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Zhao HR, Zhao JZ, Zhao N, Xue LF, Xu YX, Yue J, Xiao WL. CA1 induced dental follicle stem cells co-culture with dental pulp stem cells and loaded three-dimensional printed PCL/β-TCP scaffold: a novel strategy for alveolar cleft bone regeneration. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2025; 36:37. [PMID: 40278949 PMCID: PMC12031973 DOI: 10.1007/s10856-025-06889-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 04/06/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND Bone tissue engineering for alveolar clefts is in the early stages of development, and more research is needed to determine the optimal cell types, growth factors and delivery methods for the therapy. METHODS We co-cultured Carbonic anhydrase 1 (CA1) induced dental follicle stem cells (DFSCs) with dental pulp stem cells (DPSCs). In vitro, the Lentivirus vector overexpressing CA1 (LV-CA1) gene was constructed, transfected into DFSCs, and co-cultured with DPSCs indirectly. Osteoblast biomarkers in differentiated DFSCs were detected using quantitative real-time polymerase chain reaction and Western blotting. In vivo, establish a rat alveolar cleft model, transplanted stem cell Polycaprolactone/β-tricalcium phosphate (PCL/β-TCP) three-dimensional printed composite scaffold and samples were collected at 4 and 8 weeks postoperatively. The osteogenic effect was evaluated through micro computed tomography and histomorphometric analysis. RESULTS In vitro, the activity of DFSCs in the LV-CA1+Co-culture group was increased, and the mRNA and protein expressions of CA1, Alkaline phosphatase (ALP), Bone morphogenetic proteins 2 (BMP2), and Runt-related transcription factor 2 (RUNX2) were amplified to varying degrees (P < 0.05). In vivo, micro-CT displayed at 4 and 8 weeks postoperatively, the LV-CA1+Co-culture group had a considerably higher percentage of new bone development (39.1% and 56.9%) (P < 0.05) than the other two groups. Histomorphometric analysis displayed the LV-CA1+Co-culture group had more newly formed bone trabeculae and immature collagen. CONCLUSION A strategy based on a novel osteogenic gene CA1 and dental-derived mesenchymal stem cells co-culture is applied to the alveolar cleft, providing a novel idea for the application of bone tissue engineering in alveolar cleft bone grafting.
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Affiliation(s)
- Hao-Ran Zhao
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Jin-Ze Zhao
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Ning Zhao
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Ling-Fa Xue
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Yao-Xiang Xu
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Jin Yue
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- School of Stomatology, Qingdao University, Qingdao, 266023, China
| | - Wen-Lin Xiao
- Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
- School of Stomatology, Qingdao University, Qingdao, 266023, China.
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Bakr MM, Al Ankily M, Shamel M. The Protective Effects of MSC-Derived Exosomes Against Chemotherapy-Induced Parotid Gland Cytotoxicity. Int J Dent 2025; 2025:5517092. [PMID: 40223864 PMCID: PMC11986938 DOI: 10.1155/ijod/5517092] [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: 01/08/2025] [Accepted: 03/13/2025] [Indexed: 04/15/2025] Open
Abstract
Background: Fluorouracil (5-FU) is one of the most popular chemotherapeutic agents used in various cancer therapy protocols. Cell-free therapy utilizing exosomes is gaining increased popularity as a safer option due to concerns over potential tumor progression following stem cell therapy. Methods: Parotid glands of albino were treated with a single bone marrow mesenchymal stem cell (BMMSC)-derived exosomes injection (100 μg/kg/dose suspended in 0.2 mL phosphate-buffered saline [PBS]), a single 5-Fu injection (20 mg/kg), and BMMSC-derived exosomes plus 5-FU and compared to control group (daily saline injections). After 30 days, the parotid glands were examined using qualitative histological evaluation, immunohistochemical evaluation using rabbit polyclonal mouse antibody to Ki-67, caspase 3, and iNOS, as well as quantitative real-time polymerase chain reaction (RT-PCR) to evaluate gene expression of TGFβ1, TNF-α, and BCL-2. Results: Histological examination of the parotid gland revealed that BMMSC-derived exosomes restored the glands' architecture and repaired most of the distortion created by 5-FU. Immunohistochemical expression of tumor proliferation and cell death markers were restored to normal levels in the exosome-treated groups that were similar to the control group. Furthermore, BMMSC-derived exosomes reversed the effects of 5-FU on quantitative gene expression levels and showed a significant decrease in TNF-α (p < 0.001) and a significant increase in TGFβ (p < 0.0001) and BCL-2 (p < 0.05) when compared to 5-FU treatment. Conclusion: Within the limitations of the current study, BMMSC-derived exosomes have the potential to counteract the cytotoxic effects of 5-FU on the parotid glands of rats in vivo. Further studies are deemed necessary to simulate clinical scenarios.
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Affiliation(s)
- Mahmoud M. Bakr
- General Dental Practice, School of Medicine and Dentistry, Griffith University, Gold Coast, Queensland 4215, Australia
| | - Mahmoud Al Ankily
- Faculty of Dentistry, Oral Biology Department, The British University in Egypt, Cairo, Egypt
| | - Mohamed Shamel
- Faculty of Dentistry, Oral Biology Department, The British University in Egypt, Cairo, Egypt
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Luo L, Wang J, Zhao J, Yang B, Ma W, Lin J. Dental pulp stem cells derived exosomes inhibit ferroptosis via regulating the Nrf2-keap1/GPX4 signaling pathway to ameliorate chronic kidney disease injury. Tissue Cell 2025; 93:102670. [PMID: 39667244 DOI: 10.1016/j.tice.2024.102670] [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: 11/09/2024] [Revised: 11/29/2024] [Accepted: 12/05/2024] [Indexed: 12/14/2024]
Abstract
INTRODUCTION Chronic kidney disease (CKD) has long represented a substantial global health challenge. Regrettably, current therapeutic interventions exhibit limited efficacy in halting the progression of CKD. Ferroptosis may play a crucial role in CKD, as indicated by substantial evidence. Dental pulp stem cell-derived exosomes (DPSC-Exos) possess advantages such as abundant sources and low immunogenicity, holding promising prospects in CKD treatment. METHODS This study constructed a mouse CKD model to investigate the therapeutic effects of DPSC-Exos. First, we successfully extracted and identified DPSC-Exos. Then, mice were randomly divided into sham, PBS, CKD, and CKD+Exos groups. Our study determined the expression of ferroptosis-related pathway molecules Nrf2, GPX4, Keap1, and HO-1 in each group. Finally, we detected the expression levels of inflammatory factors, TNF-α, IL-1β, and IL-6, at the injury site. RESULTS Mice treated with DPSC-Exos showed increased expression of the ferroptosis inhibitory factor Nrf2 and its downstream regulatory factors GPX4 and HO-1, while the expression of Keap1 decreased. The expression of TNF-α, IL-1β, and IL-6 also decreased. CONCLUSION DPSC-Exos may help inhibit ferroptosis through the Keap1-Nrf2/GPX4 pathway and reduce the inflammatory response at the injury site, revealing their potential therapeutic effects on CKD.
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Affiliation(s)
- Lin Luo
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, 999078, Macao; Department of spine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Jing Wang
- Department of spine, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Jie Zhao
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Bin Yang
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.
| | - Wenzhe Ma
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, 999078, Macao.
| | - Jiaru Lin
- Department of nephropathy, the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.
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Zubair M, Abouelnazar FA, Iqbal MA, Pan J, Zheng X, Chen T, Shen W, Yin J, Yan Y, Liu P, Mao F, Chu Y. Mesenchymal stem cell-derived exosomes as a plausible immunomodulatory therapeutic tool for inflammatory diseases. Front Cell Dev Biol 2025; 13:1563427. [PMID: 40129569 PMCID: PMC11931156 DOI: 10.3389/fcell.2025.1563427] [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: 01/20/2025] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), especially, exosomes are considered to have diverse therapeutic effects for various significant diseases. MSC-derived exosomes (MSCex) offer substantial advantages over MSCs due to their long-term preservation, stability, absence of nuclei and fewer adverse effects such as infusion toxicity, thereby paving the way towards regenerative medicine and cell-free therapeutics. These exosomes harbor several cellular contents such as DNA, RNA, lipids, metabolites, and proteins, facilitating drug delivery and intercellular communication. MSCex have the ability to immunomodulate and trigger the anti-inflammatory process hence, playing a key role in alleviating inflammation and enhancing tissue regeneration. In this review, we addressed the anti-inflammatory effects of MSCex and the underlying immunomodulatory pathways. Moreover, we discussed the recent updates on MSCex in treating specific inflammatory diseases, including arthritis, inflammatory bowel disease, inflammatory eye diseases, and respiratory diseases such as asthma and acute respiratory distress syndrome (ARDS), as well as neurodegenerative and cardiac diseases. Finally, we highlighted the challenges in using MSCex as the successful therapeutic tool and discussed future perspectives.
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Affiliation(s)
- Muhammad Zubair
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
| | - Fatma A. Abouelnazar
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Faculty of Applied Health Sciences Technology, Pharos University, Alexandria, Egypt
| | | | - Jingyun Pan
- Department of Traditional Chinese Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
| | - Xuwen Zheng
- Department of Emergency, Wujin Hospital Affiliated With Jiangsu University, Changzhou, China
| | - Tao Chen
- Department of Gastroenterology, Wujin Hospital Affiliated With Jiangsu University, Changzhou, China
| | - Wenming Shen
- Department of Emergency, Wujin Hospital Affiliated With Jiangsu University, Changzhou, China
| | - Jinnan Yin
- Department of Emergency, Wujin Hospital Affiliated With Jiangsu University, Changzhou, China
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
| | - Pengjun Liu
- Department of Gastroenterology, Wujin Hospital Affiliated With Jiangsu University, Changzhou, China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ying Chu
- Wujin Clinical College, Xuzhou Medical University, Changzhou, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China
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Chen Y, Qi W, Wang Z, Niu F. Exosome Source Matters: A Comprehensive Review from the Perspective of Diverse Cellular Origins. Pharmaceutics 2025; 17:147. [PMID: 40006514 PMCID: PMC11858990 DOI: 10.3390/pharmaceutics17020147] [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: 11/29/2024] [Revised: 01/02/2025] [Accepted: 01/14/2025] [Indexed: 02/27/2025] Open
Abstract
Exosomes have emerged as promising therapeutic agents in regenerative medicine. This review introduces a novel cell type-oriented perspective to systematically analyze exosomal properties in regenerative therapies. To our knowledge, this review is the first to comprehensively compare exosomes based on cellular source type, offering unprecedented insights into selecting optimal exosome producers for targeted regenerative applications. Factors beyond cellular origin influencing exosomal therapeutic efficacy, such as donor sites and collection methods, are also explored here. By synthesizing key advances, we propose promising research directions in the end. We aim to accelerate the development of more effective exosome-based regenerative therapies and highlight underexplored directions in this rapidly evolving field.
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Affiliation(s)
| | | | | | - Feng Niu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 33 Badachu Road, Shijingshan, Beijing 100144, China; (Y.C.)
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Chen GY, Fu LL, Ye HP, Cheng P, Feng HC, Yan M. Effects of exosomes from human dental pulp stem cells on the biological behavior of human fibroblasts. Sci Rep 2025; 15:1134. [PMID: 39774130 PMCID: PMC11707004 DOI: 10.1038/s41598-024-78388-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 10/30/2024] [Indexed: 01/11/2025] Open
Abstract
The aim of this study was to investigate the effect of dental pulp stem cell-derived exosomes (DPSCs-Exos) on the biological behaviour of fibroblasts, particularly on keloid fibroblasts (KFs) and normal skin fibroblasts (NFs), with a view to providing new insights into cellular regenerative medicine. We obtained DPSCs-Exos by ultracentrifugation and co-cultured it with KFs and NFs. We detected its effect on cell proliferation using the CCK-8 assay; cell migration ability by cell scratch and Transwell assays; extracellular matrix synthesis using the hydroxyproline content assay; the expression levels of genes associated with fibrosis by PCR assay; and the expression levels of proteins related to fibrosis in the cells using the Western Blot method. DPSCs-Exos was able to be taken up by fibroblasts after addition to the culture medium and affected the biological behavior of NFs and KFs. DPSCs-Exos promoted the proliferation of NFs, inhibited the migration and extracellular matrix synthesis of KFs. In addition, DPSCs-Exos was able to inhibit the expression of fibrosis-related genes and proteins in KFs. This study highlights the role of DPSCs-Exos in regulating the biological behaviour of fibroblasts, providing new insights for future applications in the field of cell-free regenerative medicine.
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Affiliation(s)
- Guan-Yu Chen
- College of Stomatology, Guizhou Medical University, Guiyang, 550000, China
- Department of Oral and Maxillofacial Surgery, Guiyang Hospital of Stomatology, Guiyang, 550000, China
- Department of Experimental Orofacial Medicine, Philipps University Marburg, Marburg, 35039, Germany
| | - Ling-Ling Fu
- Department of Oral Implantology, Guiyang Hospital of Stomatology, Guiyang, 550000, China
- Medical College, Guizhou University, Guiyang, 550025, China
| | - Hui-Ping Ye
- Department of Otolaryngology, Guizhou Provincial People's Hospital, Guiyang, 550000, China
| | - Ping Cheng
- Department of Clinical Laboratory, Guiyang Hospital of Stomatology, Guiyang, 550000, China
| | - Hong-Chao Feng
- College of Stomatology, Guizhou Medical University, Guiyang, 550000, China.
- Department of Oral and Maxillofacial Surgery, Guiyang Hospital of Stomatology, Guiyang, 550000, China.
| | - Ming Yan
- Department of Oral and Maxillofacial Surgery, Guiyang Hospital of Stomatology, Guiyang, 550000, China.
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Li Y, He Y. Therapeutic applications of stem cell-derived exosomes in radiation-induced lung injury. Cancer Cell Int 2024; 24:403. [PMID: 39695650 DOI: 10.1186/s12935-024-03595-9] [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: 06/04/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Radiation-induced lung injury is a common complication of chest tumor radiotherapy; however, effective clinical treatments are still lacking. Stem cell-derived exosomes, which contain various signaling molecules such as proteins, lipids, and miRNAs, not only retain the tissue repair and reconstruction properties of stem cells but also offer improved stability and safety. This presents significant potential for treating radiation-induced lung injury. Nonetheless, the clinical adoption of stem cell-derived exosomes for this purpose remains limited due to scientific, practical, and regulatory challenges. In this review, we highlight the current pathology and therapies for radiation-induced lung injury, focusing on the potential applications and therapeutic mechanisms of stem cell-derived exosomes. We also discuss the limitations of existing stem cell-derived exosomes and outline future directions for exosome-based treatments for radiation-induced lung injury.
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Affiliation(s)
- Ying Li
- Department of Radiotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yan He
- Department of Radiotherapy, West China Hospital, Sichuan University, Chengdu, China.
- Department of Cancer Center, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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Liu X, Hyun Kim J, Li X, Liu R. Application of mesenchymal stem cells exosomes as nanovesicles delivery system in the treatment of breast cancer. Int J Pharm 2024; 666:124732. [PMID: 39304093 DOI: 10.1016/j.ijpharm.2024.124732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
As people's living standards continue to improve and human life span expectancy increases, the incidence and mortality rates of breast cancer are continuously rising. Early detection of breast cancer and targeted therapy for different breast cancer subtypes can significantly reduce the mortality rate and alleviate the suffering of patients. Exosomes are extracellular vesicles secreted by various cells in the body. They participate in physiological and pathological responses by releasing active substances and play an important role in regulating intercellular communication. In recent years, research on exosomes has gradually expanded, and their special membrane structure and targetable characteristics are being increasingly applied in various clinical studies. Mesenchymal stem cells (MSCs)-derived exosomes play an important role in regulating the progression of breast cancer. In this review, we summarize the current treatment methods for breast cancer, the connection between MSCs, exosomes, and breast cancer, as well as the application of exosomes derived from MSCs from different sources in cancer treatment. We highlight how the rational design of modified MSCs-derived exosomes (MSCs-Exos) delivery systems can overcome the uncertainties of stem cell therapy and overcome the clinical translation challenges of nanomaterials. This work aims to promote future research on the application of MSCs-Exos in breast cancer treatment.
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Affiliation(s)
- Xiaofan Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea; Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China
| | - June Hyun Kim
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea
| | - Xuemei Li
- Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Makers, School of Chemistry and Chemical Engineering, Linyi University, Linyi 276005, China.
| | - Rui Liu
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Republic of Korea.
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Xu J, Zhang C, Yan Z, Fan C, Yuan S, Wang J, Zhu Y, Luo L, Shi K, Deng J. Dental Pulp Stem Cell Lysate-Based Hydrogel Improves Diabetic Wound Healing via the Regulation of Anti-Inflammatory Macrophages and Keratinocytes. ACS APPLIED BIO MATERIALS 2024; 7:7684-7699. [PMID: 39503733 DOI: 10.1021/acsabm.4c01157] [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: 11/08/2024]
Abstract
The prolonged existence of chronic wounds heightens the risk of patients experiencing chronic pain, necrosis, and amputation. Dental pulp stem cells (DPSCs) have garnered attention due to their potential immunomodulatory and tissue repair regenerative effects in the management of chronic wounds. However, stem-cell-based therapy faces challenges such as malignant differentiation, immune rejection, and long-term effectiveness. To overcome these challenges, we proposed a chronic wound therapy using a hydrogel derived from human-originated dental pulp stem cell lysate (DPSCL). Our data indicate that, with the degradation of the dental pulp stem cell lysate-based hydrogel (DPSCLH), the slowly released cell lysates recruit anti-inflammatory M2 macrophages and promote the proliferation, migration, and keratinization of HacaT cells. In addition, in vivo studies revealed that DPSCLH avoids immune rejection reactions and induces a long-term accumulation of endogenous M2 macrophages. In a mouse model of diabetic wounds, DPSCLH effectively modulates the inflammatory microenvironment around diabetic wounds, promotes the formation of the stratum corneum, and facilitates the healing of wounds, thus holding tremendous potential for the treatment of diabetic wounds.
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Affiliation(s)
- Jianghua Xu
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
| | - Changhuan Zhang
- First People's Hospital of Linping District, Hangzhou, Hangzhou, Zhejiang 311100, China
| | - Zhuo Yan
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
| | - Chen Fan
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
| | - Shanshan Yuan
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
| | - Jilong Wang
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
| | - Yuting Zhu
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
| | - Lihua Luo
- School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Keqing Shi
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Junjie Deng
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China
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Hu Z, Wang W, Lin Y, Guo H, Chen Y, Wang J, Yu F, Rao L, Fan Z. Extracellular Vesicle-Inspired Therapeutic Strategies for the COVID-19. Adv Healthc Mater 2024; 13:e2402103. [PMID: 38923772 DOI: 10.1002/adhm.202402103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Indexed: 06/28/2024]
Abstract
Emerging infectious diseases like coronavirus pneumonia (COVID-19) present significant challenges to global health, extensively affecting both human society and the economy. Extracellular vesicles (EVs) have demonstrated remarkable potential as crucial biomedical tools for COVID-19 diagnosis and treatment. However, due to limitations in the performance and titer of natural vesicles, their clinical use remains limited. Nonetheless, EV-inspired strategies are gaining increasing attention. Notably, biomimetic vesicles, inspired by EVs, possess specific receptors that can act as "Trojan horses," preventing the virus from infecting host cells. Genetic engineering can enhance these vesicles by enabling them to carry more receptors, significantly increasing their specificity for absorbing the novel coronavirus. Additionally, biomimetic vesicles inherit numerous cytokine receptors from parent cells, allowing them to effectively mitigate the "cytokine storm" by adsorbing pro-inflammatory cytokines. Overall, this EV-inspired strategy offers new avenues for the treatment of emerging infectious diseases. Herein, this review systematically summarizes the current applications of EV-inspired strategies in the diagnosis and treatment of COVID-19. The current status and challenges associated with the clinical implementation of EV-inspired strategies are also discussed. The goal of this review is to provide new insights into the design of EV-inspired strategies and expand their application in combating emerging infectious diseases.
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Affiliation(s)
- Ziwei Hu
- Institute of Otolaryngology Head and neck surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510282, P. R. China
| | - Wei Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Ying Lin
- Institute of Otolaryngology Head and neck surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510282, P. R. China
| | - Hui Guo
- Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, P. R. China
| | - Yiwen Chen
- Institute of Otolaryngology Head and neck surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510282, P. R. China
| | - Junjie Wang
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, P. R. China
| | - Feng Yu
- Institute of Otolaryngology Head and neck surgery, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510282, P. R. China
| | - Lang Rao
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, P. R. China
| | - Zhijin Fan
- Institute for Engineering Medicine, Kunming Medical University, Kunming, 650500, P. R. China
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Saikia B, Dhanushkodi A. Engineered exosome therapeutics for neurodegenerative diseases. Life Sci 2024; 356:123019. [PMID: 39209250 DOI: 10.1016/j.lfs.2024.123019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 08/14/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
An increase in life expectancy comes with a higher risk for age-related neurological and cognitive dysfunctions. Given the psycho-socioeconomic burden due to unhealthy aging in the coming decades, the United Nations has declared 2021-2030 as a decade of healthy aging. In this line, multipotent mesenchymal stromal cell-based therapeutics received special interest from the research community. Based on decades of research on cell therapy, a consensus has emerged that the therapeutic effects of cell therapy are due to the paracrine mechanisms rather than cell replacement. Exosomes, a constituent of the secretome, are nano-sized vesicles that have been a focus of intense research in recent years as a possible therapeutic agent or as a cargo to deliver drugs of interest into the central nervous system to induce neurogenesis, reduce neuroinflammation, confer neuroregeneration/neuroprotection, and improve cognitive and motor functions. In this review, we have discussed the neuroprotective properties of exosomes derived from adult mesenchymal stem cells, with a special focus on the role of exosomal miRNAs. We also reviewed various strategies to improve exosome production and their content for better therapeutic effects. Further, we discussed the utilization of ectomesenchymal stem cells like dental pulp stem cells and their exosomes in treating neurodegenerative diseases.
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Affiliation(s)
- Biplob Saikia
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Manipal, India
| | - Anandh Dhanushkodi
- Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education, Manipal, India.
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12
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Xia EJ, Zou S, Zhao X, Liu W, Zhang Y, Zhao IS. Extracellular vesicles as therapeutic tools in regenerative dentistry. Stem Cell Res Ther 2024; 15:365. [PMID: 39402576 PMCID: PMC11476107 DOI: 10.1186/s13287-024-03936-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 09/13/2024] [Indexed: 10/19/2024] Open
Abstract
Dental and maxillofacial diseases are always accompanied by complicated hard and soft tissue defects, involving bone, teeth, blood vessels and nerves, which are difficult to repair and severely affect the life quality of patients. Recently, extracellular vesicles (EVs) secreted by all types of cells and extracted from body fluids have gained more attention as potential solutions for tissue regeneration due to their special physiological characteristics and intrinsic signaling molecules. Compared to stem cells, EVs present lower immunogenicity and tumorigenicity, cause fewer ethical problems, and have higher stability. Thus, EV therapy may have a broad clinical application in regenerative dentistry. Herein, we reviewed the currently available literature regarding the functional roles of EVs in oral and maxillofacial tissue regeneration, including in maxilla and mandible bone, periodontal tissues, temporomandibular joint cartilage, dental hard tissues, peripheral nerves and soft tissues. We also summarized the underlying mechanisms of actions of EVs and their delivery strategies for dental tissue regeneration. This review would provide helpful guidelines and valuable insights into the emerging potential of EVs in future research and clinical applications in regenerative dentistry.
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Affiliation(s)
- Evelyn Jingwen Xia
- School of Dentistry, Shenzhen University Medical School, 1088 Xueyuan Ave, Shenzhen, 518015, China
| | - Shasha Zou
- Longgang Center for Chronic Disease Control, Shenzhen, 518172, China
| | - Xiu Zhao
- Department of Stomatology, Shenzhen University General Hospital, Shenzhen, 518015, China
| | - Wei Liu
- Department of Stomatology, Shenzhen University General Hospital, Shenzhen, 518015, China
| | - Yang Zhang
- School of Dentistry, Shenzhen University Medical School, 1088 Xueyuan Ave, Shenzhen, 518015, China.
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, 518015, China.
| | - Irene Shuping Zhao
- School of Dentistry, Shenzhen University Medical School, 1088 Xueyuan Ave, Shenzhen, 518015, China.
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13
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Yoshimaru K, Matsuura T, Uchida Y, Sonoda S, Maeda S, Kajihara K, Kawano Y, Shirai T, Toriigahara Y, Kalim AS, Zhang XY, Takahashi Y, Kawakubo N, Nagata K, Yamaza H, Yamaza T, Taguchi T, Tajiri T. Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders. Surg Today 2024; 54:977-994. [PMID: 37668735 DOI: 10.1007/s00595-023-02741-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 08/06/2023] [Indexed: 09/06/2023]
Abstract
Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.
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Affiliation(s)
- Koichiro Yoshimaru
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Yasuyuki Uchida
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Soichiro Sonoda
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Shohei Maeda
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Keisuke Kajihara
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yuki Kawano
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takeshi Shirai
- Department of Pediatric Surgery, Miyazaki Prefectural Miyazaki Hospital, 5-30 Kitatakamatsu-cho, Miyazaki, Miyazaki, 880-8510, Japan
| | - Yukihiro Toriigahara
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Alvin Santoso Kalim
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Xiu-Ying Zhang
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoshiaki Takahashi
- Department of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757, Asahimachi-dori, Chuo-ku, Niigata, Japan
| | - Naonori Kawakubo
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kouji Nagata
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Haruyoshi Yamaza
- Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takayoshi Yamaza
- Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tomoaki Taguchi
- Fukuoka College of Health Sciences, 2-15-1 Tamura, Sawara-ku, Fukuoka, 814-0193, Japan
| | - Tatsuro Tajiri
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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14
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Umar S, Debnath K, Leung K, Huang CC, Lu Y, Gajendrareddy P, Ravindran S. Immunomodulatory properties of naïve and inflammation-informed dental pulp stem cell derived extracellular vesicles. Front Immunol 2024; 15:1447536. [PMID: 39224602 PMCID: PMC11366660 DOI: 10.3389/fimmu.2024.1447536] [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: 06/11/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
Mesenchymal stem cell derived extracellular vesicles (MSC EVs) are paracrine modulators of macrophage function. Scientific research has primarily focused on the immunomodulatory and regenerative properties MSC EVs derived from bone marrow. The dental pulp is also a source for MSCs, and their anatomical location and evolutionary function has primed them to be potent immunomodulators. In this study, we demonstrate that extracellular vesicles derived from dental pulp stem cells (DPSC EVs) have pronounced immunomodulatory effect on primary macrophages by regulating the NFκb pathway. Notably, the anti-inflammatory activity of DPSC-EVs is enhanced following exposure to an inflammatory stimulus (LPS). These inhibitory effects were also observed in vivo. Sequencing of the naïve and LPS preconditioned DPSC-EVs and comparison with our published results from marrow MSC EVs revealed that Naïve and LPS preconditioned DPSC-EVs are enriched with anti-inflammatory miRNAs, particularly miR-320a-3p, which appears to be unique to DPSC-EVs and regulates the NFκb pathway. Overall, our findings highlight the immunomodulatory properties of DPSC-EVs and provide vital clues that can stimulate future research into miRNA-based EV engineering as well as therapeutic approaches to inflammation control and disease treatment.
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Affiliation(s)
- Sadiq Umar
- Department of Oral Biology, University of Illinois, Chicago, IL, United States
| | - Koushik Debnath
- Department of Oral Biology, University of Illinois, Chicago, IL, United States
| | - Kasey Leung
- Department of Oral Biology, University of Illinois, Chicago, IL, United States
| | - Chun-Chieh Huang
- Department of Oral Biology, University of Illinois, Chicago, IL, United States
| | - Yu Lu
- Department of Oral Biology, University of Illinois, Chicago, IL, United States
| | | | - Sriram Ravindran
- Department of Oral Biology, University of Illinois, Chicago, IL, United States
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15
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Ning X, Liu R, Huang Y, Huang Z, Li H, Li Q, Sheng Z, Wu J. Dental Stem Cell-Derived Exosomes: A Review of Their Isolation, Classification, Functions, and Mechanisms. Stem Cells Int 2024; 2024:2187392. [PMID: 39184549 PMCID: PMC11343633 DOI: 10.1155/2024/2187392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 07/12/2024] [Accepted: 07/25/2024] [Indexed: 08/27/2024] Open
Abstract
The scientific field concerned with the study of regeneration has developed rapidly in recent years. Stem cell therapy is a highly promising therapeutic modality for repairing tissue defects; however, several limitations exist, such as cytotoxicity, potential immune rejection, and ethical issues. Exosomes secreted by stem cells are cell-specific secreted vesicles that play a regulatory role in many biological functions in the human body; they not only have a series of functional roles of stem cells and exert the expected therapeutic effects, but they can also overcome the mass limitations of stem cells and are thus considered in the research as an alternative treatment strategy for stem cells. Since dental stem cell-derived exosomes (DSC-Exos) are easy to acquire and present modulating effects in several fields, including neurovascular regeneration and craniofacial soft and hard tissue regeneration processes, they are served as an emerging cell-free therapeutic strategy in various systematic diseases. There is a growing body of research on various types of DSC-Exos; however, they lack systematic elaboration and tabular summarization. Therefore, this review presents the isolation, characterization, and phenotypes of DSC-Exos and focuses on their current status of functions and mechanisms, as well as the multiple challenges prior to clinical applications.
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Affiliation(s)
- Xiner Ning
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Rui Liu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and RegenerationNational Clinical Research Center for Oral DiseasesShaanxi Key Laboratory of StomatologyNursing DepartmentSchool of StomatologyThe Fourth Military Medical University, Xi'an 710032, China
| | - Yingying Huang
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Zhilong Huang
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Haodi Li
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Qiqi Li
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Zengyan Sheng
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
| | - Junjie Wu
- Department of OrthodonticsSchool of StomatologyState Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral DiseasesThe Fourth Military Medical University, Xi'an 710032, China
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16
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Liang X, Miao Y, Tong X, Chen J, Liu H, He Z, Liu A, Hu Z. Dental pulp mesenchymal stem cell-derived exosomes inhibit neuroinflammation and microglial pyroptosis in subarachnoid hemorrhage via the miRNA-197-3p/FOXO3 axis. J Nanobiotechnology 2024; 22:426. [PMID: 39030593 PMCID: PMC11264715 DOI: 10.1186/s12951-024-02708-w] [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: 01/19/2024] [Accepted: 07/05/2024] [Indexed: 07/21/2024] Open
Abstract
BACKGROUND Subarachnoid hemorrhage (SAH) is a severe stroke subtype that lacks effective treatment. Exosomes derived from human dental pulp stem cells (DPSCs) are a promising acellular therapeutic strategy for neurological diseases. However, the therapeutic effects of DPSC-derived exosomes (DPSC-Exos) on SAH remain unknown. In this study, we investigated the therapeutic effects and mechanisms of action of DPSC-Exos in SAH. MATERIALS AND METHODS SAH was established using 120 male Sprague-Dawley rats. One hour after SAH induction, DPSC-Exos were administered via tail vein injection. To investigate the effect of DPSC-Exos, SAH grading, short-term and long-term neurobehavioral assessments, brain water content, western blot (WB), immunofluorescence staining, Nissl staining, and HE staining were performed. The role of miR-197-3p/FOXO3 in regulating pyroptosis was demonstrated through miRNA sequencing, bioinformatics analysis, and rescue experiments. The SAH model in vitro was established by stimulating BV2 cells with hemoglobin (Hb) and the underlying mechanism of DPSC-Exos was investigated through WB and Hoechst/PI staining. RESULTS The expressions of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) were increased after SAH. DPSC-Exos alleviated brain edema and neuroinflammation by inhibiting the expression of FOXO3 and reducing NLRP3 inflammasome activation, leading to improved neurobehavioral functions at 24 h after SAH. In vitro, the expression of the NLRP3 inflammasome components (NLRP3 and caspase1-p20), GSDMD-N, and IL-18 was inhibited in BV2 cells pretreated with DPSC-Exos. Importantly, DPSC-Exos overexpressing miR-197-3p had a more obvious protective effect than those from NC-transfected DPSCs, while those from DPSCs transfected with the miR-197-3p inhibitor had a weaker protective effect. Functional studies indicated that miR-197-3p bound to the 3'-untranslated region of FOXO3, inhibiting its transcription. Furthermore, the overexpression of FOXO3 reversed the protective effects of miR-197-3p. CONCLUSIONS DPSC-Exos inhibited activation of the NLRP3 inflammasome and related cytokine release via the miR-197-3p/FOXO3 pathway, alleviated neuroinflammation, and inhibited microglial pyroptosis. These findings suggest that using DPSC-Exos is a promising therapeutic strategy for SAH.
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Affiliation(s)
- Xin Liang
- Department of Neurosurgery, Affiliated Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
- Department of Neurosurgery, Affiliated Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Yan Miao
- Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Xin Tong
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- Cerebrovascular Disease Department, Neurological Disease Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jigang Chen
- Department of burn and plastic surgery, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
| | - Hongyi Liu
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
- School of Biomedical Engineering, Capital Medical University, Beijing, 100069, China
| | - Zilong He
- Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Aihua Liu
- Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
- Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
- Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
- China National Clinical Research Centre for Neurological Diseases, Beijing, 100070, China.
| | - Zhiqiang Hu
- Department of Neurosurgery, Affiliated Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
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Yang K, Zhu Y, Shao Y, Jiang Y, Zhu L, Liu Y, Zhang P, Liu Y, Zhang X, Zhou Y. Apoptotic Vesicles Derived from Dental Pulp Stem Cells Promote Bone Formation through the ERK1/2 Signaling Pathway. Biomedicines 2024; 12:730. [PMID: 38672086 PMCID: PMC11048106 DOI: 10.3390/biomedicines12040730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/12/2024] [Accepted: 03/20/2024] [Indexed: 04/28/2024] Open
Abstract
Osteoporosis is a common degenerative bone disease. The treatment of osteoporosis remains a clinical challenge in light of the increasing aging population. Human dental pulp stem cells (DPSCs), a type of mesenchymal stem cells (MSCs), are easy to obtain and have a high proliferation ability, playing an important role in the treatment of osteoporosis. However, MSCs undergo apoptosis within a short time when used in vivo; therefore, apoptotic vesicles (apoVs) have attracted increasing attention. Currently, the osteogenic effect of DPSC-derived apoVs is unknown; therefore, this study aimed to determine the role of DPSC-derived apoVs and their potential mechanisms in bone regeneration. We found that MSCs could take up DPSC-derived apoVs, which then promoted MSC osteogenesis in vitro. Moreover, apoVs could increase the trabecular bone count and bone mineral density in the mouse osteoporosis model and could promote bone formation in rat cranial defects in vivo. Mechanistically, apoVs promoted MSC osteogenesis by activating the extracellular regulated kinase (ERK)1/2 signaling pathway. Consequently, we propose a novel therapy comprising DPSC-derived apoVs, representing a promising approach to treat bone loss and bone defects.
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Affiliation(s)
- Kunkun Yang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Yuan Zhu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Yuzi Shao
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Yuhe Jiang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Lei Zhu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Yaoshan Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Ping Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Yunsong Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Xiao Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
| | - Yongsheng Zhou
- Department of Prosthodontics, Peking University School and Hospital of Stomatology, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China; (K.Y.); (Y.Z.); (Y.S.); (Y.J.); (L.Z.); (Y.L.); (P.Z.); (Y.L.)
- National Center of Stomatology, National Clinical Research Center for Oral Disease, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Key Laboratory of Digital Stomatology, NMPA Key Laboratory for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, China
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Chang H, Chen E, Hu Y, Wu L, Deng L, Ye‐Lehmann S, Mao X, Zhu T, Liu J, Chen C. Extracellular Vesicles: The Invisible Heroes and Villains of COVID-19 Central Neuropathology. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305554. [PMID: 38143270 PMCID: PMC10933635 DOI: 10.1002/advs.202305554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/18/2023] [Indexed: 12/26/2023]
Abstract
Acknowledging the neurological symptoms of COVID-19 and the long-lasting neurological damage even after the epidemic ends are common, necessitating ongoing vigilance. Initial investigations suggest that extracellular vesicles (EVs), which assist in the evasion of the host's immune response and achieve immune evasion in SARS-CoV-2 systemic spreading, contribute to the virus's attack on the central nervous system (CNS). The pro-inflammatory, pro-coagulant, and immunomodulatory properties of EVs contents may directly drive neuroinflammation and cerebral thrombosis in COVID-19. Additionally, EVs have attracted attention as potential candidates for targeted therapy in COVID-19 due to their innate homing properties, low immunogenicity, and ability to cross the blood-brain barrier (BBB) freely. Mesenchymal stromal/stem cell (MSCs) secreted EVs are widely applied and evaluated in patients with COVID-19 for their therapeutic effect, considering the limited antiviral treatment. This review summarizes the involvement of EVs in COVID-19 neuropathology as carriers of SARS-CoV-2 or other pathogenic contents, as predictors of COVID-19 neuropathology by transporting brain-derived substances, and as therapeutic agents by delivering biotherapeutic substances or drugs. Understanding the diverse roles of EVs in the neuropathological aspects of COVID-19 provides a comprehensive framework for developing, treating, and preventing central neuropathology and the severe consequences associated with the disease.
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Affiliation(s)
- Haiqing Chang
- Department of AnesthesiologyWest China HospitalSichuan UniversityLaboratory of Anesthesia and Critical Care MedicineNational‐Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyWest China HospitalSichuan UniversityChengduSichuan610041China
| | - Erya Chen
- Department of AnesthesiologyWest China HospitalSichuan UniversityLaboratory of Anesthesia and Critical Care MedicineNational‐Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyWest China HospitalSichuan UniversityChengduSichuan610041China
| | - Yi Hu
- Department of Cardiology, Honghui hospitalXi'an Jiaotong UniversityXi'an710049China
| | - Lining Wu
- Department of AnesthesiologyWest China HospitalSichuan UniversityLaboratory of Anesthesia and Critical Care MedicineNational‐Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyWest China HospitalSichuan UniversityChengduSichuan610041China
| | - Liyun Deng
- Department of AnesthesiologyWest China HospitalSichuan UniversityLaboratory of Anesthesia and Critical Care MedicineNational‐Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyWest China HospitalSichuan UniversityChengduSichuan610041China
| | - Shixin Ye‐Lehmann
- Diseases and Hormones of the Nervous System University of Paris‐Scalay Bicêtre Hosptial BâtGrégory Pincus 80 Rue du Gal Leclerc, CedexLe Kremlin Bicêtre94276France
| | - Xiaobo Mao
- Department of NeurologyInstitute of Cell EngineeringSchool of MedicineJohns Hopkins UniversityBaltimoreMD21218USA
| | - Tao Zhu
- Department of AnesthesiologyWest China HospitalSichuan UniversityLaboratory of Anesthesia and Critical Care MedicineNational‐Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyWest China HospitalSichuan UniversityChengduSichuan610041China
| | - Jin Liu
- Department of AnesthesiologyWest China HospitalSichuan UniversityLaboratory of Anesthesia and Critical Care MedicineNational‐Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyWest China HospitalSichuan UniversityChengduSichuan610041China
| | - Chan Chen
- Department of AnesthesiologyWest China HospitalSichuan UniversityLaboratory of Anesthesia and Critical Care MedicineNational‐Local Joint Engineering Research Centre of Translational Medicine of AnesthesiologyWest China HospitalSichuan UniversityChengduSichuan610041China
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19
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Liu Y, Xiong W, Li J, Feng H, Jing S, Liu Y, Zhou H, Li D, Fu D, Xu C, He Y, Ye Q. Application of dental pulp stem cells for bone regeneration. Front Med (Lausanne) 2024; 11:1339573. [PMID: 38487022 PMCID: PMC10938947 DOI: 10.3389/fmed.2024.1339573] [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: 11/16/2023] [Accepted: 01/15/2024] [Indexed: 03/17/2024] Open
Abstract
Bone defects resulting from severe trauma, tumors, inflammation, and other factors are increasingly prevalent. Stem cell-based therapies have emerged as a promising alternative. Dental pulp stem cells (DPSCs), sourced from dental pulp, have garnered significant attention owing to their ready accessibility and minimal collection-associated risks. Ongoing investigations into DPSCs have revealed their potential to undergo osteogenic differentiation and their capacity to secrete a diverse array of ontogenetic components, such as extracellular vesicles and cell lysates. This comprehensive review article aims to provide an in-depth analysis of DPSCs and their secretory components, emphasizing extraction techniques and utilization while elucidating the intricate mechanisms governing bone regeneration. Furthermore, we explore the merits and demerits of cell and cell-free therapeutic modalities, as well as discuss the potential prospects, opportunities, and inherent challenges associated with DPSC therapy and cell-free therapies in the context of bone regeneration.
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Affiliation(s)
- Ye Liu
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Xiong
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
| | - Junyi Li
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
| | - Huixian Feng
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
| | - Shuili Jing
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
| | - Yonghao Liu
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
| | - Heng Zhou
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
| | - Duan Li
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
| | - Dehao Fu
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chun Xu
- Sydney Dental School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital of Wuhan University of Science and Technology, Wuhan, China
- Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Qingsong Ye
- Center of Regenerative Medicine, Department of Stomatology Renmin Hospital of Wuhan University, Wuhan, China
- Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
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20
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Poblano-Pérez LI, Castro-Manrreza ME, González-Alva P, Fajardo-Orduña GR, Montesinos JJ. Mesenchymal Stromal Cells Derived from Dental Tissues: Immunomodulatory Properties and Clinical Potential. Int J Mol Sci 2024; 25:1986. [PMID: 38396665 PMCID: PMC10888494 DOI: 10.3390/ijms25041986] [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: 12/30/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells located in different areas of the human body. The oral cavity is considered a potential source of MSCs because they have been identified in several dental tissues (D-MSCs). Clinical trials in which cells from these sources were used have shown that they are effective and safe as treatments for tissue regeneration. Importantly, immunoregulatory capacity has been observed in all of these populations; however, this function may vary among the different types of MSCs. Since this property is of clinical interest for cell therapy protocols, it is relevant to analyze the differences in immunoregulatory capacity, as well as the mechanisms used by each type of MSC. Interestingly, D-MSCs are the most suitable source for regenerating mineralized tissues in the oral region. Furthermore, the clinical potential of D-MSCs is supported due to their adequate capacity for proliferation, migration, and differentiation. There is also evidence for their potential application in protocols against autoimmune diseases and other inflammatory conditions due to their immunosuppressive capacity. Therefore, in this review, the immunoregulatory mechanisms identified at the preclinical level in combination with the different types of MSCs found in dental tissues are described, in addition to a description of the clinical trials in which MSCs from these sources have been applied.
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Affiliation(s)
- Luis Ignacio Poblano-Pérez
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
| | - Marta Elena Castro-Manrreza
- Immunology and Stem Cells Laboratory, FES Zaragoza, National Autonomous University of Mexico (UNAM), Mexico City 09230, Mexico;
| | - Patricia González-Alva
- Tissue Bioengineering Laboratory, Postgraduate Studies, Research Division, Faculty of Dentistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico;
| | - Guadalupe R. Fajardo-Orduña
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
| | - Juan José Montesinos
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
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21
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Miron RJ, Zhang Y. Understanding exosomes: Part 1-Characterization, quantification and isolation techniques. Periodontol 2000 2024; 94:231-256. [PMID: 37740431 DOI: 10.1111/prd.12520] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/21/2023] [Accepted: 07/25/2023] [Indexed: 09/24/2023]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with a diameter in the range of 30-150 nm. Their use has gained great momentum recently due to their ability to be utilized as diagnostic tools with a vast array of therapeutic applications. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be investigated. This review article first focuses on understanding exosomes, including their cellular origin, biogenesis, function, and characterization. Thereafter, overviews of the quantification methods and isolation techniques are given with discussion over their potential use as novel therapeutics in regenerative medicine.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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22
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Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: Part 3-therapeutic + diagnostic potential in dentistry. Periodontol 2000 2024; 94:415-482. [PMID: 38546137 DOI: 10.1111/prd.12557] [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: 12/18/2023] [Revised: 02/05/2024] [Accepted: 02/11/2024] [Indexed: 05/18/2024]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of various diseases. Over 5000 publications are currently being published on this topic yearly, many of which in the dental space. This extensive review article is the first scoping review aimed at summarizing all therapeutic uses of exosomes in regenerative dentistry. A total of 944 articles were identified as using exosomes in the dental field for either their regenerative/therapeutic potential or for diagnostic purposes derived from the oral cavity. In total, 113 research articles were selected for their regenerative potential (102 in vitro, 60 in vivo, 50 studies included both). Therapeutic exosomes were most commonly derived from dental pulps, periodontal ligament cells, gingival fibroblasts, stem cells from exfoliated deciduous teeth, and the apical papilla which have all been shown to facilitate the regenerative potential of a number of tissues including bone, cementum, the periodontal ligament, nerves, aid in orthodontic tooth movement, and relieve temporomandibular joint disorders, among others. Results demonstrate that the use of exosomes led to positive outcomes in 100% of studies. In the bone field, exosomes were found to perform equally as well or better than rhBMP2 while significantly reducing inflammation. Periodontitis animal models were treated with simple gingival injections of exosomes and benefits were even observed when the exosomes were administered intravenously. Exosomes are much more stable than growth factors and were shown to be far more resistant against degradation by periodontal pathogens found routinely in a periodontitis environment. Comparative studies in the field of periodontal regeneration found better outcomes for exosomes even when compared to their native parent stem cells. In total 47 diagnostic studies revealed a role for salivary/crevicular fluid exosomes for the diagnosis of birth defects, cardiovascular disease, diabetes, gingival recession detection, gingivitis, irritable bowel syndrome, neurodegenerative disease, oral lichen planus, oral squamous cell carcinoma, oropharyngeal cancer detection, orthodontic root resorption, pancreatic cancer, periodontitis, peri-implantitis, Sjögren syndrome, and various systemic diseases. Hence, we characterize the exosomes as possessing "remarkable" potential, serving as a valuable tool for clinicians with significant advantages.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
- Advanced PRF Education, Venice, Florida, USA
| | - Nathan E Estrin
- Advanced PRF Education, Venice, Florida, USA
- School of Dental Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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23
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Rupareliya M, Shende P. Therapeutic Potential of Stem Cells in Natural Killer-Like B Cell-Associated Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1470:57-72. [PMID: 38418797 DOI: 10.1007/5584_2024_799] [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: 03/02/2024]
Abstract
Stem cells are undifferentiated cells possessing a remarkable capacity to develop into multiple cell types. NKB cells, referred to "natural killer-like B cells," are recently identified subtype of B lymphocytes possessing characteristics that are similar to both natural killer (NK) cells and regular B lymphocytes. NK cells are lymphocyte-like in structure and cytotoxic in nature participating in the immediate immune response to the infected or malignant cells, whereas B lymphocytes produce antibodies and participate in adaptive immune response by binding to the specific antigen. The identification of NKB cells brings up new possibilities for studying and perhaps modulating immune responses in a variety of diseases, particularly those associated with microbial infections or inflammatory responses. Further, correlation of NKB cells with interleukins allows us to understand the molecular mechanism of diseases. Stem cell research offers a better understanding of NKB cell participation and provides new insights for novel treatment methods wherein mesenchymal stem cells (MSCs) have found to be the most promising stem cell showing positive outcomes in NKB cell-associated inflammatory diseases. Additionally, the perceptions acquired from researching NKB cells in diverse diseases leads to innovative treatment options, improving our capacity to control and cure immunological dysregulation-related ailments.
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Affiliation(s)
- Manali Rupareliya
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, Mumbai, India
| | - Pravin Shende
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, Mumbai, India.
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24
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Naeem A, Waseem A, Siddiqui AJ, Ray B, Sinha R, Khan AQ, Haque R, Raza SS. Focusing on the cytokine storm in the battle against COVID-19: the rising role of mesenchymal-derived stem cells. Stem Cells 2024:191-207. [DOI: 10.1016/b978-0-323-95545-4.00008-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Luo H, Birjandi AA, Ren F, Sun T, Sharpe PT, Sun H, An Z. Advances in oral mesenchymal stem cell-derived extracellular vesicles in health and disease. Genes Dis 2024; 11:346-357. [PMID: 37588220 PMCID: PMC10425856 DOI: 10.1016/j.gendis.2023.03.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/08/2023] [Accepted: 03/15/2023] [Indexed: 08/18/2023] Open
Abstract
Extracellular vesicles (EVs) are nano-size vesicles secreted naturally by all cells into the extracellular space and have been recognized as important cell-cell mediators in multicellular organisms. EVs contain nucleic acids, proteins, lipids, and other cellular components, regulating many basic biological processes and playing an important role in regenerative medicine and diseases. EVs can be traced to their cells of origin and exhibit a similar function. Moreover, EVs demonstrate low immunogenicity, good biocompatibility, and fewer side effects, compared to their parent cells. Mesenchymal stem cells (MSCs) are one of the most important resource cells for EVs, with a great capacity for self-renewal and multipotent differentiation, and play an essential role in stem cell therapy. The mechanism of MSC therapy was thought to be attributed to the differentiation of MSCs after targeted migration, as previously noted. However, emerging evidence shows the previously unknown role of MSC-derived paracrine factors in stem cell therapy. Especially EVs derived from oral tissue MSCs (OMSC-EVs), show more advantages than those of all other MSCs in tissue repair and regeneration, due to their lower invasiveness and easier accessibility for sample collection. Here, we systematically review the biogenesis and biological characteristics of OMSC-EVs, as well as the role of OMSC-EVs in intercellular communication. Furthermore, we discuss the potential therapeutic roles of OMSC-EVs in oral and systemic diseases. We highlight the current challenges and future directions of OMSC-EVs to focus more attention on clinical translation. We aim to provide valuable insights for the explorative clinical application of OMSC-EVs.
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Affiliation(s)
- Huanyu Luo
- Department of Oral Biology, Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, China
| | - Anahid Ahmadi Birjandi
- Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Craniofacial and Regenerative Biology, King's College London, London, SE1 9RT, UK
| | - Feilong Ren
- Department of Oral Biology, Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, China
| | - Tianmeng Sun
- Department of Oral Biology, Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, China
| | - Paul T. Sharpe
- Faculty of Dentistry, Oral & Craniofacial Sciences, Centre for Craniofacial and Regenerative Biology, King's College London, London, SE1 9RT, UK
| | - Hongchen Sun
- Department of Oral Pathology, Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, China
| | - Zhengwen An
- Department of Oral Biology, Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, China
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26
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Wang J, Tian F, Cao L, Du R, Tong J, Ding X, Yuan Y, Wang C. Macrophage polarization in spinal cord injury repair and the possible role of microRNAs: A review. Heliyon 2023; 9:e22914. [PMID: 38125535 PMCID: PMC10731087 DOI: 10.1016/j.heliyon.2023.e22914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 11/17/2023] [Accepted: 11/22/2023] [Indexed: 12/23/2023] Open
Abstract
The prevention, treatment, and rehabilitation of spinal cord injury (SCI) have always posed significant medical challenges. After mechanical injury, disturbances in microcirculation, edema formation, and the generation of free radicals lead to additional damage, impeding effective repair processes and potentially exacerbating further dysfunction. In this context, inflammatory responses, especially the activation of macrophages, play a pivotal role. Different phenotypes of macrophages have distinct effects on inflammation. Activation of classical macrophage cells (M1) promotes inflammation, while activation of alternative macrophage cells (M2) inhibits inflammation. The polarization of macrophages is crucial for disease healing. A non-coding RNA, known as microRNA (miRNA), governs the polarization of macrophages, thereby reducing inflammation following SCI and facilitating functional recovery. This study elucidates the inflammatory response to SCI, focusing on the infiltration of immune cells, specifically macrophages. It examines their phenotype and provides an explanation of their polarization mechanisms. Finally, this paper introduces several well-known miRNAs that contribute to macrophage polarization following SCI, including miR-155, miR-130a, and miR-27 for M1 polarization, as well as miR-22, miR-146a, miR-21, miR-124, miR-223, miR-93, miR-132, and miR-34a for M2 polarization. The emphasis is placed on their potential therapeutic role in SCI by modulating macrophage polarization, as well as the present developments and obstacles of miRNA clinical therapy.
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Affiliation(s)
- Jiawei Wang
- School and Hospital of Stomatology, Shanxi Medical University, Shanxi Taiyuan, China
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Taiyuan, China
| | - Feng Tian
- School and Hospital of Stomatology, Shanxi Medical University, Shanxi Taiyuan, China
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Taiyuan, China
| | - Lili Cao
- School and Hospital of Stomatology, Shanxi Medical University, Shanxi Taiyuan, China
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Taiyuan, China
| | - Ruochen Du
- Experimental Animal Center, Shanxi Medical University, Shanxi Taiyuan, China
| | - Jiahui Tong
- School and Hospital of Stomatology, Shanxi Medical University, Shanxi Taiyuan, China
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Taiyuan, China
| | - Xueting Ding
- Experimental Animal Center, Shanxi Medical University, Shanxi Taiyuan, China
| | - Yitong Yuan
- Experimental Animal Center, Shanxi Medical University, Shanxi Taiyuan, China
| | - Chunfang Wang
- School and Hospital of Stomatology, Shanxi Medical University, Shanxi Taiyuan, China
- Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Taiyuan, China
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27
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Zou J, Xia H, Jiang Q, Su Z, Wen S, Liang Z, Ouyang Y, Liu J, Zhang Z, Chen D, Yang L, Guo L. Exosomes derived from odontogenic stem cells: Its role in the dentin-pulp complex. Regen Ther 2023; 24:135-146. [PMID: 37415682 PMCID: PMC10320411 DOI: 10.1016/j.reth.2023.05.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/01/2023] [Accepted: 05/25/2023] [Indexed: 07/08/2023] Open
Abstract
Odontogenic stem cells originate from cranial neural crest cells and offer unique advantages in the regeneration of dentin-pulp complex. There is increasing evidence that stem cells exert their biological functions mainly through exosome-based paracrine effects. Exosomes contain DNA, RNA, proteins, metabolites, etc., which can play a role in intercellular communication and have similar therapeutic potential to stem cells. In addition, compared with stem cells, exosomes also have the advantages of good biocompatibility, high drug carrying capacity, easy to obtain, and few side effects. Odontogenic stem cell-derived exosomes mainly affect the regeneration of the dentin-pulp complex by regulating processes such as dentintogenesis, angiogenesis, neuroprotection and immunomodulation. This review aimed to describe "cell-free therapies" based on odontogenic stem cell-derived exosomes, which aim to regenerate the dentin-pulp complex.
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Affiliation(s)
- Jiyuan Zou
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Han Xia
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Qianzhou Jiang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Zhikang Su
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Siyi Wen
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Zitian Liang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Yuanting Ouyang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Jiaohong Liu
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Zhiyi Zhang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Ding Chen
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Li Yang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
| | - Lvhua Guo
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China
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28
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Xing WB, Wu ST, Wang XX, Li FY, Wang RX, He JH, Fu J, He Y. Potential of dental pulp stem cells and their products in promoting peripheral nerve regeneration and their future applications. World J Stem Cells 2023; 15:960-978. [PMID: 37970238 PMCID: PMC10631371 DOI: 10.4252/wjsc.v15.i10.960] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 10/07/2023] [Accepted: 10/23/2023] [Indexed: 10/26/2023] Open
Abstract
Peripheral nerve injury (PNI) seriously affects people's quality of life. Stem cell therapy is considered a promising new option for the clinical treatment of PNI. Dental stem cells, particularly dental pulp stem cells (DPSCs), are adult pluripotent stem cells derived from the neuroectoderm. DPSCs have significant potential in the field of neural tissue engineering due to their numerous advantages, such as easy isolation, multidifferentiation potential, low immunogenicity, and low transplant rejection rate. DPSCs are extensively used in tissue engineering and regenerative medicine, including for the treatment of sciatic nerve injury, facial nerve injury, spinal cord injury, and other neurodegenerative diseases. This article reviews research related to DPSCs and their advantages in treating PNI, aiming to summarize the therapeutic potential of DPSCs for PNI and the underlying mechanisms and providing valuable guidance and a foundation for future research.
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Affiliation(s)
- Wen-Bo Xing
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Shu-Ting Wu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Xin-Xin Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Fen-Yao Li
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Ruo-Xuan Wang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Ji-Hui He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Jiao Fu
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- First Clinical College, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- Department of Stomatology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430000, Hubei Province, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, Hubei Province, China.
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Wang J, Qiao J, Ma L, Li X, Wei C, Tian X, Liu K. Identification of the characteristics of infiltrating immune cells in pulpitis and its potential molecular regulation mechanism by bioinformatics method. BMC Oral Health 2023; 23:287. [PMID: 37179325 PMCID: PMC10182635 DOI: 10.1186/s12903-023-03020-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
OBJECTIVE The inflammation of dental pulp will also trigger an immune response. The purpose of this study is to demonstrate the immune cell's function and explore their regulatory molecules and signal pathways in pulpitis. METHOD The CIBERSORTx method was used to quantitatively analyze 22 types of immune cells infiltrating in the GSE77459 dataset of dental pulp tissues. The immune-related differential genes (IR-DEGs) were further screened and enriched for the GO and KEGG pathways. Protein-protein interaction (PPI) networks were constructed and the hub IR-DEGs were screened. Finally, we constructed the regulatory network of hub genes. RESULTS The GSE77459 dataset screened 166 IR-DEGs and was enriched for three signal pathways involved in pulpitis development: chemokine signaling, TNF signaling, and NF-κB signaling. Significant differences in immune cell infiltration were observed between normal and inflamed dental pulp. The proportions of M0 macrophages, neutrophils, and follicular helper T cells were significantly higher than that of the normal dental pulp, while the proportions of resting mast cells, resting dendritic cells, CD8 T cells, and monocytes were significantly lower. The random forest algorithm concluded that M0 macrophages and neutrophils were the two most important immune cells. We identified five immune-related hub genes IL-6, TNF-α, IL-1β, CXCL8, and CCL2. In addition, IL-6, IL-1β, and CXCL8 are highly correlated with M0 macrophages and neutrophils, and the five hub genes have many shared regulatory molecules: four miRNAs and two lncRNAs, three transcription factors. CONCLUSION Immune cell infiltration plays an important role in pulpitis among which M0 macrophages and neutrophils are the most significant immune cells. IL-6, TNF-α, IL-1, CXCL8, and CCL2 may be essential molecule of the immune response regulation network in pulpitis. This will help us understand the immune regulatory network in pulpitis.
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Affiliation(s)
- Jing Wang
- Department of Stomatology, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, Shandong, 252000, P.R. China
| | - Junxia Qiao
- Department of Stomatology, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, Shandong, 252000, P.R. China
| | - Lili Ma
- Department of Stomatology, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, Shandong, 252000, P.R. China
| | - Xin Li
- Department of Stomatology, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, Shandong, 252000, P.R. China
| | - Chengshi Wei
- Department of Endodontics, Liaocheng People's Hospital, Liaocheng, Shandong, 252000, P.R. China
| | - Xiufen Tian
- Department of Stomatology, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, Shandong, 252000, P.R. China.
| | - Kun Liu
- Department of Stomatology, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, Shandong, 252000, P.R. China.
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Muallah D, Matschke J, Kappler M, Kroschwald LM, Lauer G, Eckert AW. Dental Pulp Stem Cells for Salivary Gland Regeneration-Where Are We Today? Int J Mol Sci 2023; 24:ijms24108664. [PMID: 37240009 DOI: 10.3390/ijms24108664] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Xerostomia is the phenomenon of dry mouth and is mostly caused by hypofunction of the salivary glands. This hypofunction can be caused by tumors, head and neck irradiation, hormonal changes, inflammation or autoimmune disease such as Sjögren's syndrome. It is associated with a tremendous decrease in health-related quality of life due to impairment of articulation, ingestion and oral immune defenses. Current treatment concepts mainly consist of saliva substitutes and parasympathomimetic drugs, but the outcome of these therapies is deficient. Regenerative medicine is a promising approach for the treatment of compromised tissue. For this purpose, stem cells can be utilized due to their ability to differentiate into various cell types. Dental pulp stem cells are adult stem cells that can be easily harvested from extracted teeth. They can form tissues of all three germ layers and are therefore becoming more and more popular for tissue engineering. Another potential benefit of these cells is their immunomodulatory effect. They suppress proinflammatory pathways of lymphocytes and could therefore probably be used for the treatment of chronic inflammation and autoimmune disease. These attributes make dental pulp stem cells an interesting tool for the regeneration of salivary glands and the treatment of xerostomia. Nevertheless, clinical studies are still missing. This review will highlight the current strategies for using dental pulp stem cells in the regeneration of salivary gland tissue.
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Affiliation(s)
- David Muallah
- Department of Oral and Maxillofacial Surgery, University Hospital Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany
| | - Jan Matschke
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Matthias Kappler
- Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany
| | - Lysann Michaela Kroschwald
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Günter Lauer
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Alexander W Eckert
- Department of Cranio Maxillofacial Surgery, Paracelsus Medical University, Breslauer Straße 201, 90471 Nuremberg, Germany
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Min Q, Yang L, Tian H, Tang L, Xiao Z, Shen J. Immunomodulatory Mechanism and Potential Application of Dental Pulp-Derived Stem Cells in Immune-Mediated Diseases. Int J Mol Sci 2023; 24:ijms24098068. [PMID: 37175774 PMCID: PMC10178746 DOI: 10.3390/ijms24098068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/20/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Dental pulp stem cells (DPSCs) are mesenchymal stem cells (MSCs) derived from dental pulp tissue, which have high self-renewal ability and multi-lineage differentiation potential. With the discovery of the immunoregulatory ability of stem cells, DPSCs have attracted much attention because they have similar or even better immunomodulatory effects than MSCs from other sources. DPSCs and their exosomes can exert an immunomodulatory ability by acting on target immune cells to regulate cytokines. DPSCs can also migrate to the lesion site to differentiate into target cells to repair the injured tissue, and play an important role in tissue regeneration. The aim of this review is to summarize the molecular mechanism and target cells of the immunomodulatory effects of DPSCs, and the latest advances in preclinical research in the treatment of various immune-mediated diseases, providing new reflections for their clinical application. DPSCs may be a promising source of stem cells for the treatment of immune-mediated diseases.
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Affiliation(s)
- Qi Min
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou 646000, China
| | - Liqiong Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou 646000, China
| | - Hua Tian
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou 646000, China
| | - Lu Tang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou 646000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou 646000, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou 646000, China
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Ma S, Jiang Y, Qian Y, Du J, Yu X, Luo S, Chen Z. The Emerging Biological Functions of Exosomes from Dental Tissue-Derived Mesenchymal Stem Cells. Cell Reprogram 2023; 25:53-64. [PMID: 37053510 DOI: 10.1089/cell.2022.0147] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2023] Open
Abstract
Exosomes are one kind of small-cell extracellular membranous vesicles that can regulate intercellular communication and give rise to mediating the biological behaviors of cells, involving in tissue formation, repair, the modulation of inflammation, and nerve regeneration. The abundant kinds of cells can secret exosomes, among them, mesenchymal stem cells (MSCs) are very perfect cells for mass production of exosomes. Dental tissue-derived mesenchymal stem cells (DT-MSCs), including dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, stem cells from human periodontal ligament (PDLSCs), gingiva-derived mesenchymal stem cells, dental follicle stem cells, tooth germ stem cells, and alveolar bone-derived mesenchymal stem cells, are now known as a potent tool in the area of cell regeneration and therapy, more importantly, DT-MSCs can also release numerous types of exosomes, participating in the biological functions of cells. Hence, we briefly depict the characteristics of exosomes, give a detailed description of the biological functions and clinical application in some respects of exosomes from DT-MSCs through systematically reviewing the latest evidence, and provide a rationale for their use as tools for potential application in tissue engineering.
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Affiliation(s)
- Shu Ma
- Department of Endodontics, Guiyang Hospital of Stomatology, Guiyang, China
| | - Yidi Jiang
- Department of Endodontics, Guiyang Hospital of Stomatology, Guiyang, China
| | - Yuyan Qian
- Department of Endodontics, Guiyang Hospital of Stomatology, Guiyang, China
| | - Jing Du
- Department of Endodontics, Guiyang Hospital of Stomatology, Guiyang, China
| | - Xiaoyan Yu
- Department of Periodontics, Guiyang Hospital of Stomatology, Guiyang, China
| | - Shiyi Luo
- GuiZhou University Medical College, Guiyang, China
| | - Zhu Chen
- Department of Endodontics, Guiyang Hospital of Stomatology, Guiyang, China
- Key Laboratory of Oral Disease Research, School of Stomatology, Zunyi Medical University, Zunyi, China
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33
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Fu Y, Cui S, Zhou Y, Qiu L. Dental Pulp Stem Cell-Derived Exosomes Alleviate Mice Knee Osteoarthritis by Inhibiting TRPV4-Mediated Osteoclast Activation. Int J Mol Sci 2023; 24:4926. [PMID: 36902356 PMCID: PMC10003468 DOI: 10.3390/ijms24054926] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 02/25/2023] [Accepted: 02/28/2023] [Indexed: 03/08/2023] Open
Abstract
Osteoarthritis (OA) is a degenerative disease that causes chronic pain and joint swelling and even disables millions of patients. However, current non-surgical treatment for OA can only relieve pain without obvious cartilage and subchondral bone repair. Mesenchymal stem cell (MSC)-secreted exosomes have promising therapeutic effects on knee OA, but the efficacy of MSC-exosome therapy is not well determined, and the mechanisms involved are still unclear. In this study, we isolated dental pulp stem cell (DPSC)-derived exosomes by ultracentrifugation and determined the therapeutic effects of a single intra-articular injection of DPSC-derived exosomes in a mice knee OA model. The results showed that the DPSC-derived exosomes effectively improved abnormal subchondral bone remodeling, inhibited the occurrence of bone sclerosis and osteophytes, and alleviated cartilage degradation and synovial inflammation in vivo. Moreover, transient receptor potential vanilloid 4 (TRPV4) was activated during the progression of OA. Enhanced TRPV4 activation facilitated osteoclast differentiation, and TRPV4 inhibition blocked this process in vitro. DPSC-derived exosomes repressed osteoclast activation in vivo by inhibiting TRPV4 activation. Our findings demonstrated that a topical, single injection of DPSC-derived exosomes is a potential strategy for knee OA treatment, and that the exosomes regulated osteoclast activation by TRPV4 inhibition, which may act as a promising target for clinical OA treatment.
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Affiliation(s)
- Yu Fu
- Fourth Clinical Division, Peking University School and Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
| | - Shengjie Cui
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
| | - Yanheng Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
| | - Lixin Qiu
- Fourth Clinical Division, Peking University School and Hospital of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China
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The Role and Involvement of Stem Cells in Periodontology. Biomedicines 2023; 11:biomedicines11020387. [PMID: 36830924 PMCID: PMC9953576 DOI: 10.3390/biomedicines11020387] [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: 01/16/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Periodontitis is a widespread inflammatory condition, characterized by a progressive deterioration of the supporting structures of the teeth. Due to the complexity of periodontal tissue and the surrounding inflammatory microenvironment, the repair of lesions at this level represents a continuous challenge. The regeneration of periodontal tissues is considered a promising strategy. Stem cells have remarkable properties, such as immunomodulatory potential, proliferation, migration, and multilineage differentiation. Thus, they can be used to repair tissue damage and reduce inflammation, potentially leading to periodontal regeneration. Among the stem cells used for periodontal regeneration, we studied dental mesenchymal stem cells (DMSCs), non-dental stem cells, and induced pluripotent stem cells (IPSCs). Although these cells have well documented important physiological characteristics, their use in contemporary practice to repair the affected periodontium is still a challenge.
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35
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Qu Q, Fu B, Long Y, Liu ZY, Tian XH. Current Strategies for Promoting the Large-scale Production of Exosomes. Curr Neuropharmacol 2023; 21:1964-1979. [PMID: 36797614 PMCID: PMC10514529 DOI: 10.2174/1570159x21666230216095938] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/21/2022] [Accepted: 11/05/2022] [Indexed: 02/18/2023] Open
Abstract
Exosomes, as nanoscale biological vesicles, have been shown to have great potential for biomedical applications. However, the low yield of exosomes limits their application. In this review, we focus on methods to increase exosome yield. Two main strategies are used to increase exosome production, one is based on genetic manipulation of the exosome biogenesis and release pathway, and the other is by pretreating parent cells, changing the culture method or adding different components to the medium. By applying these strategies, exosomes can be produced on a large scale to facilitate their practical application in the clinic.
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Affiliation(s)
- Qing Qu
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, 77 Puhe Avenue, Shenbei New District, Shenyang, 110122, China
| | - Bin Fu
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, 77 Puhe Avenue, Shenbei New District, Shenyang, 110122, China
| | - Yong Long
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, 77 Puhe Avenue, Shenbei New District, Shenyang, 110122, China
| | - Zi-Yu Liu
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, 77 Puhe Avenue, Shenbei New District, Shenyang, 110122, China
| | - Xiao-Hong Tian
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, 77 Puhe Avenue, Shenbei New District, Shenyang, 110122, China
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36
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Kong H, Liu P, Li H, Zeng X, Xu P, Yao X, Liu S, Cheng CK, Xu J. Mesenchymal Stem Cell-Derived Extracellular Vesicles: The Novel Therapeutic Option for Regenerative Dentistry. Stem Cell Rev Rep 2023; 19:46-58. [PMID: 35132538 DOI: 10.1007/s12015-022-10342-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2022] [Indexed: 01/29/2023]
Abstract
Dental mesenchymal stem cells (MSCs) are characterized by unlimited self-renewal ability and high multidirectional differentiation potential. Since dental MSCs can be easily isolated and exhibit a high capability to differentiate into odontogenic cells, they are considered as attractive therapeutic agents in regenerative dentistry. Recently, MSC-derived extracellular vesicles (MSC-EVs) have attracted widespread attention as carriers for cell-free therapy due to their potential functions. Many studies have shown that MSC-EVs can mediate microenvironment at tissue damage site, and coordinate the regeneration process. Additionally, MSC-EVs can mediate intercellular communication, thus affecting the phenotypes and functions of recipient cells. In this review, we mainly summarized the types of MSCs that could be potentially applied in regenerative dentistry, the possible molecular cargos of MSC-EVs, and the major effects of MSC-EVs on the therapeutic induction of osteogenic differentiation.
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Affiliation(s)
- Haiying Kong
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Peiqi Liu
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China.,Second School of Clinical Medicine, Guangdong Medical University, Dongguan, Guangdong, China
| | - Hongwen Li
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China.,Shenzhen Longgang Institute of Stomatology, Shenzhen, Guangdong, China
| | - Xiantao Zeng
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Peiwu Xu
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Xinhui Yao
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Senqing Liu
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China
| | - Chak Kwong Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Jian Xu
- Department of Dentistry, Longgang E.N.T. Hospital & Shenzhen Key Laboratory of E.N.T, Institute of E.N.T, Shenzhen, Guangdong, China. .,Shenzhen Longgang Institute of Stomatology, Shenzhen, Guangdong, China.
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37
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MSC-EV therapy for bone/cartilage diseases. Bone Rep 2022; 17:101636. [DOI: 10.1016/j.bonr.2022.101636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022] Open
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38
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Tian J, Chen W, Xiong Y, Li Q, Kong S, Li M, Pang C, Qiu Y, Xu Z, Gong Q, Wei X. Small extracellular vesicles derived from hypoxic preconditioned dental pulp stem cells ameliorate inflammatory osteolysis by modulating macrophage polarization and osteoclastogenesis. Bioact Mater 2022; 22:326-342. [PMID: 36311048 PMCID: PMC9587346 DOI: 10.1016/j.bioactmat.2022.10.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/23/2022] [Accepted: 10/01/2022] [Indexed: 11/05/2022] Open
Abstract
Extensive macrophage inflammatory responses and osteoclast formation are predominant during inflammatory or infective osteolysis. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEV) have been shown to exert therapeutic effects on bone defects. However, cultured MSCs are typically exposed to normoxia (21% O2) in vitro, which differs largely from the oxygen concentration in vivo under hypoxic conditions. It is largely unknown whether sEV derived from dental pulp stem cells (DPSCs) cultured under hypoxic conditions (Hypo-sEV) exert better therapeutic effects on lipopolysaccharide (LPS)-induced inflammatory osteolysis than those cultured under normoxic conditions (Nor-sEV) by simultaneously inhibiting the macrophage inflammatory response and osteoclastogenesis. In this study, we show that hypoxia significantly induces the release of sEV from DPSCs. Moreover, Hypo-sEV exhibit significantly improved efficacy in promoting M2 macrophage polarization and suppressing osteoclast formation to alleviate LPS-induced inflammatory calvarial bone loss compared with Nor-sEV. Mechanistically, hypoxia preconditioning markedly alters the miRNA profiles of DPSC-sEV. MiR-210-3p is enriched in Hypo-sEV, and can simultaneously induce M2 macrophage generation and inhibit osteoclastogenesis by targeting NF-κB1 p105, which attenuates osteolysis. Our study suggests a promising potential for hypoxia-induced DPSC-sEV to treat inflammatory or infective osteolysis and identifies a novel role of miR-210-3p in concurrently hindering osteoclastogenesis and macrophage inflammatory response by inhibiting NF-kB1 expression.
Hypoxia promotes the release of sEV from DPSCs. Hypoxia-induced DPSC-sEV (Hypo-sEV) show increased potential to inhibit inflammatory osteolysis. The miR-210-3p enriched in Hypo-sEV contributes to therapeutic effects of Hypo-sEV. MiR-210-3p concurrently induces M2 macrophage generation and inhibits osteoclastogenesis by targeting NF-κB1. Hypoxia-induced DPSC-sEV represent a promising therapy for inflammatory osteolysis.
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Affiliation(s)
- Jun Tian
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Weiyang Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Yuhua Xiong
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Qianer Li
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Siyi Kong
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Mengjie Li
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Chunfeng Pang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Yu Qiu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Zhezhen Xu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China
| | - Qimei Gong
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China,Corresponding author. Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, 56 Ling Yuan Xi Road, Guangzhou, 510055, China.
| | - Xi Wei
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510055, PR China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong, 510055, PR China,Corresponding author. Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, 56 Ling Yuan Xi Road, Guangzhou, 510055, China.
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DPSCs Protect Architectural Integrity and Alleviate Intervertebral Disc Degeneration by Regulating Nucleus Pulposus Immune Status. Stem Cells Int 2022; 2022:7590337. [PMID: 36299466 PMCID: PMC9590116 DOI: 10.1155/2022/7590337] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/17/2022] [Accepted: 09/20/2022] [Indexed: 11/23/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is the primary cause for low back pain that has a high prevalence in modern society and poses enormous economic burden on patients. Few effective therapeutic strategies are available for IVD degeneration treatment. To understand the biological effects of dental pulp stem cells (DPSCs) on nucleus pulposus (NP) cells, we carried out RNA sequencing, bioinformatic analysis which unveiled gene expression differences, and pathway variation in primarily isolated patients' NP cells after treatment with DPSCs supernatant. Western blot and immunofluorescence were used to verify these molecular alterations. Besides, to evaluate the therapeutic effect of DPSCs in IVD degeneration treatment, DPSCs were injected into a degeneration rat model in situ, with treatment outcome measured by micro-CT and histological analysis. RNA sequencing and in vitro experiments demonstrated that DPSCs supernatant could downregulate NP cells' inflammation-related NF-κB and JAK-STAT pathways, reduce IL-6 production, increase collagen II expression, and mitigate apoptosis. In vivo results showed that DPSCs treatment protected the integrity of the disc structure, alleviated extracellular matrix degradation, and increased collagen fiber expression. In this study, we verified the therapeutic effect of DPSCs in an IVD degeneration rat model and elucidated the underlying molecular mechanism of DPSCs treatment, which provides a foundation for the application of DPSCs in IVD degeneration treatment.
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40
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Luo X, Xiao D, Zhang C, Wang G. The Roles of Exosomes upon Metallic Ions Stimulation in Bone Regeneration. J Funct Biomater 2022; 13:jfb13030126. [PMID: 36135561 PMCID: PMC9506099 DOI: 10.3390/jfb13030126] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/11/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Metallic ions have been widely investigated and incorporated into bone substitutes for bone regeneration owing to their superior capacity to induce angiogenesis and osteogenesis. Exosomes are key paracrine mediators that play a crucial role in cell-to-cell communication. However, the role of exosomes in metallic ion-induced bone formation and their underlying mechanisms remain unclear. Thus, this review systematically analyzes the effects of metallic ions and metallic ion-incorporated biomaterials on exosome secretion from mesenchymal stem cells (MSCs) and macrophages, as well as the effects of secreted exosomes on inflammation, angiogenesis, and osteogenesis. In addition, possible signaling pathways involved in metallic ion-mediated exosomes, followed by bone regeneration, are discussed. Despite limited investigation, metallic ions have been confirmed to regulate exosome production and function, affecting immune response, angiogenesis, and osteogenesis. Although the underlying mechanism is not yet clear, these insights enrich our understanding of the mechanisms of the metallic ion-induced microenvironment for bone regeneration, benefiting the design of metallic ion-incorporated implants.
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Affiliation(s)
- Xuwei Luo
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
- Research Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong 637000, China
| | - Dongqin Xiao
- Research Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong 637000, China
- Correspondence: (D.X.); (G.W.)
| | - Chengdong Zhang
- Research Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong 637000, China
| | - Guanglin Wang
- Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
- Correspondence: (D.X.); (G.W.)
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41
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Pishavar E, Trentini M, Zanotti F, Camponogara F, Tiengo E, Zanolla I, Bonora M, Zavan B. Exosomes as Neurological Nanosized Machines. ACS NANOSCIENCE AU 2022; 2:284-296. [PMID: 37102062 PMCID: PMC10125174 DOI: 10.1021/acsnanoscienceau.1c00062] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
In the past few decades, nanomedicine research has advanced dramatically. In spite of this, traditional nanomedicine faces major obstacles, such as blood-brain barriers, low concentrations at target sites, and rapid removal from the body. Exosomes as natural extracellular vesicles contain special bioactive molecules for cell-to-cell communications and nervous tissue function, which could overcome the challenges of nanoparticles. Most recently, microRNAs, long noncoding RNA, and circulating RNA of exosomes have been appealing because of their critical effect on the molecular pathway of target cells. In this review, we have summarized the important role of exosomes of noncoding RNAs in the occurrence of brain diseases.
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Affiliation(s)
- Elham Pishavar
- Department
of Translational Medicine, University of
Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Martina Trentini
- Department
of Translational Medicine, University of
Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Federica Zanotti
- Department
of Translational Medicine, University of
Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Francesca Camponogara
- Department
of Translational Medicine, University of
Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Elena Tiengo
- Department
of Translational Medicine, University of
Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Ilaria Zanolla
- Department
of Medical Science, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Massimo Bonora
- Department
of Medical Science, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Barbara Zavan
- Department
of Translational Medicine, University of
Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
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Feng ZY, Zhang QY, Tan J, Xie HQ. Techniques for increasing the yield of stem cell-derived exosomes: what factors may be involved? SCIENCE CHINA. LIFE SCIENCES 2022; 65:1325-1341. [PMID: 34637101 PMCID: PMC8506103 DOI: 10.1007/s11427-021-1997-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 08/11/2021] [Indexed: 02/05/2023]
Abstract
Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication. The main contents of the exosomes include proteins, microRNAs, and lipids. The mechanism and safety of stem cell-derived exosomes have rendered them a promising therapeutic strategy for regenerative medicine. Nevertheless, limited yield has restrained full explication of their functions and clinical applications To address this, various attempts have been made to explore the up- and down-stream manipulations in a bid to increase the production of exosomes. This review has recapitulated factors which may influence the yield of stem cell-derived exosomes, including selection and culture of stem cells, isolation and preservation of the exosomes, and development of artificial exosomes.
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Affiliation(s)
- Zi-Yuan Feng
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qing-Yi Zhang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jie Tan
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hui-Qi Xie
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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43
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Ogata K, Moriyama M, Matsumura-Kawashima M, Kawado T, Yano A, Nakamura S. The Therapeutic Potential of Secreted Factors from Dental Pulp Stem Cells for Various Diseases. Biomedicines 2022; 10:biomedicines10051049. [PMID: 35625786 PMCID: PMC9138802 DOI: 10.3390/biomedicines10051049] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/18/2022] [Accepted: 04/27/2022] [Indexed: 11/16/2022] Open
Abstract
An alternative source of mesenchymal stem cells has recently been discovered: dental pulp stem cells (DPSCs), including deciduous teeth, which can thus comprise potential tools for regenerative medicine. DPSCs derive from the neural crest and are normally implicated in dentin homeostasis. The clinical application of mesenchymal stem cells (MSCs) involving DPSCs contains various limitations, such as high cost, low safety, and cell handling issues, as well as invasive sample collection procedures. Although MSCs implantation offers favorable outcomes on specific diseases, implanted MSCs cannot survive for a long period. It is thus considered that their mediated mechanism of action involves paracrine effects. It has been recently reported that secreted molecules in DPSCs-conditioned media (DPSC-CM) contain various trophic factors and cytokines and that DPSC-CM are effective in models of various diseases. In the current study, we focus on the characteristics of DPSC-CM and their therapeutic potential against various disorders.
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Chouaib B, Cuisinier F, Collart-Dutilleul PY. Dental stem cell-conditioned medium for tissue regeneration: Optimization of production and storage. World J Stem Cells 2022; 14:287-302. [PMID: 35662860 PMCID: PMC9136565 DOI: 10.4252/wjsc.v14.i4.287] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/19/2021] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSC) effects on tissue regeneration are mainly mediated by their secreted substances (secretome), inducing their paracrine activity. This Conditioned medium (CM), including soluble factors (proteins, nucleic acids, lipids) and extracellular vesicles is emerging as a potential alternative to cell therapy. However, the manufacturing of CM suffers from variable procedures and protocols leading to varying results between studies. Besides, there is no well-defined optimized procedure targeting specific applications in regenerative medicine. AIM To focus on conditioned medium produced from dental MSC (DMSC-CM), we reviewed the current parameters and manufacturing protocols, in order to propose a standardization and optimization of these manufacturing procedures. METHODS We have selected all publications investigating the effects of dental MSC secretome in in vitro and in vivo models of tissue regeneration, in accordance with the PRISMA guidelines. RESULTS A total of 351 results were identified. And based on the inclusion criteria described above, 118 unique articles were included in the systematic review. DMSC-CM production was considered at three stages: before CM recovery (cell sources for CM), during CM production (culture conditions) and after production (CM treatment). CONCLUSION No clear consensus could be recovered as evidence-based methods, but we were able to describe the most commonly used protocols: donors under 30 years of age, dental pulp stem cells and exfoliated deciduous tooth stem cells with cell passage between 1 and 5, at a confluence of 70% to 80%. CM were often collected during 48 h, and stored at -80 °C. It is important to point out that the preconditioning environment had a significant impact on DMSC-CM content and efficiency.
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Affiliation(s)
- Batoul Chouaib
- Laboratory Bioengineering and Nanosciences UR_UM104, University of Montpellier, Montpellier 34000, France
| | - Frédéric Cuisinier
- Laboratory Bioengineering and Nanosciences UR_UM104, University of Montpellier, Montpellier 34000, France
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Brunello G, Zanotti F, Trentini M, Zanolla I, Pishavar E, Favero V, Favero R, Favero L, Bressan E, Bonora M, Sivolella S, Zavan B. Exosomes Derived from Dental Pulp Stem Cells Show Different Angiogenic and Osteogenic Properties in Relation to the Age of the Donor. Pharmaceutics 2022; 14:pharmaceutics14050908. [PMID: 35631496 PMCID: PMC9146046 DOI: 10.3390/pharmaceutics14050908] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/16/2022] [Accepted: 04/19/2022] [Indexed: 12/12/2022] Open
Abstract
Craniofacial tissue reconstruction still represents a challenge in regenerative medicine. Mesenchymal stem cell (MSC)-based tissue engineering strategies have been introduced to enhance bone tissue repair. However, the risk of related complications is limiting their usage. To overcome these drawbacks, exosomes (EXOs) derived from MSCs have been recently proposed as a cell-free alternative to MSCs to direct tissue regeneration. It was hypothesized that there is a correlation between the biological properties of exosomes derived from the dental pulp and the age of the donor. The aim of the study was to investigate the effect of EXOs derived from dental pulp stem cells of permanent teeth (old donor group) or exfoliated deciduous teeth (young donor group) on MSCs cultured in vitro. Proliferation potential was evaluated by doubling time, and commitment ability by gene expression and biochemical quantification for tissue-specific factors. Results showed a well-defined proliferative influence for the younger donor aged group. Similarly, a higher commitment ability was detected in the young group. In conclusion, EXOs could be employed to promote bone regeneration, likely playing an important role in neo-angiogenesis in early healing phases.
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Affiliation(s)
- Giulia Brunello
- Department of Neurosciences, School of Dentistry, University of Padua, 35128 Padua, Italy; (G.B.); (R.F.); (L.F.); (E.B.); (S.S.)
- Department of Oral Surgery, University Hospital of Düsseldorf, 40225 Dusseldorf, Germany
| | - Federica Zanotti
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.Z.); (M.T.); (I.Z.); (E.P.)
| | - Martina Trentini
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.Z.); (M.T.); (I.Z.); (E.P.)
| | - Ilaria Zanolla
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.Z.); (M.T.); (I.Z.); (E.P.)
| | - Elham Pishavar
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.Z.); (M.T.); (I.Z.); (E.P.)
| | - Vittorio Favero
- Unit of Maxillofacial Surgery and Dentistry, University of Verona, 37129 Verona, Italy;
| | - Riccardo Favero
- Department of Neurosciences, School of Dentistry, University of Padua, 35128 Padua, Italy; (G.B.); (R.F.); (L.F.); (E.B.); (S.S.)
| | - Lorenzo Favero
- Department of Neurosciences, School of Dentistry, University of Padua, 35128 Padua, Italy; (G.B.); (R.F.); (L.F.); (E.B.); (S.S.)
| | - Eriberto Bressan
- Department of Neurosciences, School of Dentistry, University of Padua, 35128 Padua, Italy; (G.B.); (R.F.); (L.F.); (E.B.); (S.S.)
| | - Massimo Bonora
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Stefano Sivolella
- Department of Neurosciences, School of Dentistry, University of Padua, 35128 Padua, Italy; (G.B.); (R.F.); (L.F.); (E.B.); (S.S.)
| | - Barbara Zavan
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.Z.); (M.T.); (I.Z.); (E.P.)
- Correspondence:
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Li L, Ge J. Exosome‑derived lncRNA‑Ankrd26 promotes dental pulp restoration by regulating miR‑150‑TLR4 signaling. Mol Med Rep 2022; 25:152. [PMID: 35244185 DOI: 10.3892/mmr.2022.12668] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 12/30/2021] [Indexed: 11/06/2022] Open
Abstract
At present, retaining the biological function of dental pulp is an urgent requirement in the treatment of pulp disease; it has been recognized that application of dental pulp stem cells (DPSCs) in regenerating dental pulp and dentin complexes is expected to become a safe and effective treatment of pulp disease; meanwhile the role of DPSC‑derived exosomes in dental pulp regeneration and repair is gaining attention. However, the underlying mechanism of DPSCs in dental pulp regeneration and repair is still unclear. In the present study, a variety of in vitro biological experiments and an animal model, as well as next‑generation sequencing and bioinformatics analysis, demonstrated that DPSCs promoted migration and osteoblastic differentiation of mesenchymal stem cells (MSCs) via exosomes; this was induced by DPSC‑derived exosomal long non‑coding (lnc)RNA‑ankyrin repeat domain (Ankrd)26. Mechanistically, the effect of exosomal lncRNA‑Ankrd26 on migration and osteoblastic differentiation of MSCs was dependent on microRNA (miR)‑150/Toll‑like receptor (TLR)4 signaling; this was regulated by lncRNA‑Ankrd26. The present study demonstrated that exosomes‑derived lncRNA‑Ankrd26 from DPSCs promoted dental pulp restoration via regulating miR‑150‑TLR4 signaling in MSCs; these findings help to understand the mechanism of dental pulp repair, identify therapeutic targets in the development of pulpitis and develop clinical treatments.
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Affiliation(s)
- Lin Li
- Department of Endodontics, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, P.R. China
| | - Jianping Ge
- Department of Endodontics, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, P.R. China
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Liu C, Hu F, Jiao G, Guo Y, Zhou P, Zhang Y, Zhang Z, Yi J, You Y, Li Z, Wang H, Zhang X. Dental pulp stem cell-derived exosomes suppress M1 macrophage polarization through the ROS-MAPK-NFκB P65 signaling pathway after spinal cord injury. J Nanobiotechnology 2022; 20:65. [PMID: 35109874 PMCID: PMC8811988 DOI: 10.1186/s12951-022-01273-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/17/2022] [Indexed: 12/31/2022] Open
Abstract
Stem cell-derived exosomes have recently been regarded as potential drugs for treating spinal cord injury (SCI) by reducing reactive oxygen species (ROS) and suppressing M1 macrophage polarization. However, the roles of ROS and exosomes in the process of M1 macrophage polarization are not known. Herein, we demonstrated that ROS can induce M1 macrophage polarization and have a concentration-dependent effect. ROS can induce M1 macrophage polarization through the MAPK-NFκB P65 signaling pathway. Dental pulp stem cell (DPSC)-derived exosomes can reduce macrophage M1 polarization through the ROS-MAPK-NFκB P65 signaling pathway in treating SCI. This study suggested that DPSC-derived exosomes might be a potential drug for treating SCI. Disruption of the cycle between ROS and M1 macrophage polarization might also be a potential effective treatment by reducing secondary damage.
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Affiliation(s)
- Chao Liu
- Department of Orthopaedics, The First Affiliated Hospital of Jinan University, Huangpu Avenue West Road, Guangzhou, People's Republic of China
| | - Fanqi Hu
- Department of Orthopaedics, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
| | - Genlong Jiao
- Department of Orthopaedics, The First Affiliated Hospital of Jinan University, Huangpu Avenue West Road, Guangzhou, People's Republic of China
| | - Yue Guo
- Department of Orthopaedics, The First Affiliated Hospital of Jinan University, Huangpu Avenue West Road, Guangzhou, People's Republic of China
| | - Pan Zhou
- Department of Orthopaedics, The First Affiliated Hospital of Jinan University, Huangpu Avenue West Road, Guangzhou, People's Republic of China
| | - Yuning Zhang
- Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
| | - Zhen Zhang
- Department of Orthopaedics, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China
| | - Jing Yi
- Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
| | - Yonggang You
- Department of Orthopaedics, The First Affiliated Hospital of Jinan University, Huangpu Avenue West Road, Guangzhou, People's Republic of China
- Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
| | - Zhizhong Li
- Department of Orthopaedics, The First Affiliated Hospital of Jinan University, Huangpu Avenue West Road, Guangzhou, People's Republic of China.
| | - Hua Wang
- Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
| | - Xuesong Zhang
- Department of Orthopaedics, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China.
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Wu X, Wang Z, Wang J, Tian X, Cao G, Gu Y, Shao F, Yan T. Exosomes Secreted by Mesenchymal Stem Cells Induce Immune Tolerance to Mouse Kidney Transplantation via Transporting LncRNA DANCR. Inflammation 2022; 45:460-475. [PMID: 34596768 DOI: 10.1007/s10753-021-01561-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/02/2021] [Accepted: 09/06/2021] [Indexed: 11/30/2022]
Abstract
Mesenchymal stem cells induce kidney transplant tolerance by increasing regulatory T (Treg) cells. Bone marrow mesenchymal stem cell exosomes (BMMSC-Ex) promote Treg cell differentiation. Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is expressed in BMMSCs and can be encapsulated in exosomes. We aimed to explore the role of DANCR in BMMSC-Ex in immune tolerance after kidney transplantation and related mechanism. The isogenic/allograft kidney transplantation mouse model was established, and levels of serum creatinine (SCr) were determined. Hematoxylin-eosin staining was conducted to detect the inflammation, and immunohistochemistry was performed to detect the infiltration of CD4+ T cells. Levels of IFN-γ, IL-17, and IL-2 were examined by ELISA. Flow cytometry was conducted to determine Treg cells. In the allograft group, the inflammatory response was severe, CD4+ T cell infiltration, SCr levels, and plasma rejection-related factors were up-regulated, while injection of BMMSC-Ex reversed the results. BMMSC-Ex increased Treg cells in kidney transplantation mice. Interference with DANCR reversed the promoting effect of BMMSC-Ex on Treg cell differentiation. DANCR bound to SIRT1, promoted ubiquitination and accelerated its degradation. The injection of BMMSC-Ex (after interference with DANCR) promoted SIRT1 levels, inflammatory response, CD4+ T cell infiltration, SCr levels, and plasma rejection related factors' expression, while Treg cells were decreased. LncRNA DANCR in BMMSC-Ex promoted Treg cell differentiation and induced immune tolerance of kidney transplantation by down-regulating SIRT1 expression in CD4+ T cells.
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Affiliation(s)
- Xiaoqiang Wu
- Department of Urology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, China
| | - Zhiwei Wang
- Department of Urology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, China
| | - Junpeng Wang
- Department of Urology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, China
| | - Xiangyong Tian
- Department of Urology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, China
| | - Guanghui Cao
- Department of Urology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, China
| | - Yue Gu
- Department of Nephrology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Fengmin Shao
- Department of Nephrology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China
| | - Tianzhong Yan
- Department of Urology, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, China.
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Dental Pulp Stem Cell Heterogeneity: Finding Superior Quality "Needles" in a Dental Pulpal "Haystack" for Regenerative Medicine-Based Applications. Stem Cells Int 2022; 2022:9127074. [PMID: 35027930 PMCID: PMC8752304 DOI: 10.1155/2022/9127074] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 11/03/2021] [Indexed: 12/14/2022] Open
Abstract
Human dental pulp stem/stromal cells (hDPSCs) derived from the permanent secondary dentition are recognised to possess certain advantageous traits, which support their potential use as a viable source of mesenchymal stem/stromal cells (MSCs) for regenerative medicine-based applications. However, the well-established heterogeneous nature of hDPSC subpopulations, coupled with their limited numbers within dental pulp tissues, has impeded our understanding of hDPSC biology and the translation of sufficient quantities of these cells from laboratory research, through successful therapy development and clinical applications. This article reviews our current understanding of hDPSC biology and the evidence underpinning the molecular basis of their heterogeneity, which may be exploited to distinguish individual subpopulations with specific or superior characteristics for regenerative medicine applications. Pertinent unanswered questions which still remain, regarding the developmental origins, hierarchical organisation, and stem cell niche locations of hDPSC subpopulations and their roles in hDPSC heterogeneity and functions, will further be explored. Ultimately, a greater understanding of how key features, such as specific cell surface, senescence and other relevant genes, and protein and metabolic markers, delineate between hDPSC subpopulations with contrasting stemness, proliferative, multipotency, immunomodulatory, anti-inflammatory, and other relevant properties is required. Such knowledge advancements will undoubtedly lead to the development of novel screening, isolation, and purification strategies, permitting the routine and effective identification, enrichment, and expansion of more desirable hDPSC subpopulations for regenerative medicine-based applications. Furthermore, such innovative measures could lead to improved cell expansion, manufacture, and banking procedures, thereby supporting the translational development of hDPSC-based therapies in the future.
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Gugliandolo A, Mazzon E. Dental Mesenchymal Stem Cell Secretome: An Intriguing Approach for Neuroprotection and Neuroregeneration. Int J Mol Sci 2021; 23:ijms23010456. [PMID: 35008878 PMCID: PMC8745761 DOI: 10.3390/ijms23010456] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are known for their beneficial effects and regenerative potential. In particular, dental-derived MSCs have the advantage of easier accessibility and a non-invasive isolation method. Moreover, thanks to their neural crest origin, dental MSCs seem to have a more prominent neuroregenerative potential. Indeed, in basal conditions they also express neuronal markers. However, it is now well known that the beneficial actions of MSCs depend, at least in part, on their secretome, referring to all the bioactive molecules released in the conditioned medium (CM) or in extracellular vesicles (EVs). In this review we focus on the applications of the secretome derived from dental MSCs for neuroregeneration and neuroprotection. The secretomes of different dental MSCs have been tested for their effects for neuroregenerative purposes, and the secretomes of dental pulp stem cells and stem cells from human exfoliated deciduous teeth are the most studied. Both the CM and EVs obtained from dental MSCs showed that they are able to promote neurite outgrowth and neuroprotective effects. Interestingly, dental-derived MSC secretome showed stronger neuroregenerative and neuroprotective effects compared to that obtained from other MSC sources. For these reasons, the secretome obtained from dental MSCs may represent a promising approach for neuroprotective treatments.
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