, both of the GP and GPL groups enhanced microvascular formation and pulp-like tissue regeneration. This work demonstrated that PL-incorporating GelMA microsphere system was a promising functional vehicle for promoting vascularized endodontic regeneration. STATEMENT OF SIGNIFICANCE: Polymeric microsphere system loaded with pro-angiogenic growth factors (GFs) shows great promise for regeneration of vascularized dental pulp. Herein, we prepared a functional GelMA microsphere system incorporated with human platelet lysates (PL) and nanoclay Laponite by the electrostatic microdroplet method. The results demonstrated that the GelMA/PL/Laponite microspheres significantly improved the spreading, proliferation, and odontogenic differentiation of the encapsulated hDPSCs compared with pure GelMA microspheres. Moreover, they also enhanced microvascular formation and pulp-like tissue regeneration in vivo. This hybrid microsphere system has great potential to accelerate microvessel formation in regenerated dental pulp and other tissues.
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Zhang SY, Ren JY, Yang B. Priming strategies for controlling stem cell fate: Applications and challenges in dental tissue regeneration. World J Stem Cells 2021; 13:1625-1646. [PMID: 34909115 PMCID: PMC8641023 DOI: 10.4252/wjsc.v13.i11.1625] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/14/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) have attracted intense interest in the field of dental tissue regeneration. Dental tissue is a popular source of MSCs because MSCs can be obtained with minimally invasive procedures. MSCs possess distinct inherent properties of self-renewal, immunomodulation, proangiogenic potential, and multilineage potency, as well as being readily available and easy to culture. However, major issues, including poor engraftment and low survival rates in vivo, remain to be resolved before large-scale application is feasible in clinical treatments. Thus, some recent investigations have sought ways to optimize MSC functions in vitro and in vivo. Currently, priming culture conditions, pretreatment with mechanical and physical stimuli, preconditioning with cytokines and growth factors, and genetic modification of MSCs are considered to be the main strategies; all of which could contribute to improving MSC efficacy in dental regenerative medicine. Research in this field has made tremendous progress and continues to gather interest and stimulate innovation. In this review, we summarize the priming approaches for enhancing the intrinsic biological properties of MSCs such as migration, antiapoptotic effect, proangiogenic potential, and regenerative properties. Challenges in current approaches associated with MSC modification and possible future solutions are also indicated. We aim to outline the present understanding of priming approaches to improve the therapeutic effects of MSCs on dental tissue regeneration.
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Affiliation(s)
- Si-Yuan Zhang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yin Ren
- Department of Oral Radiology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Bo Yang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
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He B, Pang V, Liu X, Xu S, Zhang Y, Djuanda D, Wu G, Xu Y, Zhu Z. Interactions Among Nerve Regeneration, Angiogenesis, and the Immune Response Immediately After Sciatic Nerve Crush Injury in Sprague-Dawley Rats. Front Cell Neurosci 2021; 15:717209. [PMID: 34671243 PMCID: PMC8522912 DOI: 10.3389/fncel.2021.717209] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022] Open
Abstract
To preliminarily explore the primary changes in the expression of genes involved in peripheral nerve processes, namely, regeneration, angiogenesis, and the immune response, and to identify important molecular therapeutic targets, 45 Sprague-Dawley (SD) rats were randomly divided into a control group and an injury group. In the injury group, tissue samples were collected at 4 and 7 days after the injury for next-generation sequencing (NGS) analysis combined with gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Venn diagram construction to identify the differentially expressed mRNAs (DEmRNAs) associated with regeneration, angiogenesis, and the immune response of the nerve. The expression of genes in the distal and proximal ends of the injured nerve after injury was analyzed by qRT-PCR. NGS revealed that compared with the control group, the injury group had 4020 DEmRNAs 4 days after injury and 3278 DEmRNAs 7 days after injury. A bioinformatics analysis showed that C-C chemokine receptor type 5 (CCR5), Thy1 cell surface antigen (Thy1), Notch homolog 1 (Notch1), and semaphorin 4A (Sema4A) were all associated with regeneration, angiogenesis, and the immune response of the nerve at both 4 and 7 days after injury, but qPCR revealed no significant difference in the expression of Thy1 (P = 0.29) or Sema4A (P = 0.82) in the proximal end, whereas a significant difference was observed in CCR5 and Notch1 (P < 0.05). The trend in the Notch1 change was basically consistent with the RNA-seq result after injury, which implied its indispensable role during endothelial cell proliferation and migration, macrophage recruitment, and neurotrophic factor secretion.
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Affiliation(s)
- Bo He
- Department of Orthopaedics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Plastic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Vincent Pang
- Department of Plastic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiangxia Liu
- Department of Plastic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Plastic Surgery, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Shuqia Xu
- Department of Plastic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yi Zhang
- Department of Plastic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - David Djuanda
- Department of Plastic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guanggeng Wu
- Department of Plastic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yangbin Xu
- Department of Orthopaedics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhaowei Zhu
- Department of Orthopaedics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Liu K, Yu S, Ye L, Gao B. The Regenerative Potential of bFGF in Dental Pulp Repair and Regeneration. Front Pharmacol 2021; 12:680209. [PMID: 34354584 PMCID: PMC8329335 DOI: 10.3389/fphar.2021.680209] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/22/2021] [Indexed: 02/05/2023] Open
Abstract
Regenerative endodontic therapy intends to induce the host’s natural wound-healing process, which can restore the vitality, immunity, and sensitivity of the inflammatory or necrotic pulp tissue destroyed by infection or trauma. Myriads of growth factors are critical in the processes of pulp repair and regeneration. Among the key regulatory factors are the fibroblast growth factors, which have turned out to be the master regulators of both organogenesis and tissue homeostasis. Fibroblast growth factors, a family composed of 22 polypeptides, have been used in tissue repair and regeneration settings, in conditions as diverse as burns, ulcers, bone-related diseases, and spinal cord injuries. Meanwhile, in dentistry, the basic fibroblast growth factor is the most frequently investigated. Thereby, the aim of this review is 2-fold: 1) foremost, to explore the underlying mechanisms of the bFGF in dental pulp repair and regeneration and 2) in addition, to shed light on the potential therapeutic strategies of the bFGF in dental pulp–related clinical applications.
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Affiliation(s)
- Keyue Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Sijing Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Gao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Mangione F, Salmon B, EzEldeen M, Jacobs R, Chaussain C, Vital S. Characteristics of Large Animal Models for Current Cell-Based Oral Tissue Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:489-505. [PMID: 33882717 DOI: 10.1089/ten.teb.2020.0384] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The recent advances in the field of cell-based therapeutics open promising perspectives for oral tissue regeneration. The development of large animal models, which overcome the limits of the rodent models and allow to emulate clinical situations, is crucial for the validation of regenerative strategies to move toward clinical application. Currently, porcine, canine, and ovine models are mainly developed for oral regeneration and their specific characteristics have an impact on the outcomes of the studies. Thus, this systematic review investigates the application of porcine, canine, and ovine models in present cell-based oral regeneration, according to the species characteristics and the targeted tissue to regenerate. A customized search of PubMed, EMBASE, Scopus, and Web of Science databases from January 2015 to March 2020 was conducted. Relevant articles about cell-based oral tissues engineering in porcine, canine, and ovine models were evaluated. Among the evaluated articles, 58 relevant studies about cell-based oral regeneration in porcine, canine, and ovine models matched the eligibility criteria and were selected for full analysis. Porcine models, the most similar species with humans, were mostly used for bone and periodontium regeneration; tooth regeneration was reported only in pig, except for one study in dog. Canine models were the most transversal models, successfully involved for all oral tissue regeneration and notably in implantology. However, differences with humans and ethical concerns affect the use of these models. Ovine models, alternative to porcine and canine ones, were mainly used for bone and, scarcely, periodontium regeneration. The anatomy and physiology of these animals restrain their involvement. If consistency was found in defect specificities and cell trends among different species animal models of bone, dentin-pulp complex, or tooth regeneration, variability appeared in periodontium. Regeneration assessment methods were more elaborate in porcines and canines than in ovines. Risk of bias was low for selection, attrition and reporting, but unclear for performance and detection. Overall, if none of the large animal models can be considered an ideal one, they are of deemed importance for oral cell-based tissue engineering and researchers should consider their relevance to establish favorable conditions for a given preclinical cell-based therapeutics.
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Affiliation(s)
- Francesca Mangione
- URP 2496 Laboratory Orofacial Pathologies, Imaging and Biotherapies, Life Imaging Platform (PIV), UFR Odontology, Université de Paris, Montrouge, France.,Henri Mondor Hospital, AP-HP, Créteil, France
| | - Benjamin Salmon
- URP 2496 Laboratory Orofacial Pathologies, Imaging and Biotherapies, Life Imaging Platform (PIV), UFR Odontology, Université de Paris, Montrouge, France.,Bretonneau Hospital, AP-HP, Paris, France.,Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR, AP-HP, Paris, France
| | - Mostafa EzEldeen
- OMFS-IMPATH Research Group, Department of Imaging and Pathology, Faculty of Medicine, University of Leuven, Leuven, Belgium.,Maxillofacial Surgery Department, University Hospitals Leuven, Leuven, Belgium.,Department of Oral Health Sciences, KU Leuven and Paediatric Dentistry and Special Dental Care, University Hospitals Leuven, Leuven, Belgium
| | - Reinhilde Jacobs
- OMFS-IMPATH Research Group, Department of Imaging and Pathology, Faculty of Medicine, University of Leuven, Leuven, Belgium.,Maxillofacial Surgery Department, University Hospitals Leuven, Leuven, Belgium.,Department of Dental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Catherine Chaussain
- URP 2496 Laboratory Orofacial Pathologies, Imaging and Biotherapies, Life Imaging Platform (PIV), UFR Odontology, Université de Paris, Montrouge, France.,Bretonneau Hospital, AP-HP, Paris, France.,Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Filière OSCAR, AP-HP, Paris, France
| | - Sibylle Vital
- URP 2496 Laboratory Orofacial Pathologies, Imaging and Biotherapies, Life Imaging Platform (PIV), UFR Odontology, Université de Paris, Montrouge, France.,AP-HP, Hôpital Louis Mourier, DMU ESPRIT, Colombes, France
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Shoushrah SH, Transfeld JL, Tonk CH, Büchner D, Witzleben S, Sieber MA, Schulze M, Tobiasch E. Sinking Our Teeth in Getting Dental Stem Cells to Clinics for Bone Regeneration. Int J Mol Sci 2021; 22:6387. [PMID: 34203719 PMCID: PMC8232184 DOI: 10.3390/ijms22126387] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 12/12/2022] Open
Abstract
Dental stem cells have been isolated from the medical waste of various dental tissues. They have been characterized by numerous markers, which are evaluated herein and differentiated into multiple cell types. They can also be used to generate cell lines and iPSCs for long-term in vitro research. Methods for utilizing these stem cells including cellular systems such as organoids or cell sheets, cell-free systems such as exosomes, and scaffold-based approaches with and without drug release concepts are reported in this review and presented with new pictures for clarification. These in vitro applications can be deployed in disease modeling and subsequent pharmaceutical research and also pave the way for tissue regeneration. The main focus herein is on the potential of dental stem cells for hard tissue regeneration, especially bone, by evaluating their potential for osteogenesis and angiogenesis, and the regulation of these two processes by growth factors and environmental stimulators. Current in vitro and in vivo publications show numerous benefits of using dental stem cells for research purposes and hard tissue regeneration. However, only a few clinical trials currently exist. The goal of this review is to pinpoint this imbalance and encourage scientists to pick up this research and proceed one step further to translation.
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Affiliation(s)
| | | | | | | | | | | | | | - Edda Tobiasch
- Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig- Strasse. 20, 53359 Rheinbach, Germany; (S.H.S.); (J.L.T.); (C.H.T.); (D.B.); (S.W.); (M.A.S.); (M.S.)
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Li Q, Hu Z, Liang Y, Xu C, Hong Y, Liu X. Multifunctional peptide-conjugated nanocarriers for pulp regeneration in a full-length human tooth root. Acta Biomater 2021; 127:252-265. [PMID: 33813092 DOI: 10.1016/j.actbio.2021.03.059] [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: 01/22/2021] [Revised: 03/22/2021] [Accepted: 03/25/2021] [Indexed: 02/09/2023]
Abstract
Dental pulp is a highly vascularized tissue, situated in an inextensible environment surrounded by rigid dentinal walls. The pulp receives its blood supply solely from the small apical foramen of a tooth root. Due to the unique anatomy that controls nutrition supply, regeneration of pulp tissue in a full-length tooth root has long been a challenge in regenerative endodontics. In this study, we designed and synthesized a multifunctional peptide-conjugated, pH-sensitive, non-viral gene vector for fast revascularization and pulp regeneration in a full-length human tooth root. The multifunctional peptide was designed to have distinctive features, including a cell-penetrating peptide to enhance cellular uptake, a nuclear localization signal peptide to assist in the translocation of an angiogenic gene into the nucleus, and a fluorescent tryptophan residue to visualize and quantify the transfection efficiency. Furthermore, a pH-sensitive dimethylmaleic anhydride (DMA) was integrated with the multifunctional peptide to enhance the transfected gene complex to escape from endosomes/lysosomes after internalization. In vitro experiments showed that the multifunctional non-viral gene vector significantly increased internalization and gene transfection efficiency as well as reduced cytotoxicity. After dental pulp stem cells (DPSCs) were transfected with the multifunctional gene vector/pVEGF complexes, the expression of VEGF from the DPSCs was upregulated for more than eight folds, which in turn greatly enhanced endothelial cell migration and vascular-like tube formation. Six weeks after implantation, the VEGF-transfected DPSCs accelerated new blood vessel formation and the regenerated pulp tissue occupied most of the area in the canal of a full-length human tooth root. The multifunctional peptide conjugated non-viral gene delivery is a safe and effective approach for regenerative endodontics. STATEMENT OF SIGNIFICANCE: Pulp regeneration in a full-length tooth root canal has long been a challenge in regenerative endodontics. This is due to the unique root anatomy that allows the blood supply of the tooth root only from a small apical foramen (< 1 mm), leading to a severe barrier for revascularization during pulp regeneration. In this work, we designed a multifunctional peptide-conjugated, pH-sensitive, non-viral gene vector to address this challenge. Our work shows that the peptide-conjugated system was an excellent carrier for fast revascularization and pulp tissue regeneration in a full-length toot root. This study will interest the multidisciplinary readership in gene delivery, biomaterials, and dental/craniofacial tissue engineering community.
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Characteristics, Classification, and Application of Stem Cells Derived from Human Teeth. Stem Cells Int 2021; 2021:8886854. [PMID: 34194509 PMCID: PMC8184333 DOI: 10.1155/2021/8886854] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/12/2021] [Accepted: 05/07/2021] [Indexed: 12/31/2022] Open
Abstract
Since mesenchymal stem cells derived from human teeth are characterized as having the properties of excellent proliferation, multilineage differentiation, and immune regulation. Dental stem cells exhibit fibroblast-like microscopic appearance and express mesenchymal markers, embryonic markers, and vascular markers but do not express hematopoietic markers. Dental stem cells are a mixed population with different sensitive markers, characteristics, and therapeutic effects. Single or combined surface markers are not only helpful for understanding the subpopulation of mixed stem cell populations according to cell function but also for improving the stable treatment effect of dental stem cells. Focusing on the discovery and characterization of stem cells isolated from human teeth over the past 20 years, this review outlines the effect of marker sorting on cell proliferation and differentiation ability and the assessment of the clinical application potential. Classified dental stem cells from markers and functional molecules can solve the problem of heterogeneity and ensure the efficacy of cell therapy strategies including dentistry, neurologic diseases, bone repair, and tissue engineering.
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Novais A, Chatzopoulou E, Chaussain C, Gorin C. The Potential of FGF-2 in Craniofacial Bone Tissue Engineering: A Review. Cells 2021; 10:932. [PMID: 33920587 PMCID: PMC8073160 DOI: 10.3390/cells10040932] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/10/2021] [Accepted: 04/15/2021] [Indexed: 12/21/2022] Open
Abstract
Bone is a hard-vascularized tissue, which renews itself continuously to adapt to the mechanical and metabolic demands of the body. The craniofacial area is prone to trauma and pathologies that often result in large bone damage, these leading to both aesthetic and functional complications for patients. The "gold standard" for treating these large defects is autologous bone grafting, which has some drawbacks including the requirement for a second surgical site with quantity of bone limitations, pain and other surgical complications. Indeed, tissue engineering combining a biomaterial with the appropriate cells and molecules of interest would allow a new therapeutic approach to treat large bone defects while avoiding complications associated with a second surgical site. This review first outlines the current knowledge of bone remodeling and the different signaling pathways involved seeking to improve our understanding of the roles of each to be able to stimulate or inhibit them. Secondly, it highlights the interesting characteristics of one growth factor in particular, FGF-2, and its role in bone homeostasis, before then analyzing its potential usefulness in craniofacial bone tissue engineering because of its proliferative, pro-angiogenic and pro-osteogenic effects depending on its spatial-temporal use, dose and mode of administration.
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Affiliation(s)
- Anita Novais
- Pathologies, Imagerie et Biothérapies Orofaciales, Université de Paris, URP2496, 1 rue Maurice Arnoux, 92120 Montrouge, France; (A.N.); (E.C.); (C.C.)
- AP-HP Département d’Odontologie, Services d’odontologie, GH Pitié Salpêtrière, Henri Mondor, Paris Nord, Hôpital Rothschild, Paris, France
| | - Eirini Chatzopoulou
- Pathologies, Imagerie et Biothérapies Orofaciales, Université de Paris, URP2496, 1 rue Maurice Arnoux, 92120 Montrouge, France; (A.N.); (E.C.); (C.C.)
- AP-HP Département d’Odontologie, Services d’odontologie, GH Pitié Salpêtrière, Henri Mondor, Paris Nord, Hôpital Rothschild, Paris, France
- Département de Parodontologie, Université de Paris, UFR Odontologie-Garancière, 75006 Paris, France
| | - Catherine Chaussain
- Pathologies, Imagerie et Biothérapies Orofaciales, Université de Paris, URP2496, 1 rue Maurice Arnoux, 92120 Montrouge, France; (A.N.); (E.C.); (C.C.)
- AP-HP Département d’Odontologie, Services d’odontologie, GH Pitié Salpêtrière, Henri Mondor, Paris Nord, Hôpital Rothschild, Paris, France
| | - Caroline Gorin
- Pathologies, Imagerie et Biothérapies Orofaciales, Université de Paris, URP2496, 1 rue Maurice Arnoux, 92120 Montrouge, France; (A.N.); (E.C.); (C.C.)
- AP-HP Département d’Odontologie, Services d’odontologie, GH Pitié Salpêtrière, Henri Mondor, Paris Nord, Hôpital Rothschild, Paris, France
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Davis C, Savitz SI, Satani N. Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke. Cells 2021; 10:cells10040767. [PMID: 33807314 PMCID: PMC8065444 DOI: 10.3390/cells10040767] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.
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Bergamo MT, Zhang Z, Oliveira TM, Nör JE. VEGFR1 primes a unique cohort of dental pulp stem cells for vasculogenic differentiation. Eur Cell Mater 2021; 41:332-344. [PMID: 33724439 PMCID: PMC8561749 DOI: 10.22203/ecm.v041a21] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Dental pulp stem cells (DPSCs) constitute a unique group of cells endowed with multipotency, self-renewal, and capacity to regenerate the dental pulp tissue. While much has been learned about these cells in recent years, it is still unclear if each DPSC is multipotent or if unique sub-populations of DPSCs are "primed" to undergo specific differentiation paths. The purpose of the present study was to define whether a sub-population of DPSCs was uniquely primed to undergo vasculogenic differentiation. Permanent-tooth DPSCs or stem cells from human exfoliated deciduous teeth (SHED) were flow-sorted for vascular endothelial growth factor receptor 1 (VEGFR1) and exposed to vasculogenic differentiation medium, i.e., Microvascular-Endothelial-Cell-Growth-Medium-2-BulletKit™ supplemented with 50 ng/mL rhVEGF165 in the presence of 0 or 25 μg/mL anti-human VEGF antibody (bevacizumab; Genentech). In addition, sorted SHED (i.e., VEGFR1high or VEGFR1low) were seeded in biodegradable scaffolds and transplanted into the subcutaneous space of immunodeficient mice. Despite proliferating at a similar rate, VEGFR1high generated more in vitro sprouts than VEGFR1low cells (p < 0.05). Blockade of VEGF signaling with bevacizumab inhibited VEGFR1high-derived sprouts, demonstrating specificity of responses. Similarly, VEGFR1high SHED generated more blood vessels when transplanted into murine hosts than VEGFR1low cells (p < 0.05). Collectively, these data demonstrated that DPSCs contain a unique sub-population of cells defined by high VEGFR1 expression that are primed to differentiate into vascular endothelial cells. These data raise the possibility of purifying stem cells with high vasculogenic potential for regeneration of vascularized tissues or for vascular engineering in the treatment of ischemic conditions.
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Affiliation(s)
| | | | | | - J E Nör
- Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, 1011 N. University Rm. G049, Ann Arbor, MI 48109-1078,
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Matsubara K, Matsubara Y, Uchikura Y, Sugiyama T. Pathophysiology of Preeclampsia: The Role of Exosomes. Int J Mol Sci 2021; 22:ijms22052572. [PMID: 33806480 PMCID: PMC7961527 DOI: 10.3390/ijms22052572] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022] Open
Abstract
The pathogenesis of preeclampsia begins when a fertilized egg infiltrates the decidua, resulting in implantation failure (e.g., due to extravillous trophoblast infiltration disturbance and abnormal spiral artery remodeling). Thereafter, large amounts of serum factors (e.g., soluble fms-like tyrosine kinase 1 and soluble endoglin) are released into the blood from the hypoplastic placenta, and preeclampsia characterized by multiorgan disorder caused by vascular disorders develops. Successful implantation and placentation require immune tolerance to the fertilized egg as a semi-allograft and the stimulation of extravillous trophoblast infiltration. Recently, exosomes with diameters of 50-100 nm have been recognized to be involved in cell-cell communication. Exosomes affect cell functions in autocrine and paracrine manners via their encapsulating microRNA/DNA and membrane-bound proteins. The microRNA profiles of blood exosomes have been demonstrated to be useful for the evaluation of preeclampsia pathophysiology and prediction of the disease. In addition, exosomes derived from mesenchymal stem cells have been found to have cancer-suppressing effects. These exosomes may repair the pathophysiology of preeclampsia through the suppression of extravillous trophoblast apoptosis and promotion of these cells' invasive ability. Exosomes secreted by various cells have received much recent attention and may be involved in the maintenance of pregnancy and pathogenesis of preeclampsia.
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Affiliation(s)
- Keiichi Matsubara
- Department of Regional Pediatrics and Perinatology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan
- Correspondence:
| | - Yuko Matsubara
- Department of Obstetrics and Gynecology, Ehime University School of Medicine, Toon 791-0295, Japan; (Y.M.); (Y.U.); (T.S.)
| | - Yuka Uchikura
- Department of Obstetrics and Gynecology, Ehime University School of Medicine, Toon 791-0295, Japan; (Y.M.); (Y.U.); (T.S.)
| | - Takashi Sugiyama
- Department of Obstetrics and Gynecology, Ehime University School of Medicine, Toon 791-0295, Japan; (Y.M.); (Y.U.); (T.S.)
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Belmans N, Gilles L, Welkenhuysen J, Vermeesen R, Baselet B, Salmon B, Baatout S, Jacobs R, Lucas S, Lambrichts I, Moreels M. In vitro Assessment of the DNA Damage Response in Dental Mesenchymal Stromal Cells Following Low Dose X-ray Exposure. Front Public Health 2021; 9:584484. [PMID: 33692980 PMCID: PMC7939020 DOI: 10.3389/fpubh.2021.584484] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 01/13/2021] [Indexed: 12/11/2022] Open
Abstract
Stem cells contained within the dental mesenchymal stromal cell (MSC) population are crucial for tissue homeostasis. Assuring their genomic stability is therefore essential. Exposure of stem cells to ionizing radiation (IR) is potentially detrimental for normal tissue homeostasis. Although it has been established that exposure to high doses of ionizing radiation (IR) has severe adverse effects on MSCs, knowledge about the impact of low doses of IR is lacking. Here we investigated the effect of low doses of X-irradiation with medical imaging beam settings (<0.1 Gray; 900 mGray per hour), in vitro, on pediatric dental mesenchymal stromal cells containing dental pulp stem cells from deciduous teeth, dental follicle progenitor cells and stem cells from the apical papilla. DNA double strand break (DSB) formation and repair kinetics were monitored by immunocytochemistry of γH2AX and 53BP1 as well as cell cycle progression by flow cytometry and cellular senescence by senescence-associated β-galactosidase assay and ELISA. Increased DNA DSB repair foci, after exposure to low doses of X-rays, were measured as early as 30 min post-irradiation. The number of DSBs returned to baseline levels 24 h after irradiation. Cell cycle analysis revealed marginal effects of IR on cell cycle progression, although a slight G2/M phase arrest was seen in dental pulp stromal cells from deciduous teeth 72 h after irradiation. Despite this cell cycle arrest, no radiation-induced senescence was observed. In conclusion, low X-ray IR doses (< 0.1 Gray; 900 mGray per hour), were able to induce significant increases in the number of DNA DSBs repair foci, but cell cycle progression seems to be minimally affected. This highlights the need for more detailed and extensive studies on the effects of exposure to low IR doses on different mesenchymal stromal cells.
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Affiliation(s)
- Niels Belmans
- Morphology Group, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.,Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Liese Gilles
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium.,Environmental Risk and Health Unit, Flemish Institute for Technological Research (VITO), Mol, Belgium
| | | | - Randy Vermeesen
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Bjorn Baselet
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Benjamin Salmon
- Université de Paris, Orofacial Pathologies, Imaging and Biotherapies UR2496 Lab, Montrouge, France.,Dental Medicine Department, AP-HP, Bretonneau hospital, Paris, France
| | - Sarah Baatout
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Reinhilde Jacobs
- Oral and Maxillofacial Surgery, Dentomaxillofacial Imaging Center, Department of Imaging and Pathology, OMFS-IMPATH Research Group, and University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium.,Department Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Stéphane Lucas
- Laboratory of Analysis by Nuclear Reaction (LARN/PMR), Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium
| | - Ivo Lambrichts
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
| | - Marjan Moreels
- Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium
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50
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Miceli V, Bulati M, Iannolo G, Zito G, Gallo A, Conaldi PG. Therapeutic Properties of Mesenchymal Stromal/Stem Cells: The Need of Cell Priming for Cell-Free Therapies in Regenerative Medicine. Int J Mol Sci 2021; 22:763. [PMID: 33466583 PMCID: PMC7828743 DOI: 10.3390/ijms22020763] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/10/2021] [Accepted: 01/12/2021] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are multipotent adult stem cells that support homeostasis during tissue regeneration. In the last decade, cell therapies based on the use of MSCs have emerged as a promising strategy in the field of regenerative medicine. Although these cells possess robust therapeutic properties that can be applied in the treatment of different diseases, variables in preclinical and clinical trials lead to inconsistent outcomes. MSC therapeutic effects result from the secretion of bioactive molecules affected by either local microenvironment or MSC culture conditions. Hence, MSC paracrine action is currently being explored in several clinical settings either using a conditioned medium (CM) or MSC-derived exosomes (EXOs), where these products modulate tissue responses in different types of injuries. In this scenario, MSC paracrine mechanisms provide a promising framework for enhancing MSC therapeutic benefits, where the composition of secretome can be modulated by priming of the MSCs. In this review, we examine the literature on the priming of MSCs as a tool to enhance their therapeutic properties applicable to the main processes involved in tissue regeneration, including the reduction of fibrosis, the immunomodulation, the stimulation of angiogenesis, and the stimulation of resident progenitor cells, thereby providing new insights for the therapeutic use of MSCs-derived products.
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Affiliation(s)
- Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), 90127 Palermo, Italy; (M.B.); (G.I.); (G.Z.); (A.G.); (P.G.C.)
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