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Li P, Sun S, Zhu X, Liu X, Yin R, Chen Y, Chang J, Ye L, Gao J, Zhao X, Xu H, Wang Y, Zuo W, Sun Z, Wang S, Zhang X, Wei J, Zhao RC, Han Q. Intranasal delivery of engineered extracellular vesicles promotes neurofunctional recovery in traumatic brain injury. J Nanobiotechnology 2025; 23:229. [PMID: 40114197 PMCID: PMC11927228 DOI: 10.1186/s12951-025-03181-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/01/2025] [Indexed: 03/22/2025] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of disability in adults, significantly affecting patients' quality of life. Extracellular vesicles (EVs) derived from human adipose-derived mesenchymal stem cells (hADSCs) have demonstrated therapeutic potential in TBI treatment. However, their limited targeting ability, short half-life, and low bioavailability present significant challenges for clinical application. In this study, we engineered extracellular vesicles (EEVs) by transfecting hADSCs with lentivirus and incorporating ultra-small paramagnetic nanoparticles (USPNs), resulting in EVs with enhanced miRNA expression and targeted delivery capabilities. These EEVs were administered intranasally to specifically target injury sites, effectively modulating the NF-κB signaling pathway to suppress neuroinflammation. In both in vitro and in vivo assessments, EEVs exhibited superior efficacy in promoting neurofunctional recovery and neurogenesis after brain injury compared to unmodified EVs. Furthermore, validation using human brain organoid models confirmed EEVs' remarkable ability to suppress neuroinflammation, offering a promising strategy for TBI treatment.
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Affiliation(s)
- Pengtao Li
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Sishuai Sun
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xingyu Zhu
- School of Basic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Xiaoyu Liu
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Yin
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yihao Chen
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jianbo Chang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Liguo Ye
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jingxi Gao
- School of Basic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Xiaoyan Zhao
- School of Basic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Houshi Xu
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yue Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Zuo
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhao Sun
- Department of Oncology, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Shihua Wang
- School of Basic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Xiao Zhang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Junji Wei
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
| | - Robert Chunhua Zhao
- School of Basic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
| | - Qin Han
- School of Basic Medicine, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 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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Karpenko DV. Immune modulatory stem cells represent a significant component of the immune system. Front Immunol 2025; 16:1543495. [PMID: 40098974 PMCID: PMC11911480 DOI: 10.3389/fimmu.2025.1543495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 02/18/2025] [Indexed: 03/19/2025] Open
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Fan L, Zhang Y, Huang S, Chen J, Wang J, Meng F, Zhang J, Xue Q. Effects of multiple treatments with stem cell therapy in patients with multiple sclerosis. Mult Scler Relat Disord 2024; 92:105944. [PMID: 39442287 DOI: 10.1016/j.msard.2024.105944] [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: 12/04/2023] [Revised: 07/29/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
OBJECTIVE This study was to evaluate the effectiveness of stem cell therapies (AHSCT: autologous hematopoietic stem cell transplantation and MSCs: mesenchymal stem cells) compared to non-stem cell therapies in multiple sclerosis (MS) patients. DESIGN Clinical trials to investigate the therapeutic effects of stem cells therapy was searched by PubMed, Embase, Web of Science, and the Cochrane Library. The Cochrane Risk of Bias Assessment Tool and data analysis software will be applied. RESULTS Data were collected between the earliest available date and August 2023. Ten studies were included, with a sample size of 5288 used in the studies. Results showed that human umbilical cord-derived mesenchymal stem cells reduced the Annualized Relapse Rate (SUCRA: 70.9 %) and Expanded Disability Status Scale (SUCRA: 77.1 %) of MS patients, AHSCT reduced mortality rate (SUCRA: 69.8 %), autologous peripheral blood stem cell transplantation (APBSCT) reduced recurrence rate (SUCRA: 86.7 %) and improved No Evidence of Disease Activity-3 (SUCRA: 92.8 %). CONCLUSION At present, AHSCT and MSCs have been demonstrated to reduce the recurrence rate of multiple sclerosis and improve disability, particularly in the case of hUC-MSCs. However, APBSCT and AHSCT in the context of the NEDA-3 criteria have not yielded the desired outcomes.
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Affiliation(s)
- Liding Fan
- Jining Medical University, Second Clinical Medical College, Shandong, 272067, China
| | - Yunfei Zhang
- Jining Medical University, School of Clinical Medicine, Shandong, 272067, China
| | - Shuo Huang
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, 215123, China
| | - Jie Chen
- Jining Medical University, School of Clinical Medicine, Shandong, 272067, China
| | - Junying Wang
- Jining Medical University, School of Clinical Medicine, Shandong, 272067, China
| | - Furen Meng
- Jining Medical University, School of Clinical Medicine, Shandong, 272067, China
| | - Jiarui Zhang
- Jining Medical University, Second Clinical Medical College, Shandong, 272067, China
| | - Qingjie Xue
- Jining Medical University, Second Clinical Medical College, Shandong, 272067, China.
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Ali NH, Al-Kuraishy HM, Al-Gareeb AI, Alnaaim SA, Hetta HF, Saad HM, Batiha GES. A Mutual Nexus Between Epilepsy and α-Synuclein: A Puzzle Pathway. Mol Neurobiol 2024; 61:10198-10215. [PMID: 38703341 DOI: 10.1007/s12035-024-04204-6] [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: 07/01/2023] [Accepted: 04/12/2024] [Indexed: 05/06/2024]
Abstract
Alpha-synuclein (α-Syn) is a specific neuronal protein that regulates neurotransmitter release and trafficking of synaptic vesicles. Exosome-associated α-Syn which is specific to the central nervous system (CNS) is involved in the pathogenesis of epilepsy. Therefore, this review aimed to elucidate the possible link between α-Syn and epilepsy, and how it affects the pathophysiology of epilepsy. A neurodegenerative protein such as α-Syn is implicated in the pathogenesis of epilepsy. Evidence from preclinical and clinical studies revealed that upregulation of α-Syn induces progressive neuronal dysfunctions through induction of oxidative stress, neuroinflammation, and inhibition of autophagy in a vicious cycle with subsequent development of severe epilepsy. In addition, accumulation of α-Syn in epilepsy could be secondary to the different cellular alterations including oxidative stress, neuroinflammation, reduction of brain-derived neurotrophic factor (BDNF) and progranulin (PGN), and failure of the autophagy pathway. However, the mechanism of α-Syn-induced-epileptogenesis is not well elucidated. Therefore, α-Syn could be a secondary consequence of epilepsy. Preclinical and clinical studies are warranted to confirm this causal relationship.
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Affiliation(s)
- Naif H Ali
- Department of Internal Medicine, Medical College, Najran University, Najran, Kingdom of Saudi Arabia
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, M.B.Ch.B, FRCP, P.O. Box 14132, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Jabir Ibn Hayyan Medical University, Al-Ameer Qu, P.O. Box 13, Kufa, Najaf, Iraq
| | - Saud A Alnaaim
- Clinical Neurosciences Department, College of Medicine, King Faisal University, Hofuf, Saudi Arabia
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, 51744, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt.
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Sun D, Altalbawy FMA, Yumashev A, Hjazi A, Menon SV, Kaur M, Deorari M, Abdulwahid AS, Shakir MN, Gabal BC. Shedding Light on the Role of Exosomal PD-L1 (ExoPD-L1) in Cancer Progression: an Update. Cell Biochem Biophys 2024; 82:1709-1720. [PMID: 38907940 DOI: 10.1007/s12013-024-01340-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2024] [Indexed: 06/24/2024]
Abstract
Exosomes are the primary category of extracellular vesicles (EVs), which are lipid-bilayer vesicles with biological activity spontaneously secreted from either normal or tansformed cells. They serve a crucial role for intercellular communication and affect extracellular environment and the immune system. Tumor-derived exosomes (TEXs) enclose high levels of immunosuppressive proteins, including programmed death-ligand 1 (PD-L1). PD-L1 and its receptor PD-1 act as crucial immune checkpoint molecules, thus facilitating tumor advancement by inhibiting immune responses. PDL-1 is abundantly present on tumor cells and interacts with PD-1 on activated T cells, resulting in T cell suppression and allowing immune evasion of cancer cells. Various FDA-approved monoclonal antibodies inhibiting the PD-1/PD-L1 interaction are commonly used to treat a diverse range of tumors. Although the achieved results are significant, some individuals have a poor reaction to PD-1/PD-L1 blocking. PD-L1-enriched TEXs may mimic the impact of cell-surface PD-L1, consequently potentiating tumor resistance to PD1/PD-L1 based therapy. In light of this, a strong correlation between circulating exosomal PD-L1 levels and response rate to anti-PD-1/PD-L1 antibody treatment has been evinced. This article inspects the function of exosomal PDL-1 in developing resistance to anti-PD-1/PD-L1 therapy for opening new avenues for overcoming tumor resistance to such modalities and development of more favored combination therapy.
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Affiliation(s)
- Dongmei Sun
- Siping City Central People's Hospital, Siping, Jilin, 136000, P. R. China
| | - Farag M A Altalbawy
- Department of Biochemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia.
| | - Alexey Yumashev
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Soumya V Menon
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mandeep Kaur
- Department of Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Alzahraa S Abdulwahid
- Department of Medical Laboratories Technology, Al-Hadi University College, Baghdad, 10011, Iraq
| | - Maha Noori Shakir
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | - Baneen Chasib Gabal
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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Rasouli A, Roshangar L, Hosseini M, Pourmohammadfazel A, Nikzad S. Beyond boundaries: The therapeutic potential of exosomes in neural microenvironments in neurological disorders. Neuroscience 2024; 553:98-109. [PMID: 38964450 DOI: 10.1016/j.neuroscience.2024.06.031] [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: 06/18/2024] [Accepted: 06/25/2024] [Indexed: 07/06/2024]
Abstract
Neurological disorders are a diverse group of conditions that can significantly impact individuals' quality of life. The maintenance of neural microenvironment homeostasis is essential for optimal physiological cellular processes. Perturbations in this delicate balance underlie various pathological manifestations observed across various neurological disorders. Current treatments for neurological disorders face substantial challenges, primarily due to the formidable blood-brain barrier and the intricate nature of neural tissue structures. These obstacles have resulted in a paucity of effective therapies and inefficiencies in patient care. Exosomes, nanoscale vesicles that contain a complex repertoire of biomolecules, are identifiable in various bodily fluids. They hold substantial promise in numerous therapeutic interventions due to their unique attributes, including targeted drug delivery mechanisms and the ability to cross the BBB, thereby enhancing their therapeutic potential. In this review, we investigate the therapeutic potential of exosomes across a range of neurological disorders, including neurodegenerative disorders, traumatic brain injury, peripheral nerve injury, brain tumors, and stroke. Through both in vitro and in vivo studies, our findings underscore the beneficial influence of exosomes in enhancing the neural microenvironment following neurological diseases, offering promise for improved neural recovery and management in these conditions.
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Affiliation(s)
- Arefe Rasouli
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Roshangar
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammadbagher Hosseini
- Department of Pediatrics, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Pourmohammadfazel
- Department of Anatomical Sciences, School of Medicine Tabriz University of Medical Sciences, Tabriz, Iran
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Huang Y, Li M, Liu Q, Song L, Wang Q, Ding P, Tian W, Guo S. Small extracellular vesicles derived from lipopolysaccharide-preconditioned dental follicle cells inhibit cell apoptosis and alveolar bone loss in periodontitis. Arch Oral Biol 2024; 162:105964. [PMID: 38582010 DOI: 10.1016/j.archoralbio.2024.105964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 03/11/2024] [Accepted: 03/31/2024] [Indexed: 04/08/2024]
Abstract
OBJECTIVE This study aimed to explore the effects of small extracellular vesicles derived from lipopolysaccharide-preconditioned dental follicle cells (L-D-sEV) on periodontal ligament cells from periodontitis affected teeth (p-PDLCs) in vitro and experimental periodontitis in mice. DESIGN In vitro, the biological function of p-PDLCs and the underlying molecular mechanism were investigated by flow cytometry, Western blot, and quantitative real-time PCR (qRT-PCR) analysis. Eighteen-eight-week-old male C57BL/6 mice were randomly divided into three groups: control (Con), periodontitis (Peri), and L-D-sEV groups. Mice periodontitis model was induced by placing the 5-0 silk thread (around the maxillary second molar) and P.gingivalis (1 ×107 CFUs per mouse). In vivo, the alveolar bone loss, osteoclast activity, and macrophage polarization were measured by micro-computed tomography and histological analysis. RESULTS In vitro, the RANKL/OPG ratio and phosphorylation of JNK and P38 protein levels of p-PDLCs were significantly decreased after L-D-sEV administration. Besides, flow cytometry and qRT-PCR analysis showed that L-D-sEV reduced apoptosis of p-PDLCs, down-regulated apoptosis-related genes Caspase-3 and BCL-2-Associated X expression, and up-regulated B-cell lymphoma-2 gene levels. In vivo, L-D-sEV administration significantly reduced alveolar bone loss, inhibited osteoclast activity, and induced M2 polarization. The histological analysis showed that iNOS/CD206, RANKL/OPG, p-JNK/JNK, and p-P38/P38 ratios were significantly lower in the L-D-sEV group than in the Peri group. CONCLUSIONS L-D-sEV administration alleviated alveolar bone loss by mediating RANKL/OPG-related osteoclast activity and M2 macrophage polarization, alleviating p-PDLCs apoptosis and proliferation via the JNK and P38 pathways.
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Affiliation(s)
- Yanli Huang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, People's Republic of China
| | - Mujia Li
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, People's Republic of China
| | - Qian Liu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, People's Republic of China
| | - Lu Song
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, People's Republic of China
| | - Qianting Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, People's Republic of China
| | - Peihui Ding
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, People's Republic of China
| | - Weidong Tian
- State Key Laboratory of Oral Disease & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Oral Regenerative Medicine, Engineering Research Center of Oral Translational Medicine, Ministry of Education, Department of Periodontics, West China School of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Shujuan Guo
- State Key Laboratory of Oral Disease & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Oral Regenerative Medicine, Engineering Research Center of Oral Translational Medicine, Ministry of Education, Department of Periodontics, West China School of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China.
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Saleh RO, Hjazi A, Bansal P, Ahmad I, Kaur H, Ali SHJ, Deorari M, Abosaoda MK, Hamzah HF, Mohammed BA. Mysterious interactions between macrophage-derived exosomes and tumors; what do we know? Pathol Res Pract 2024; 256:155261. [PMID: 38518733 DOI: 10.1016/j.prp.2024.155261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 03/24/2024]
Abstract
Through their ability to modify the tumor microenvironment and cancer cells, macrophages play a crucial role in the promotion of tumorigenesis, development of tumors and metastasis, and chemotherapy resistance. A growing body of research has indicated that exosomes may be essential for coordinating the communication between cancer cells and macrophages. One type of extracellular vehicle called an exosome is utilized for delivering a variety of molecules, such as proteins, lipids, and nucleic acids, to specific cells in order to produce pleiotropic effects. Exosomes derived from macrophages exhibit heterogeneity across various cancer types and function paradoxically, suppressing tumor growth while stimulating it, primarily through post-transcriptional control and protein phosphorylation regulation in the receiving cells. Exosomes released by various macrophage phenotypes offer a variety of therapeutic alternatives in the interim. We outlined the most recent developments in this article, including our understanding of the roles that mechanisms and macrophage-derived exosomal biogenesis play in mediating the progression of cancer and their possible therapeutic uses.
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Affiliation(s)
- Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq.
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India.
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia.
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh 247341, India; Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand 831001, India.
| | - Saad Hayif Jasim Ali
- Department of medical laboratory, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq.
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
| | - Munther Kadhim Abosaoda
- College of pharmacy, the Islamic University, Najaf, Iraq; College of pharmacy, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; College of pharmacy, the Islamic University of Babylon, Al Diwaniyah, Iraq.
| | - Hamza Fadhel Hamzah
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq.
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da Silva Gonçalves CE, Fock RA. Semaphorins and the bone marrow microenvironment: New candidates that influence the hematopoietic system. Cytokine Growth Factor Rev 2024; 76:22-29. [PMID: 38472041 DOI: 10.1016/j.cytogfr.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024]
Abstract
The bone marrow is a haven for hematopoietic and non-hematopoietic cells, creating complex micro-anatomical regions called niches. These distinct niches all participate in an intricate orchestra of cellular interactions that regulates the hematopoietic stem cell and its progenies. In this review, we provide a detailed description of the three most well-known bone marrow niches and their participation in hematopoiesis. We use pre-clinical data, including different in vitro and in vivo studies to discuss how a group of proteins called Semaphorins could potentially modulate both hematopoietic and non-hematopoietic cells, establishing links between the niches, semaphorins, and hematopoietic regulation. Thus, here we provide a deep dive into the inner functioning of the bone marrow and discuss the overarching implications that semaphorins might have on blood formation.
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Affiliation(s)
- Carlos E da Silva Gonçalves
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
| | - Ricardo A Fock
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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Yadav A, Nandy A, Sharma A, Ghatak S. Exosome Mediated Cell-Cell Crosstalk in Tissue Injury and Repair. Results Probl Cell Differ 2024; 73:249-297. [PMID: 39242383 DOI: 10.1007/978-3-031-62036-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2024]
Abstract
The landscape of exosome research has undergone a significant paradigm shift, with a departure from early conceptions of exosomes as vehicles for cellular waste disposal towards their recognition as integral components of cellular communication with therapeutic potential. This chapter presents an exhaustive elucidation of exosome biology, detailing the processes of exosome biogenesis, release, and uptake, and their pivotal roles in signal transduction, tissue repair, regeneration, and intercellular communication. Additionally, the chapter highlights recent innovations and anticipates future directions in exosome research, emphasizing their applicability in clinical settings. Exosomes have the unique ability to navigate through tissue spaces to enter the circulatory system, positioning them as key players in tissue repair. Their contributory role in various processes of tissue repair, although in the nascent stages of investigation, stands out as a promising area of research. These vesicles function as a complex signaling network for intracellular and organ-level communication, critical in both pathological and physiological contexts. The chapter further explores the tissue-specific functionality of exosomes and underscores the advancements in methodologies for their isolation and purification, which have been instrumental in expanding the scope of exosome research. The differential cargo profiles of exosomes, dependent on their cellular origin, position them as prospective diagnostic biomarkers for tissue damage and regenerative processes. Looking ahead, the trajectory of exosome research is anticipated to bring transformative changes to biomedical fields. This includes advancing diagnostic and prognostic techniques that utilize exosomes as non-invasive biomarkers for a plethora of diseases, such as cancer, neurodegenerative, and cardiovascular conditions. Additionally, engineering exosomes through alterations of their native content or surface properties presents a novel frontier, including the synthesis of artificial or hybrid variants with enhanced functional properties. Concurrently, the ethical and regulatory frameworks surrounding exosome research, particularly in clinical translation, will require thorough deliberation. In conclusion, the diverse aspects of exosome research are coalescing to redefine the frontiers of diagnostic and therapeutic methodologies, cementing its importance as a discipline of considerable consequence in the biomedical sciences.
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Affiliation(s)
- Anita Yadav
- McGowan Institute for Regenerative Medicine, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Aparajita Nandy
- McGowan Institute for Regenerative Medicine, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anu Sharma
- McGowan Institute for Regenerative Medicine, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Subhadip Ghatak
- McGowan Institute for Regenerative Medicine, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Haghmorad D, Khaleghian A, Eslami M, Sadeghnejad A, Tarahomi M, Yousefi B. Bone marrow mesenchymal stem cells to ameliorate experimental autoimmune encephalomyelitis via modifying expression patterns of miRNAs. Mol Biol Rep 2023; 50:9971-9984. [PMID: 37897611 DOI: 10.1007/s11033-023-08843-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 09/25/2023] [Indexed: 10/30/2023]
Abstract
INTRODUCTION Clinical and experimental studies highlighted the significant therapeutic role of Mesenchymal stem cells (MSCs) in neurodegenerative diseases. MSCs possess potent immunomodulatory properties by releasing exosomes, which generate a suitable microenvironment. microRNAs (miRNAs), as one of several effective bioactive molecules of exosomes, influence cellular communication and activities in recipient cells. Recent studies revealed that miRNAs could control the progression of multiple sclerosis (MS) via differentiation and function of T helper cells (Th). METHODS Here, we investigated the therapeutic effects of syngeneic-derived BM-MSC in experimental autoimmune encephalomyelitis (EAE) mouse model of MS by evaluating expression profile of miRNAs, pro- and anti-inflammatory in serum and brain tissues. Three-time scheme groups (6th day, 6th & 12th days, and 12th day, of post-EAE induction) were applied to determine the therapeutic effects of intraperitoneally received 1*106 of BM-MSCs. RESULTS The expression levels of mature isoforms of miR-193, miR-146a, miR-155, miR-21, and miR-326 showed that BM-MSCs treatment attenuated the EAE clinical score and reduced clinical inflammation as well as demyelination. The improved neurological functional outcome associated with enhanced expression of miR-193 and miR-146a, but decreased expression levels of miR-155, miR-21, and miR-326 were followed by suppressing effects on Th1/Th17 immune responses (reduced levels of IFN-γand IL-17 cytokine expression) and induction of Treg cells, immunoregulatory responses (increase of IL-10, TGF-β, and IL-4) in treatment groups. CONCLUSION Our findings suggest that BM-MSCs administration might change expression patterns of miRNAs and downstream interactions followed by immune system modulation. However, there is a need to carry out future human clinical trials and complementary experiments.
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Affiliation(s)
- Dariush Haghmorad
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Khaleghian
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Mahdieh Tarahomi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran.
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13
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Jahangiri B, Khalaj-Kondori M, Asadollahi E, Kian Saei A, Sadeghizadeh M. Dual impacts of mesenchymal stem cell-derived exosomes on cancer cells: unravelling complex interactions. J Cell Commun Signal 2023:10.1007/s12079-023-00794-3. [PMID: 37973719 DOI: 10.1007/s12079-023-00794-3] [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: 06/10/2023] [Accepted: 11/06/2023] [Indexed: 11/19/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent, self-renewing stromal cells found in a variety of adult tissues. MSCs possess a remarkable ability to migrate towards tumor sites, known as homing. This homing process is mediated by various factors, including chemokines, growth factors, and extracellular matrix components present in the tumor microenvironment. MSCs release extracellular vesicles known as exosomes (MSC-Exos), which have been suggested to serve a key role in mediating a wide variety of MSC activities. Through cell-cell communication, MSC-Exos have been shown to alter recipient cell phenotype or function and play as a novel cell-free alternative for MSC-based cell therapy. However, MSC recruitment to tumors allows for their interaction with cancer cells and subsequent regulation of tumor behavior. MSC-Exos act as tumor niche modulators via transferring exosomal contents, such as specific proteins or genetic materials, to the nearby cancer cells, leading to either promotion or suppression of tumorigenesis, angiogenesis, and metastasis, depending on the specific microenvironmental cues and recipient cell characteristics. Consequently, there is still a debate about the precise relationship between tumor cells and MSC-Exos, and it is unclear how MSC-Exos impacts tumor cells. Although the dysregulation of miRNAs is caused by the progression of cancer, they also play a direct role in either promoting or inhibiting tumor growth as they act as either oncogenes or tumor suppressors. The utilization of MSC-Exos may prove to be an effective method for restoring miRNA as a means of treating cancer. This review aimed to present the existing understanding of the impact that MSC-Exos could have on cancer. To begin with, we presented a brief explanation of exosomes, MSCs, and MSC-Exos. Following this, we delved into the impact of MSC-Exos on cancer growth, EMT, metastasis, angiogenesis, resistance to chemotherapy and radiotherapy, and modulation of the immune system. Opposing effects of mesenchymal stem cells-derived exosomes on cancer cells.
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Affiliation(s)
- Babak Jahangiri
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Elahe Asadollahi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Kian Saei
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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14
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Karpenko DV. Immune Privileges as a Result of Mutual Regulation of Immune and Stem Systems. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:1818-1831. [PMID: 38105201 DOI: 10.1134/s0006297923110123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 12/19/2023]
Abstract
Immune privileges of cancer stem cells is a well-known and widely studied problem, as presence of such cells in tumors is associated with refractoriness, recurrence, and metastasis. Accumulating evidence also suggests presence of immune privileges in non-pathological stem cells in addition to their other defense mechanisms against damaging factors. This similarity between pathological and normal stem cells raises the question of why stem cells have such a potentially dangerous property. Regulation of vital processes of autoimmunity control and regeneration realized through interactions between immune cells, stem cells, and their microenvironment are reviewed in this work as causes of formation of the stem cell immune privilege. Deep mutual integration between regulations of stem and immune cells is noted. Considering diversity and complexity of mutual regulation of stem cells, their microenvironment, and immune system, I suggest the term "stem system".
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Affiliation(s)
- Dmitriy V Karpenko
- Laboratory of Epigenetic Regulation of Hematopoiesis, National Medical Research Center for Hematology, Moscow, 125167, Russia.
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15
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Li P, Yin R, Chen Y, Chang J, Yang L, Liu X, Xu H, Zhang X, Wang S, Han Q, Wei J. Engineered extracellular vesicles for ischemic stroke: a systematic review and meta-analysis of preclinical studies. J Nanobiotechnology 2023; 21:396. [PMID: 37904204 PMCID: PMC10617166 DOI: 10.1186/s12951-023-02114-8] [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: 06/21/2023] [Accepted: 09/15/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND This systematic review and meta-analysis aimed to evaluate the efficacy of engineered extracellular vesicles (EEVs) in the treatment of ischemic stroke (IS) in preclinical studies and to compare them with natural extracellular vesicles (EVs). The systematic review provides an up-to-date overview of the current state of the literature on the use of EEVs for IS and informs future research in this area. METHODS We searched PubMed, EMBASE, Web of Science, Cochrane Library, and Scopus databases for peer-reviewed preclinical studies on the therapeutic effect of EEVs on IS.Databases ranged from the inception to August 1, 2023. The outcome measures included infarct volumes, neurological scores, behavioral scores, apoptosis rates, numbers of neurons, and levels of IL-1β, IL-6, and TNF-α. The CAMARADES checklist was used to assess the quality and bias risks of the studies. All statistical analyses were performed using RevMan 5.4 software. RESULTS A total of 28 studies involving 1760 animals met the inclusion criteria. The results of the meta-analysis showed that compared to natural EVs, EEVs reduced infarct volume (percentage: SMD = -2.33, 95% CI: -2.92, -1.73; size: SMD = -2.36, 95% CI: -4.09, -0.63), improved neurological scores (mNSS: SMD = -1.78, 95% CI: -2.39, -1.17; Zea Longa: SMD = -2.75, 95% CI: -3.79, -1.71), promoted behavioral recovery (rotarod test: SMD = 2.50, 95% CI: 1.81, 3.18; grid-walking test: SMD = -3.45, 95% CI: -5.15, -1.75; adhesive removal test: SMD = -2.60, 95% CI: -4.27, -0.93; morris water maze test: SMD = -3.91, 95% CI: -7.03, -0.79), and reduced the release of proinflammatory factors (IL-1β: SMD = -2.02, 95% CI: -2.77, -1.27; IL-6: SMD = -3.01, 95% CI: -4.47, -1.55; TNF-α: SMD = -2.72, 95% CI: -4.30, -1.13), increasing the number of neurons (apoptosis rate: SMD = -2.24, 95% CI: -3.32, -1.16; the number of neurons: SMD = 3.70, 95% CI: 2.44, 4.96). The funnel plots for the two main outcome measures were asymmetric, indicating publication bias. The median score on the CAMARADES checklist was 7 points (IQR: 6-9). CONCLUSIONS This meta-analysis shows that EEVs are superior to natural EVs for the treatment of IS. However, research in this field is still at an early stage, and more research is needed to fully understand the potential therapeutic mechanism of EEVs and their potential use in the treatment of IS. PROSPERO REGISTRATION NUMBER CRD42022368744.
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Affiliation(s)
- Pengtao Li
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Yin
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yihao Chen
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jianbo Chang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Lang Yang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoyu Liu
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Houshi Xu
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Zhang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Shihua Wang
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Qin Han
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
| | - Junji Wei
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
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Niu S, Li B, Gu H, Huang Q, Cheng Y, Wang C, Cao G, Yang Q, Zhang D, Cao J. Knowledge mapping of extracellular vesicles in wound healing: A bibliometric analysis (2002-2022). Int Wound J 2023; 20:3221-3240. [PMID: 37183322 PMCID: PMC10502250 DOI: 10.1111/iwj.14202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 05/16/2023] Open
Abstract
Extracellular vesicles in wound healing have become an active research field with substantial value and potential. Nevertheless, there are few bibliometric studies in this field. We aimed to visualise the research hot spots and trends of extracellular vesicles in wound healing using a bibliometric analysis to help understand the future development of basic and clinical research. The articles and reviews regarding extracellular vesicles in the wound healing were selected from the Web of Science Core Collection. VOSviewers, CiteSpace and R package "bibliometric" were used to conduct this bibliometric analysis. A total of 1225 articles from 56 countries led by China and the United States were included. The number of publications related to extracellular vesicles increased year by year. Shanghai Jiaotong University, Huazhong University of Science and Technology, Sun Yat-sen University and Central South University are the main research institutions. International Journal of Molecular Sciences is the most popular journal in this field, while Stem Cell Research & Therapy is the most frequently cited journal. These papers come from 7546 authors, among which Zhang Wei has published the most papers and Zhang Bin has the most cocited papers. The research on the treatment strategy of extracellular vesicles in the process of wound healing is the main topic in this field. "exosomes", "miRNA", "angiogenesis", "regenerative medicine", "inflammation" and "diabetic wound" are the main key words of emerging research hotspots. This is the first bibliometric study, which comprehensively summarises the research trend and development of extracellular vesicles and exocrine bodies in wound healing. These informations determine the latest research frontiers and hot directions, and provide reference for the study of extracellular vesicles and exosomes.
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Affiliation(s)
- Shao‐hui Niu
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Bei Li
- Shanxi University of Chinese MedicineTaiyuanChina
| | - Han‐cheng Gu
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Qiang Huang
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Ya‐qing Cheng
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Chang Wang
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Gang Cao
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Qiaoli Yang
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
| | - Dong‐ping Zhang
- Dongzhimen HospitalBeijing University of Chinese MedicineBeijingChina
| | - Jian‐chun Cao
- Dongfang HospitalBeijing University of Chinese MedicineBeijingChina
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17
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Lin FH, Yang YX, Wang YJ, Subbiah SK, Wu XY. Amniotic membrane mesenchymal stromal cell-derived secretome in the treatment of acute ischemic stroke: A case report. World J Clin Cases 2023; 11:6543-6550. [PMID: 37900223 PMCID: PMC10601006 DOI: 10.12998/wjcc.v11.i27.6543] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/30/2023] [Accepted: 08/18/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND Stroke is the second and third leading cause of death and disability, respectively. To date, no definitive treatment can repair lost brain function. Recently, various preclinical studies have been reported on mesenchymal stromal cells (MSCs) and their derivatives and their potential as alternative therapies for stroke. CASE SUMMARY A 45-year-old female suffered an acute stroke, which led to paralysis in the left upper and lower limbs. The amniotic membrane MSC-derived secretome (MSC-secretome) was intravenously transplanted once a week for 4 wk. MSC-secretome-regulated regulatory T cells were investigated for the beneficial effects. The clinical improvement of this patient was accompanied by an increased frequency of regulatory T cells after transplantation. CONCLUSION Intravenous administration of MSC-secretome can potentially treat patients who suffer from acute ischemic stroke.
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Affiliation(s)
- Fu-Hong Lin
- Department of Neurology, Affiliated Hospital of Chifeng College, Chifeng 024000, Inner Mongolia Autonomous Region, China
| | - Yu-Xiao Yang
- Department of Technology, Beijing Protercell Biotechnology Co. Ltd., Beijing 102600, China
- Department of Technology, Inner Mongolia Protercell Biotechnology Co. Ltd., Hohhot 010000, Inner Mongolia Autonomous Region, China
| | - Yu-Jun Wang
- Department of Technology, Beijing Protercell Biotechnology Co. Ltd., Beijing 102600, China
- Department of Technology, Inner Mongolia Protercell Biotechnology Co. Ltd., Hohhot 010000, Inner Mongolia Autonomous Region, China
| | - Suresh Kumar Subbiah
- Centre for Materials Engineering and Regenerative Medicine, Bharath Institute of Higher Education and Research, Chennai 600126, India
| | - Xiao-Yun Wu
- Department of Technology, Beijing Protercell Biotechnology Co. Ltd., Beijing 102600, China
- Department of Technology, Inner Mongolia Protercell Biotechnology Co. Ltd., Hohhot 010000, Inner Mongolia Autonomous Region, China
- Department of Interventional, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
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18
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Zhao W, Zhang H, Liu R, Cui R. Advances in Immunomodulatory Mechanisms of Mesenchymal Stem Cells-Derived Exosome on Immune Cells in Scar Formation. Int J Nanomedicine 2023; 18:3643-3662. [PMID: 37427367 PMCID: PMC10327916 DOI: 10.2147/ijn.s412717] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/19/2023] [Indexed: 07/11/2023] Open
Abstract
Pathological scars are the result of over-repair and excessive tissue proliferation of the skin injury. It may cause serious dysfunction, resulting in psychological and physiological burdens on the patients. Currently, mesenchymal stem cells-derived exosomes (MSC-Exo) displayed a promising therapeutic effect on wound repair and scar attenuation. But the regulatory mechanisms are opinions vary. In view of inflammation has long been proven as the initial factor of wound healing and scarring, and the unique immunomodulation mechanism of MSC-Exo, the utilization of MSC-Exo may be promising therapeutic for pathological scars. However, different immune cells function differently during wound repair and scar formation. The immunoregulatory mechanism of MSC-Exo would differ among different immune cells and molecules. Herein, this review gave a comprehensive summary of MSC-Exo immunomodulating different immune cells in wound healing and scar formation to provide basic theoretical references and therapeutic exploration of inflammatory wound healing and pathological scars.
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Affiliation(s)
- Wen Zhao
- Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China
| | - Huimin Zhang
- Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China
| | - Rui Liu
- Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China
| | - Rongtao Cui
- Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China
- Department of Burn and Plastic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China
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Rizzo MG, Best TM, Huard J, Philippon M, Hornicek F, Duan Z, Griswold AJ, Kaplan LD, Hare JM, Kouroupis D. Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents. Cells 2023; 12:1421. [PMID: 37408255 PMCID: PMC10217382 DOI: 10.3390/cells12101421] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/08/2023] [Accepted: 05/13/2023] [Indexed: 07/07/2023] Open
Abstract
Osteoarthritis (OA) is the most common cause of disability worldwide among the elderly. Alarmingly, the incidence of OA in individuals less than 40 years of age is rising, likely due to the increase in obesity and post-traumatic osteoarthritis (PTOA). In recent years, due to a better understanding of the underlying pathophysiology of OA, several potential therapeutic approaches targeting specific molecular pathways have been identified. In particular, the role of inflammation and the immune system has been increasingly recognized as important in a variety of musculoskeletal diseases, including OA. Similarly, higher levels of host cellular senescence, characterized by cessation of cell division and the secretion of a senescence-associated secretory phenotype (SASP) within the local tissue microenvironments, have also been linked to OA and its progression. New advances in the field, including stem cell therapies and senolytics, are emerging with the goal of slowing disease progression. Mesenchymal stem/stromal cells (MSCs) are a subset of multipotent adult stem cells that have demonstrated the potential to modulate unchecked inflammation, reverse fibrosis, attenuate pain, and potentially treat patients with OA. Numerous studies have demonstrated the potential of MSC extracellular vesicles (EVs) as cell-free treatments that comply with FDA regulations. EVs, including exosomes and microvesicles, are released by numerous cell types and are increasingly recognized as playing a critical role in cell-cell communication in age-related diseases, including OA. Treatment strategies for OA are being developed that target senescent cells and the paracrine and autocrine secretions of SASP. This article highlights the encouraging potential for MSC or MSC-derived products alone or in combination with senolytics to control patient symptoms and potentially mitigate the progression of OA. We will also explore the application of genomic principles to the study of OA and the potential for the discovery of OA phenotypes that can motivate more precise patient-driven treatments.
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Affiliation(s)
- Michael G. Rizzo
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Thomas M. Best
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Johnny Huard
- Center for Regenerative and Personalized Medicine (CRPM), Steadman Philippon Research Institute, Vail, CO 81657, USA (M.P.)
| | - Marc Philippon
- Center for Regenerative and Personalized Medicine (CRPM), Steadman Philippon Research Institute, Vail, CO 81657, USA (M.P.)
| | - Francis Hornicek
- Department of Orthopedics, Sarcoma Biology Laboratory, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.H.); (Z.D.)
| | - Zhenfeng Duan
- Department of Orthopedics, Sarcoma Biology Laboratory, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (F.H.); (Z.D.)
| | - Anthony J. Griswold
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA;
| | - Lee D. Kaplan
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
| | - Joshua M. Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33101, USA
| | - Dimitrios Kouroupis
- Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL 33146, USA; (M.G.R.); (T.M.B.)
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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20
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Teo KYW, Zhang S, Loh JT, Lai RC, Hey HWD, Lam KP, Lim SK, Toh WS. Mesenchymal Stromal Cell Exosomes Mediate M2-like Macrophage Polarization through CD73/Ecto-5'-Nucleotidase Activity. Pharmaceutics 2023; 15:pharmaceutics15051489. [PMID: 37242732 DOI: 10.3390/pharmaceutics15051489] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/06/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to involve the activation of the MyD88-mediated toll-like receptor (TLR) signaling pathway by the presence of extra domain A-fibronectin (EDA-FN) within the MSC exosomes. Here, we uncovered an additional mechanism where MSC exosomes mediate M2-like macrophage polarization through exosomal CD73 activity. Specifically, we observed that polarization of M2-like macrophages by MSC exosomes was abolished in the presence of inhibitors of CD73 activity, adenosine receptors A2A and A2B, and AKT/ERK phosphorylation. These findings suggest that MSC exosomes promote M2-like macrophage polarization by catalyzing the production of adenosine, which then binds to adenosine receptors A2A and A2B to activate AKT/ERK-dependent signaling pathways. Thus, CD73 represents an additional critical attribute of MSC exosomes in mediating M2-like macrophage polarization. These findings have implications for predicting the immunomodulatory potency of MSC exosome preparations.
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Affiliation(s)
- Kristeen Ye Wen Teo
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
| | - Shipin Zhang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
| | - Jia Tong Loh
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Singapore 138648, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Hwee Weng Dennis Hey
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Kong-Peng Lam
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Singapore 138648, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Wei Seong Toh
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
- Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, Singapore 117510, Singapore
- Integrative Sciences and Engineering Program, NUS Graduate School, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore
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21
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Zhang B, Zhang B, Lai RC, Sim WK, Lam KP, Lim SK. MSC-sEV Treatment Polarizes Pro-Fibrotic M2 Macrophages without Exacerbating Liver Fibrosis in NASH. Int J Mol Sci 2023; 24:ijms24098092. [PMID: 37175803 PMCID: PMC10179074 DOI: 10.3390/ijms24098092] [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: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Mesenchymal stem/stromal cell small extracellular vesicles (MSC-sEVs) have shown promise in treating a wide range of animal models of various human diseases, which has led to their consideration for clinical translation. However, the possibility of contraindication for MSC-sEV use is an important consideration. One concern is that MSC-sEVs have been shown to induce M2 macrophage polarization, which is known to be pro-fibrotic, potentially indicating contraindication in fibrotic diseases such as liver fibrosis. Despite this concern, previous studies have shown that MSC-sEVs alleviate high-fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH). To assess whether the pro-fibrotic M2 macrophage polarization induced by MSC-sEVs could worsen liver fibrosis, we first verified that our MSC-sEV preparations could promote M2 polarization in vitro prior to their administration in a mouse model of NASH. Our results showed that treatment with MSC-sEVs reduced or had comparable NAFLD Activity Scores and liver fibrosis compared to vehicle- and Telmisartan-treated animals, respectively. Although CD163+ M2 macrophages were increased in the liver, and serum IL-6 levels were reduced in MSC-sEV treated animals, our data suggests that MSC-sEV treatment was efficacious in reducing liver fibrosis in a mouse model of NASH despite an increase in pro-fibrotic M2 macrophage polarization.
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Affiliation(s)
- Bin Zhang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Biyan Zhang
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Wei Kian Sim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Kong Peng Lam
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore
- School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
- Department of Surgery, YLL School of Medicine, NUS, 5 Lower Kent Ridge Road, Singapore 119074, Singapore
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22
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Almahasneh F, Abu-El-Rub E, Khasawneh RR. Mechanisms of analgesic effect of mesenchymal stem cells in osteoarthritis pain. World J Stem Cells 2023; 15:196-208. [PMID: 37181003 PMCID: PMC10173815 DOI: 10.4252/wjsc.v15.i4.196] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/25/2023] [Accepted: 03/27/2023] [Indexed: 04/26/2023] Open
Abstract
Osteoarthritis (OA) is the most common musculoskeletal disease, and it is a major cause of pain, disability and health burden. Pain is the most common and bothersome presentation of OA, but its treatment is still suboptimal, due to the short-term action of employed analgesics and their poor adverse effect profile. Due to their regenerative and anti-inflammatory properties, mesenchymal stem cells (MSCs) have been extensively investigated as a potential therapy for OA, and numerous preclinical and clinical studies found a significant improvement in joint pathology and function, pain scores and/or quality of life after administration of MSCs. Only a limited number of studies, however, addressed pain control as the primary end-point or investigated the potential mechanisms of analgesia induced by MSCs. In this paper, we review the evidence reported in literature that support the analgesic action of MSCs in OA, and we summarize the potential mechanisms of these antinociceptive effects.
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Affiliation(s)
- Fatimah Almahasneh
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan
| | - Ejlal Abu-El-Rub
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan
| | - Ramada R Khasawneh
- Basic Medical Sciences, Faculty of Medicine -Yarmouk University, Irbid 21163, Jordan
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23
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Dong J, Wu B, Tian W. Human adipose tissue-derived small extracellular vesicles promote soft tissue repair through modulating M1-to-M2 polarization of macrophages. Stem Cell Res Ther 2023; 14:67. [PMID: 37024970 PMCID: PMC10080905 DOI: 10.1186/s13287-023-03306-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 03/28/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND Successful regenerative medicine strategies need the manipulation and control of macrophages' phenotypic switching. Our previous study indicated that rat and porcine adipose tissue-derived small extracellular vesicles could successfully promote soft tissue repair. However, whether human adipose tissue-derived small extracellular vesicles (h-sEV-AT) showed the same ability to promote soft tissue regeneration and whether adipose tissue-derived small extracellular vesicles (sEV-AT) contribute to modulating the polarization of macrophages were unknown. METHODS In this study, we, for the first time, isolated h-sEV-AT from liposuction adipose tissue and characterized the morphology, size distribution, and marker protein. In vitro, we treated adipose-derived stromal/stem cells (ASCs), endothelial cells (ECs), and M1 macrophages with h-sEV-AT. In vivo, the ability of h-sEV-AT to promote soft tissue regeneration and polarize macrophages was investigated. RESULTS The results indicated that h-sEV-AT possessed the characteristics of small extracellular vesicles (sEVs). In vitro, an obvious increase in adipogenesis and angiogenesis was induced by h-sEV-AT. In vivo, h-sEV-AT successfully induced the regeneration of adipose tissue and effectively accelerated full-thickness skin wound healing. Besides, we found that h-sEV-AT showed the ability to increase the percentage of M2 macrophages both in vivo and in vitro, which had been reported to contribute to tissue repair and regeneration. CONCLUSIONS Taken together, these results suggested that h-sEV-AT showed the ability to induce soft tissue repair supported by not only the differentiation of ASCs and ECs but also the polarization of macrophages. Considering the abundant sources, high yield, and guaranteed effectiveness, this study provided a cell-free strategy for soft tissue regeneration that directly isolated small extracellular vesicles from human liposuction adipose tissue.
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Affiliation(s)
- Jia Dong
- State Key Laboratory of Oral Disease and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Sichuan, 610041, Chengdu, China.
- Department of Stomatology, People's Hospital of Longhua Shenzhen, Shenzhen, 518109, Guangdong, China.
| | - Bin Wu
- Department of Stomatology, People's Hospital of Longhua Shenzhen, Shenzhen, 518109, Guangdong, China
| | - Weidong Tian
- State Key Laboratory of Oral Disease and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Sichuan, 610041, Chengdu, China.
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24
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Circulating MiRNA-21-enriched extracellular vesicles promote bone remodeling in traumatic brain injury patients. Exp Mol Med 2023; 55:587-596. [PMID: 36869070 PMCID: PMC10073188 DOI: 10.1038/s12276-023-00956-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 03/05/2023] Open
Abstract
Fracture combined with traumatic brain injury (TBI) is one of the most common and serious types of compound trauma in the clinic and is characterized by dysfunction of cellular communication in injured organs. Our prior studies found that TBI was capable of enhancing fracture healing in a paracrine manner. Exosomes (Exos), as small extracellular vesicles, are important paracrine vehicles for noncell therapy. However, whether circulating Exos derived from TBI patients (TBI-Exos) regulate the prohealing effects of fractures remains unclear. Thus, the present study aimed to explore the biological effects of TBI-Exos on fracture healing and reveal the potential molecular mechanism. TBI-Exos were isolated by ultracentrifugation, and the enriched miR-21-5 p was identified by qRT‒PCR analysis. The beneficial effects of TBI-Exos on osteoblastic differentiation and bone remodeling were determined by a series of in vitro assays. Bioinformatics analyses were conducted to identify the potential downstream mechanisms of the regulatory effect of TBI-Exos on osteoblasts. Furthermore, the role of the potential signaling pathway of TBI-Exos in mediating the osteoblastic activity of osteoblasts was assessed. Subsequently, a murine fracture model was established, and the effect of TBI-Exos on bone modeling was demonstrated in vivo. TBI-Exos can be internalized by osteoblasts, and in vitro, suppression of SMAD7 promoted osteogenic differentiation, whereas knockdown of miR-21-5 p in TBI-Exos strongly inhibited this bone-beneficial effect. Similarly, our results confirmed that preinjection of TBI-Exos led to enhanced bone formation, whereas knockdown of exosomal miR-21-5 p substantially impaired this bone-beneficial effect in vivo.
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25
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TLR3 stimulation improves the migratory potency of adipose-derived mesenchymal stem cells through the stress response pathway in the melanoma mouse model. Mol Biol Rep 2023; 50:2293-2304. [PMID: 36575321 DOI: 10.1007/s11033-022-08111-8] [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: 07/09/2022] [Accepted: 11/09/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are utilized as a carrier of anti-tumor agents in targeted anti-cancer therapy. Despite the improvements in this area, there are still some unsolved issues in determining the appropriate dose, method of administration and biodistribution of MSCs. The current study aimed to determine the influence of toll-like receptor 3 (TLR3) stimulation on the potential of MSCs migration to the neoplasm environment in the mouse melanoma model. METHODS AND RESULTS Adipose-derived MSCs (ADMSCs) were isolated from the GFP+ transgenic C57BL/6 mouse and treated with different doses (1 µg/ml and 10 µg/ml) of polyinosinic-polycytidylic acid, the related TLR3 agonist, at various time points (1 and 4 h). Following the treatment, the expression of targeted genes such as α4, α5, and β1 integrins and TGF-β and IL-10 anti-inflammatory cytokines was determined using real-time PCR. In vivo live imaging evaluated the migration index of the intraperitoneally (IP) injected treated ADMSCs in a lung tumor-bearing mouse (C57BL/6) melanoma model (n = 5). The presented findings demonstrated that TLR3 stimulation enhanced both migration of ADMSCs to the tumor area compared with control group (n = 5) and expression of α4, α5, and β1 integrins. It was also detected that the engagement of TLR3 resulted in the anti-inflammatory behavior of the cells, which might influence the directed movement of ADMSCs. CONCLUSION This research identified that TLR3 activation might improve the migration via the stimulation of stress response in the cells and depending on the agonist concentration and time exposure, this activated pathway drives the migratory behavior of MSCs.
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26
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Xiong Y, Mi BB, Lin Z, Hu YQ, Yu L, Zha KK, Panayi AC, Yu T, Chen L, Liu ZP, Patel A, Feng Q, Zhou SH, Liu GH. The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity. Mil Med Res 2022; 9:65. [PMID: 36401295 PMCID: PMC9675067 DOI: 10.1186/s40779-022-00426-8] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 10/30/2022] [Indexed: 11/21/2022] Open
Abstract
Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.
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Affiliation(s)
- Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Bo-Bin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Yi-Qiang Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Le Yu
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA
| | - Kang-Kang Zha
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.,Key Laboratory of Biorheological Science and Technology,Ministry of Education College of Bioengineering, Chongqing University, Shapingba, Chongqing, 400044, China
| | - Adriana C Panayi
- Department of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02152, USA
| | - Tao Yu
- Department of Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.,Department of Physics, Center for Hybrid Nanostructure (CHyN), University of Hamburg, Hamburg, 22761, Germany
| | - Zhen-Ping Liu
- Department of Physics, Center for Hybrid Nanostructure (CHyN), University of Hamburg, Hamburg, 22761, Germany.,Joint Laboratory of Optofluidic Technology and System,National Center for International Research on Green Optoelectronics, South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou, 510006, China
| | - Anish Patel
- Skeletal Biology Laboratory, Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02120, USA
| | - Qian Feng
- Key Laboratory of Biorheological Science and Technology,Ministry of Education College of Bioengineering, Chongqing University, Shapingba, Chongqing, 400044, China.
| | - Shuan-Hu Zhou
- Skeletal Biology Laboratory, Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02120, USA. .,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA.
| | - Guo-Hui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. .,Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China.
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27
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Mesenchymal Stem Cell-Derived Extracellular Vesicles Therapy for Pulmonary Hypertension: A Comprehensive Review of Preclinical Studies. J Interv Cardiol 2022; 2022:5451947. [PMID: 36419957 PMCID: PMC9652076 DOI: 10.1155/2022/5451947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 10/09/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Pulmonary hypertension (PH) is a type of clinical pathophysiological syndrome characterized by a progressive increase in pulmonary vascular resistance and subsequent progressive failure of the right heart function, and is a common complication of many diseases. Mesenchymal stem cells (MSCs) autonomously home to sites damaged by disease, repair damaged tissues, and participate in the regulation of systemic inflammation and immune responses, which have good clinical application prospects. Extracellular vesicles (EVs), such as exosomes and microvesicles, participate in various biological activities by regulating intercellular communication. Exosomes secreted into the extracellular environment also affect the host immune system. MSC-derived extracellular vesicles (MSC-EVs), as a mediator in the paracrine processes of MSCs, carry biologically active substances such as proteins, lipids, mRNA, and micro-RNA. MSC-EVs therapies, safer than cell-based treatments, have been shown to be effective in modulating macrophages to support anti-inflammatory phenotypes, which are strongly related to histological and functional benefits in preclinical models of pulmonary hypertension. The main effects of active substances and their potential medical value have attracted wide attention from researchers. This article reviews the role and relevant mechanisms of MSC-EVs in the treatment of pulmonary hypertension in recent studies and provides a basis for their future clinical applications.
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28
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Pan Z, Sun W, Chen Y, Tang H, Lin W, Chen J, Chen C. Extracellular Vesicles in Tissue Engineering: Biology and Engineered Strategy. Adv Healthc Mater 2022; 11:e2201384. [PMID: 36053562 DOI: 10.1002/adhm.202201384] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/07/2022] [Indexed: 01/28/2023]
Abstract
Extracellular vesicles (EVs), acting as an important ingredient of intercellular communication through paracrine actions, have gained tremendous attention in the field of tissue engineering (TE). Moreover, these nanosized extracellular particles (30-140 nm) can be incorporated into biomaterials according to different principles to facilitate signal delivery in various regenerative processes directly or indirectly. Bioactive biomaterials as the carrier will extend the retention time and realize the controlled release of EVs, which further enhance their therapeutic efficiency in tissue regeneration. Herein, the basic biological characteristics of EVs are first introduced, and then their outstanding performance in exerting direct impacts on target cells in tissue regeneration as well as indirect effects on promoting angiogenesis and regulating the immune environment, due to specific functional components of EVs (nucleic acid, protein, lipid, etc.), is emphasized. Furthermore, different design ideas for suitable EV-loaded biomaterials are also demonstrated. In the end, this review also highlights the engineered strategies, which aim at solving the problems related to natural EVs such as highly heterogeneous functions, inadequate tissue targeting capabilities, insufficient yield and scalability, etc., thus promoting the therapeutic pertinence and clinical potential of EV-based approaches in TE.
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Affiliation(s)
- Ziyin Pan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School Of Medicine, Shanghai, 200092, China.,Shanghai Engineering Research Center of Lung Transplantation, Shanghai, 200433, China
| | - Weiyan Sun
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School Of Medicine, Shanghai, 200092, China.,Shanghai Engineering Research Center of Lung Transplantation, Shanghai, 200433, China
| | - Yi Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School Of Medicine, Shanghai, 200092, China.,Shanghai Engineering Research Center of Lung Transplantation, Shanghai, 200433, China
| | - Hai Tang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School Of Medicine, Shanghai, 200092, China.,Shanghai Engineering Research Center of Lung Transplantation, Shanghai, 200433, China
| | - Weikang Lin
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School Of Medicine, Shanghai, 200092, China.,Shanghai Engineering Research Center of Lung Transplantation, Shanghai, 200433, China
| | - Jiafei Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School Of Medicine, Shanghai, 200092, China
| | - Chang Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School Of Medicine, Shanghai, 200092, China.,Shanghai Engineering Research Center of Lung Transplantation, Shanghai, 200433, China
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29
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Azapira N, Pourjafar S, Habibi A, Tayebi L, Keshtkar S, Kaviani M. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Promising Treatment for COVID-19 Pandemic. EXP CLIN TRANSPLANT 2022; 20:980-983. [PMID: 33622217 DOI: 10.6002/ect.2020.0296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The pandemic of severe acute respiratory syndrome coronavirus-2 infection has prompted the urgent need for novel therapeutic approaches, especially for patients in critically severe conditions. To date, the pathogenesis of COVID-19 is not completely understood, and finding an effective new drug is still inconclusive. Mesenchymal stromal cell-derived extracellular vesicles contain large amounts of proteins, messenger RNA, and microRNAs that act as vehicles that transfer the cargo between cells. These nanotherapeutic materials exert anti-inflammatory effects on the immune system, which are necessary for subsidence of acute inflammation and promotion of tissue repair and regeneration. Therefore, the consideration of mesenchymal stromal cell-derived extracellular vesicles as a new, safe, and effective therapeutic approach in the treatment of COVID-19 pneumonia is suggested.
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Affiliation(s)
- Negar Azapira
- From the Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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30
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Rudiansyah M, El-Sehrawy AA, Ahmad I, Terefe EM, Abdelbasset WK, Bokov DO, Salazar A, Rizaev JA, Muthanna FMS, Shalaby MN. Osteoporosis treatment by mesenchymal stromal/stem cells and their exosomes: Emphasis on signaling pathways and mechanisms. Life Sci 2022; 306:120717. [PMID: 35792178 DOI: 10.1016/j.lfs.2022.120717] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/30/2022] [Accepted: 06/09/2022] [Indexed: 02/07/2023]
Abstract
Osteoporosis is the loss of bone density, which is one of the main problems in developed and developing countries and is more common in the elderly. Because this disease is often not diagnosed until a bone fracture, it can become a life-threatening disease and cause hospitalization. With the increase of older people in a population, this disease's personal and social costs increase year by year and affect different communities. Most current treatments focus on pain relief and usually do not lead to bone tissue recovery and regeneration. But today, the use of stem cell therapy is recommended to treat and improve this disease recovery, which helps restore bone tissue by improving the imbalance in the osteoblast-osteoclast axis. Due to mesenchymal stromal/stem cells (MSCs) characteristics and their exosomes, these cells and vesicles are excellent sources for treating and preventing the progression and improvement of osteoporosis. Due to the ability of MSCs to differentiate into different cells and migrate to the site of injury, these cells are used in tissue regenerative medicine. Also, due to their contents, the exosomes of these cells help regenerate and treat various tissue injuries by affecting the injury site's cells. In this article, we attempted to review new studies in which MSCs and their exosomes were used to treat osteoporosis.
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Affiliation(s)
- Mohammad Rudiansyah
- Division of Nephrology & Hypertension, Department of Internal Medicine, Faculty of Medicine, Universitas Lambung Mangkurat/Ulin Hospital, Banjarmasin, Indonesia
| | - Amr A El-Sehrawy
- Department of Internal Medicine, Mansoura Specialized Medical Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Ermias Mergia Terefe
- School of pharmacy and Health science, United States International University, Nairobi, Kenya
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia; Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow 109240, Russian Federation
| | - Aleli Salazar
- Neuroimmunology Department, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City, Mexico
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector of Samarkand State Medical Institute, Samarkand, Uzbekistan
| | | | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Egypt
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31
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Effects of Hypoxia on RNA Cargo in Extracellular Vesicles from Human Adipose-Derived Stromal/Stem Cells. Int J Mol Sci 2022; 23:ijms23137384. [PMID: 35806391 PMCID: PMC9266528 DOI: 10.3390/ijms23137384] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stromal/stem cells and their derivates are the most promising cell source for cell therapies in regenerative medicine. The application of extracellular vesicles (EVs) as cell-free therapeuticals requires particles with a maximum regenerative capability to enhance tissue and organ regeneration. The cargo of mRNA and microRNA (miR) in EVs after hypoxic preconditioning has not been extensively investigated. Therefore, the aim of our study was the characterization of mRNA and the miR loading of EVs. We further investigated the effects of the isolated EVs on renal tubular epithelial cells in vitro. We found 3131 transcripts to be significantly regulated upon hypoxia. Only 15 of these were downregulated, but 3116 were up-regulated. In addition, we found 190 small RNAs, 169 of these were miRs and 21 were piwi-interacting RNAs (piR). However, only 18 of the small RNAs were significantly altered, seven were miRs and 11 were piRs. Interestingly, all seven miRs were down-regulated after hypoxic pretreatment, whereas all 11 piRs were up-regulated. Gene ontology term enrichment and miR-target enrichment analysis of the mRNAs and miR were also performed in order to study the biological background. Finally, the therapeutic effect of EVs on human renal tubular epithelial cells was shown by the increased expression of three anti-inflammatory molecules after incubation with EVs from hypoxic pretreatment. In summary, our study demonstrates the altered mRNA and miR load in EVs after hypoxic preconditioning, and their anti-inflammatory effect on epithelial cells.
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Prasad R, Conde J. Bioinspired soft nanovesicles for site-selective cancer imaging and targeted therapies. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2022; 14:e1792. [PMID: 35318815 DOI: 10.1002/wnan.1792] [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: 11/05/2021] [Revised: 02/17/2022] [Accepted: 03/03/2022] [Indexed: 06/14/2023]
Abstract
Cell-to-cell communication within the heterogeneous solid tumor environment plays a significant role in the uncontrolled metastasis of cancer. To inhibit the metastasis and growth of cancer cells, various chemically designed and biologically derived nanosized biomaterials have been applied for targeted cancer therapeutics applications. Over the years, bioinspired soft nanovesicles have gained tremendous attention for targeted cancer therapeutics due to their easy binding with tumor microenvironment, natural targeting ability, bio-responsive nature, better biocompatibility, high cargo capacity for multiple therapeutics agents, and long circulation time. These cell-derived nanovesicles guard their loaded cargo molecules from immune clearance and make them site-selective to cancer cells due to their natural binding and delivery abilities. Furthermore, bioinspired soft nanovesicles prevent cell-to-cell communication and secretion of cancer cell markers by delivering the therapeutics agents predominantly. Cell-derived vesicles, namely, exosomes, extracellular vesicles, and so forth have been recognized as versatile carriers for therapeutic biomolecules. However, low product yield, poor reproducibility, and uncontrolled particle size distribution have remained as major challenges of these soft nanovesicles. Furthermore, the surface biomarkers and molecular contents of these vesicles change with respect to the stage of disease and types. Here in this review, we have discussed numerous examples of bioinspired soft vesicles for targeted imaging and cancer therapeutic applications with their advantages and limitations. Importance of bioengineered soft nanovesicles for localized therapies with their clinical relevance has also been addressed in this article. Overall, cell-derived nanovesicles could be considered as clinically relevant platforms for cancer therapeutics. This article is categorized under: Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Rajendra Prasad
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
| | - João Conde
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
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Wang HN, Rong X, Yang LM, Hua WZ, Ni GX. Advances in Stem Cell Therapies for Rotator Cuff Injuries. Front Bioeng Biotechnol 2022; 10:866195. [PMID: 35694228 PMCID: PMC9174670 DOI: 10.3389/fbioe.2022.866195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Rotator cuff injury is a common upper extremity musculoskeletal disease that may lead to persistent pain and functional impairment. Despite the clinical outcomes of the surgical procedures being satisfactory, the repair of the rotator cuff remains problematic, such as through failure of healing, adhesion formation, and fatty infiltration. Stem cells have high proliferation, strong paracrine action, and multiple differentiation potential, which promote tendon remodeling and fibrocartilage formation and increase biomechanical strength. Additionally, stem cell-derived extracellular vesicles (EVs) can increase collagen synthesis and inhibit inflammation and adhesion formation by carrying regulatory proteins and microRNAs. Therefore, stem cell-based therapy is a promising therapeutic strategy that has great potential for rotator cuff healing. In this review, we summarize the advances of stem cells and stem cell-derived EVs in rotator cuff repair and highlight the underlying mechanism of stem cells and stem cell-derived EVs and biomaterial delivery systems. Future studies need to explore stem cell therapy in combination with cellular factors, gene therapy, and novel biomaterial delivery systems.
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Affiliation(s)
- Hao-Nan Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing, China
| | - Xiao Rong
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu, China
| | - Lu-Ming Yang
- Musculoskeletal Sonography and Occupational Performance Lab, Chan Division of Occupational Science and Occupational Therapy, University of Southern California, Los Angeles, CA, United States
| | - Wei-Zhong Hua
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing, China
| | - Guo-Xin Ni
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing, China
- *Correspondence: Guo-Xin Ni,
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Xie Y, Yu L, Cheng Z, Peng Y, Cao Z, Chen B, Duan Y, Wang Y. SHED-derived exosomes promote LPS-induced wound healing with less itching by stimulating macrophage autophagy. J Nanobiotechnology 2022; 20:239. [PMID: 35597946 PMCID: PMC9124392 DOI: 10.1186/s12951-022-01446-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/29/2022] [Indexed: 12/15/2022] Open
Abstract
High-quality cutaneous wound healing is associated with rapid wound closure and a comfortable healing process. Currently, exosomes derived from mesenchymal stem cells displayed a prominent therapeutic effect on skin wound closure. But the therapeutic approaches for wound itching are very limited in clinical. Stem cells from human exfoliated deciduous teeth (SHED) may offer a unique exosome resource for cell-free therapeutics in potential clinical applications. Here, we investigated the common mechanisms underlying wound closure and unpleasant sensation of itching, focusing on the contribution of the SHED-derived exosome to immune response and wound itching during healing. The effects of SHED-derived exosomes on inflammatory wound healing were examined using lipopolysaccharide (LPS)-induced wounds in a mouse model. We found prolonged inflammation and distinct itch responses in skin wound tissue during LPS-induced wound healing. SHED-derived exosomes facilitated LPS-induced wound closure and relieved wound itching. Therefore, they are ideal for the treatment of wound healing. Macrophages in skin wound tissues are responsible for autophagy during wound healing. Macrophage autophagy also regulates cell proliferation, migration, and neuronal signal transduction in vitro. SHED-derived exosomes containing miR-1246 enhanced autophagy by regulating macrophage function through the AKT, ERK1/2, and STAT3 signaling pathways. Thus, SHED-derived exosomes promote wound healing with less itching in an LPS-induced wound model by stimulating macrophage autophagy, which has implications for the treatment of inflammatory wound healing.
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Affiliation(s)
- Yunyi Xie
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 56 Lingyuanxi Road, Guangzhou, 510055, People's Republic of China
| | - Le Yu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 56 Lingyuanxi Road, Guangzhou, 510055, People's Republic of China
| | - Zhilan Cheng
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 56 Lingyuanxi Road, Guangzhou, 510055, People's Republic of China
| | - Yingying Peng
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 56 Lingyuanxi Road, Guangzhou, 510055, People's Republic of China
| | - Zeyuan Cao
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 56 Lingyuanxi Road, Guangzhou, 510055, People's Republic of China
| | - Beichen Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 56 Lingyuanxi Road, Guangzhou, 510055, People's Republic of China
| | - Yihong Duan
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 56 Lingyuanxi Road, Guangzhou, 510055, People's Republic of China
| | - Yan Wang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Stomatology, 56 Lingyuanxi Road, Guangzhou, 510055, People's Republic of China.
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35
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Liu S, Deng Z, Chen K, Jian S, Zhou F, Yang Y, Fu Z, Xie H, Xiong J, Zhu W. Cartilage tissue engineering: From proinflammatory and anti‑inflammatory cytokines to osteoarthritis treatments (Review). Mol Med Rep 2022; 25:99. [PMID: 35088882 PMCID: PMC8809050 DOI: 10.3892/mmr.2022.12615] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/07/2021] [Indexed: 12/17/2022] Open
Abstract
Osteoarthritis (OA), one of the most common joint diseases, is characterized by fibrosis, rhagadia, ulcers and attrition of articular cartilage due to a number of factors. The etiology of OA remains unclear, but its occurrence has been associated with age, obesity, inflammation, trauma and genetic factors. Inflammatory cytokines are crucial for the occurrence and progression of OA. The intra-articular proinflammatory and anti-inflammatory cytokines jointly maintain a dynamic balance, in accordance with the physiological metabolism of articular cartilage. However, dynamic imbalance between proinflammatory and anti-inflammatory cytokines can cause abnormal metabolism in knee articular cartilage, which leads to deformation, loss and abnormal regeneration, and ultimately destroys the normal structure of the knee joint. The ability of articular cartilage to self-repair once damaged is limited, due to its inability to obtain nutrients from blood vessels, nerves and lymphatic vessels, as well as limitations in the extracellular matrix. There are several disadvantages inherent to conventional repair methods, while cartilage tissue engineering (CTE), which combines proinflammatory and anti-inflammatory cytokines, offers a new therapeutic approach for OA. The aim of the present review was to examine the proinflammatory factors implicated in OA, including IL-1β, TNF-α, IL-6, IL-15, IL-17 and IL-18, as well as the key anti-inflammatory factors reducing OA-related articular damage, including IL-4, insulin-like growth factor and TGF-β. The predominance of proinflammatory over anti-inflammatory cytokine effects ultimately leads to the development of OA. CTE, which employs mesenchymal stem cells and scaffolding technology, may prevent OA by maintaining the homeostasis of pro- and anti-inflammatory factors.
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Affiliation(s)
- Shuyu Liu
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Zhenhan Deng
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Kang Chen
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Shengsheng Jian
- Department of Orthopedics, Luo Hu Hospital, Shenzhen, Guangdong 518001, P.R. China
| | - Feifei Zhou
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Yuan Yang
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Zicai Fu
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Huanyu Xie
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Jianyi Xiong
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
| | - Weimin Zhu
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, Guangdong 518035, P.R. China
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Xing X, Han S, Ni Y, Cheng G, Cheng Y, Ni X, Deng Y, Li Z, Li Z. Mussel-inspired functionalization of electrospun scaffolds with polydopamine-assisted immobilization of mesenchymal stem cells-derived small extracellular vesicles for enhanced bone regeneration. Int J Pharm 2021; 609:121136. [PMID: 34592398 DOI: 10.1016/j.ijpharm.2021.121136] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 09/09/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells-derived small extracellular vesicles (MSCs-sEV) have shown promising prospects as a cell-free strategy for bone tissue regeneration. Here, a bioactive MSCs-sEV-loaded electrospun silk fibroin/poly(ε-caprolactone) (SF/PCL) scaffold was synthesized via a mussel-inspired immobilization strategy assisted by polydopamine (pDA). This pDA modification endowed the as-prepared scaffold with high loading efficiency and sustained release profile of sEV. In addition, the fabricated composite scaffold exhibited good physiochemical, mechanical, and biocompatible properties. In vitro cellular experiments indicated that the MSCs-sEV-loaded composite scaffold promoted the adhesion and spreading of preosteoblast and endothelial cells, as well as enhanced osteogenic differentiation and angiogenic activity. In vivo experiments showed that the functionalized electrospun scaffolds promoted bone regeneration in a rat calvarial bone defect model. Results suggest that the developed MSCs-sEV-anchored pDA-modified SF/PCL electrospun scaffolds possess high application potential in bone tissue engineering owing to their powerful pro-angiogenic and -osteogenic capacities, cell-free bioactivity, and cost effectiveness.
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Affiliation(s)
- Xin Xing
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; The Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Shuang Han
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yifeng Ni
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Gu Cheng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; The Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yuet Cheng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xiaoqi Ni
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yunfan Deng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhi Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; The Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
| | - Zubing Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China; The Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
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Merimi M, El-Majzoub R, Lagneaux L, Moussa Agha D, Bouhtit F, Meuleman N, Fahmi H, Lewalle P, Fayyad-Kazan M, Najar M. The Therapeutic Potential of Mesenchymal Stromal Cells for Regenerative Medicine: Current Knowledge and Future Understandings. Front Cell Dev Biol 2021; 9:661532. [PMID: 34490235 PMCID: PMC8416483 DOI: 10.3389/fcell.2021.661532] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/28/2021] [Indexed: 12/11/2022] Open
Abstract
In recent decades, research on the therapeutic potential of progenitor cells has advanced considerably. Among progenitor cells, mesenchymal stromal cells (MSCs) have attracted significant interest and have proven to be a promising tool for regenerative medicine. MSCs are isolated from various anatomical sites, including bone marrow, adipose tissue, and umbilical cord. Advances in separation, culture, and expansion techniques for MSCs have enabled their large-scale therapeutic application. This progress accompanied by the rapid improvement of transplantation practices has enhanced the utilization of MSCs in regenerative medicine. During tissue healing, MSCs may exhibit several therapeutic functions to support the repair and regeneration of injured tissue. The process underlying these effects likely involves the migration and homing of MSCs, as well as their immunotropic functions. The direct differentiation of MSCs as a cell replacement therapeutic mechanism is discussed. The fate and behavior of MSCs are further regulated by their microenvironment, which may consequently influence their repair potential. A paracrine pathway based on the release of different messengers, including regulatory factors, chemokines, cytokines, growth factors, and nucleic acids that can be secreted or packaged into extracellular vesicles, is also implicated in the therapeutic properties of MSCs. In this review, we will discuss relevant outcomes regarding the properties and roles of MSCs during tissue repair and regeneration. We will critically examine the influence of the local microenvironment, especially immunological and inflammatory signals, as well as the mechanisms underlying these therapeutic effects. Importantly, we will describe the interactions of local progenitor and immune cells with MSCs and their modulation during tissue injury. We will also highlight the crucial role of paracrine pathways, including the role of extracellular vesicles, in this healing process. Moreover, we will discuss the therapeutic potential of MSCs and MSC-derived extracellular vesicles in the treatment of COVID-19 (coronavirus disease 2019) patients. Overall, this review will provide a better understanding of MSC-based therapies as a novel immunoregenerative strategy.
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Affiliation(s)
- Makram Merimi
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium.,LBBES Laboratory, Genetics and Immune-Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Rania El-Majzoub
- Department of Biomedical Sciences, School of Pharmacy, Lebanese International University, Beirut, Lebanon.,Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Douâa Moussa Agha
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Fatima Bouhtit
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium.,LBBES Laboratory, Genetics and Immune-Cell Therapy Unit, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Nathalie Meuleman
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Mohammad Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.,Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon
| | - Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.,Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
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38
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Jayaraman S, Gnanasampanthapandian D, Rajasingh J, Palaniyandi K. Stem Cell-Derived Exosomes Potential Therapeutic Roles in Cardiovascular Diseases. Front Cardiovasc Med 2021; 8:723236. [PMID: 34447796 PMCID: PMC8382889 DOI: 10.3389/fcvm.2021.723236] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Owing to myocardial abnormalities, cardiac ailments are considered to be the major cause of morbidity and mortality worldwide. According to a recent study, membranous vesicles that are produced naturally, termed as "exosomes", have emerged as the potential candidate in the field of cardiac regenerative medicine. A wide spectrum of stem cells has also been investigated in the treatment of cardiovascular diseases (CVD). Exosomes obtained from the stem cells are found to be cardioprotective and offer great hope in the treatment of CVD. The basic nature of exosomes is to deal with the intracellular delivery of both proteins and nucleic acids. This activity of exosomes helps us to rely on them as the attractive pharmaceutical delivery agents. Most importantly, exosomes derived from microRNAs (miRNAs) hold great promise in assessing the risk of CVD, as they serve as notable biomarkers of the disease. Exosomes are small, less immunogenic, and lack toxicity. These nanovesicles harbor immense potential as a therapeutic entity and would provide fruitful benefits if consequential research were focused on their upbringing and development as a useful diagnostic and therapeutic tool in the field of medicine.
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Affiliation(s)
- Selvaraj Jayaraman
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Dhanavathy Gnanasampanthapandian
- Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Chennai, India
| | - Johnson Rajasingh
- Department of Bioscience Research & Medicine-Cardiology, The University of Tennessee Health Science Center, Memphis, TN, United States
| | - Kanagaraj Palaniyandi
- Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Chennai, India
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39
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Ahmadvand Koohsari S, Absalan A, Azadi D. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines. Sci Rep 2021; 11:11658. [PMID: 34079033 PMCID: PMC8172573 DOI: 10.1038/s41598-021-91291-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023] Open
Abstract
The therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.
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Affiliation(s)
| | - Abdorrahim Absalan
- Department of Medical Laboratory Sciences, Khomein University of Medical Sciences, Ghods Avenue, Khomein, Markazi Province, 38818-58573, Iran.
| | - Davood Azadi
- Department of Medical Laboratory Sciences, Khomein University of Medical Sciences, Ghods Avenue, Khomein, Markazi Province, 38818-58573, Iran
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40
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Gupta A, Shivaji K, Kadam S, Gupta M, Rodriguez HC, Potty AG, El-Amin SF, Maffulli N. Immunomodulatory extracellular vesicles: an alternative to cell therapy for COVID-19. Expert Opin Biol Ther 2021; 21:1551-1560. [PMID: 33886388 DOI: 10.1080/14712598.2021.1921141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: SARS-CoV-2 induces a cytokine storm and can cause inflammation, fibrosis and apoptosis in the lungs, leading to acute respiratory distress syndrome (ARDS). ARDS is the leading cause of mortality and morbidity the associated to COVID-19, and the cytokine storm is a prominent etiological factor. Mesenchymal stem cell-derived extracellular vesicles are an alternative therapy for the management of inflammatory and autoimmune conditions due to their immunosuppressive properties. The immunomodulatory and tissue regeneration capabilities of extracellular vesicles may support their application as a prospective therapy for COVID-19.Areas Covered: We explored the clinical evidence on extracellular vesicles as antiviral agents and in mitigating ARDS, and their therapeutic potential in COVID-19.Expert Opinion: Clinical trials using extracellular vesicles are registered against COVID-19 associated complications, with some evidence of safety and efficacy. Extracellular vesicles present an alternative potential for cell therapy for COVID-19 management, but further preclinical and clinical investigations are needed.
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Affiliation(s)
- Ashim Gupta
- Future Biologics, Lawrenceville, USA.,BioIntegrate, Lawrenceville, USA.,South Texas Orthopedic Research Institute (STORI Inc), Laredo, USA.,Veterans in Pain, Los Angeles, USA
| | - Kashte Shivaji
- Department of Stem Cell & Regenerative Medicine, Centre for Interdisciplinary Research, D. Y. Patil Education Society (Institution Deemed to Be University), Kolhapur, India
| | - Sachin Kadam
- Department of Stem Cell & Regenerative Medicine, Centre for Interdisciplinary Research, D. Y. Patil Education Society (Institution Deemed to Be University), Kolhapur, India.,Advancells Group, Noida, India
| | | | - Hugo C Rodriguez
- Future Biologics, Lawrenceville, USA.,South Texas Orthopedic Research Institute (STORI Inc), Laredo, USA.,Future Physicians of South Texas, San Antonio, USA.,School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, USA
| | - Anish G Potty
- South Texas Orthopedic Research Institute (STORI Inc), Laredo, USA.,School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, USA.,The Institute of Musculoskeletal Excellence (TIME Orthopaedics), Laredo, USA
| | - Saadiq F El-Amin
- BioIntegrate, Lawrenceville, USA.,El-Amin Orthopaedic & Sports Medicine Institute, Lawrenceville, USA
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, School of Medicine and Surgery, University of Salerno, Fisciano, Italy.,San Giovanni Di Dio E Ruggi D'Aragona Hospital "Clinica Orthopedica" Department, Hospital of Salerno, Salerno, Italy.,Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, London, England
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41
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Li Y, Lyu P, Ze Y, Li P, Zeng X, Shi Y, Qiu B, Gong P, Yao Y. Exosomes derived from plasma: promising immunomodulatory agents for promoting angiogenesis to treat radiation-induced vascular dysfunction. PeerJ 2021; 9:e11147. [PMID: 33859878 PMCID: PMC8020864 DOI: 10.7717/peerj.11147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/03/2021] [Indexed: 02/05/2023] Open
Abstract
Ionizing radiation (IR)-induced vascular disorders slow down tissue regeneration. Exosomes derived from plasma exhibit potential to promote angiogenesis; meanwhile, the immune microenvironment plays a significant role in the process. This study aimed to test the hypothesis that plasma exosomes promote angiogenesis in irradiated tissue by mediating the immune microenvironment. First, we explored the impact of IR on macrophages. We found that cell viability and capacity for promoting angiogenesis were decreased in irradiated macrophages compared to control macrophages. Then, we isolated and characterized rat plasma-derived exosomes (RP-Exos) which were defined as 40-160 nm extracellular vesicles extracted from rat plasma. Afterward, we evaluated the effects of RP-Exos on the behaviors of irradiated macrophages. Our results show that RP-Exos promoted cell proliferation. More importantly, we found that RP-Exos stimulated the immune microenvironment in a manner that improved the angiogenesis-related genes and proteins of irradiated macrophages. The supernatant of macrophage cell cultures was used as conditioned medium to treat human primary umbilical vein endothelial cells, further confirming the pro-angiogenic ability of macrophages receiving RP-Exo intervention. RP-Exos were used in vivo to treat irradiated skin or calvarial defects in irradiated Sprague-Dawley male rats. The results indicated the ability of RP-Exos to enhance angiogenesis and promote tissue regeneration. Our research suggested the potential of plasma exosomes to be used as immunomodulatory agents with angiogenic capacity to treat radiation-associated vascular disorders and facilitate tissue repair.
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Affiliation(s)
- Yanxi Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Ping Lyu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yiting Ze
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Peiran Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xinyi Zeng
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yixin Shi
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Bingrun Qiu
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yang Yao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Dorronsoro A, Santiago FE, Grassi D, Zhang T, Lai RC, McGowan SJ, Angelini L, Lavasani M, Corbo L, Lu A, Brooks RW, Garcia‐Contreras M, Stolz DB, Amelio A, Boregowda SV, Fallahi M, Reich A, Ricordi C, Phinney DG, Huard J, Lim SK, Niedernhofer LJ, Robbins PD. Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging. Aging Cell 2021; 20:e13337. [PMID: 33728821 PMCID: PMC8045949 DOI: 10.1111/acel.13337] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/30/2021] [Accepted: 02/12/2021] [Indexed: 12/15/2022] Open
Abstract
Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow-derived mesenchymal stem cells (BM-MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM-MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM-MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM-MSC CM extended life span of Ercc1-/- mice similarly to injection of young BM-MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC-derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.
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Affiliation(s)
- Akaitz Dorronsoro
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
| | - Fernando E. Santiago
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
- Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota Minneapolis Minnesota USA
| | - Diego Grassi
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
| | - Tianpeng Zhang
- Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota Minneapolis Minnesota USA
| | | | - Sara J. McGowan
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
- Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota Minneapolis Minnesota USA
| | - Luise Angelini
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
- Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota Minneapolis Minnesota USA
| | | | - Lana Corbo
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
| | - Aiping Lu
- The Steadman Philippon Research Institute Vail Colorado USA
| | - Robert W. Brooks
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
| | | | - Donna B. Stolz
- Department of Cell Biology University of Pittsburgh School of Medicine Pittsburgh Pennsylveniya USA
| | - Antonio Amelio
- Lineberger Cancer Center University of North Carolina Chapel Hill North Carolina USA
- Department of Bioinformatics Scripps Research Jupiter Florida USA
| | - Siddaraju V. Boregowda
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
| | - Mohammad Fallahi
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
- Department of Bioinformatics Scripps Research Jupiter Florida USA
| | - Adrian Reich
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
- Department of Bioinformatics Scripps Research Jupiter Florida USA
| | - Camillo Ricordi
- Diabetes Research Institute University of Miami Miami Florida USA
| | - Donald G. Phinney
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
| | - Johnny Huard
- The Steadman Philippon Research Institute Vail Colorado USA
| | - Sai Kiang Lim
- Institute of Medical Biology ASTAR Singapore Singapore
| | - Laura J. Niedernhofer
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
- Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota Minneapolis Minnesota USA
| | - Paul D. Robbins
- Center on Aging and Departments of Molecular Medicine Scripps Research Jupiter Florida USA
- Institute on the Biology of Aging and Metabolism and Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota Minneapolis Minnesota USA
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Shi QZ, Yu HM, Chen HM, Liu M, Cheng X. Exosomes derived from mesenchymal stem cells regulate Treg/Th17 balance in aplastic anemia by transferring miR-23a-3p. Clin Exp Med 2021; 21:429-437. [PMID: 33779886 DOI: 10.1007/s10238-021-00701-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/07/2021] [Indexed: 12/23/2022]
Abstract
Imbalanced Th17/Treg ratio is implicated in the pathogenesis of aplastic anemia. Studies have indicated that bone marrow-derived mesenchymal stem cells-derived exosomes (BMSC-Exo) could correct imbalanced Th17/Treg in aplastic anemia, but the mechanism remains not fully understand. This study was designed to investigate whether BMSC-Exo regulates the Th17/Treg balance in aplastic anemia by transferring miR-23a-3p. Here, miR-23a-3p inhibitor was utilized to knockdown the expression of miR-23a-3p in BMSC-Exo. A co-culture system of CD4+ T cells from aplastic anemia patients and BMSC-Exo was used to explore the effects of BMSC-Exo on the Th17/Treg balance and the underlying mechanism in aplastic anemia. The patients with aplastic anemia exhibited Th17/Treg imbalance favoring the Th17 cells. BMSC-Exo could balance the percentage of Th17 and Treg cells in aplastic anemia, but the effects of BMSC-Exo can be eliminated when miR-23a-3p expression was silenced in BMSCs. IL-6 was a direct target of miR-23a-3p. IL-6 overexpression could abrogate BMSC-Exo-induced balance in Th17/Treg ratio. Overall, BMSC-Exo could balance Th17/Treg ratio in aplastic anemia via suppressing IL-6 expression by transferring miR-23a-3p at least in part. These data indicated miR-23a-3p may be a potential target for the treatment of aplastic anemia. Our study may provide a new idea for the therapy of the disease.
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Affiliation(s)
- Qing-Zhao Shi
- Department of Pediatrics, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, China.
| | - Hong-Mei Yu
- Department of Pediatrics, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, China
| | - Hong-Mei Chen
- Department of Burn, Wuhan Third Hospital, No.241 Pengliuyang Road, Wuhan, 430060, China
| | - Miao Liu
- Department of Pediatrics, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, China
| | - Xue Cheng
- Department of Pediatrics, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, 430060, China
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Markov A, Thangavelu L, Aravindhan S, Zekiy AO, Jarahian M, Chartrand MS, Pathak Y, Marofi F, Shamlou S, Hassanzadeh A. Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders. Stem Cell Res Ther 2021; 12:192. [PMID: 33736695 PMCID: PMC7971361 DOI: 10.1186/s13287-021-02265-1] [Citation(s) in RCA: 165] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn's disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.
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Affiliation(s)
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Surendar Aravindhan
- Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Angelina Olegovna Zekiy
- Department of Prosthetic Dentistry, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), 69120 Heidelberg, Germany
| | | | - Yashwant Pathak
- Professor and Associate Dean for Faculty Affairs, Taneja College of Pharmacy, University of South Florida, Tampa, FL USA
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Cell Therapy and Regenerative Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Geßner A, Koch B, Klann K, Fuhrmann DC, Farmand S, Schubert R, Münch C, Geiger H, Baer PC. Characterization of Extracellular Vesicles from Preconditioned Human Adipose-Derived Stromal/Stem Cells. Int J Mol Sci 2021; 22:ijms22062873. [PMID: 33808970 PMCID: PMC7999156 DOI: 10.3390/ijms22062873] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Cell-free therapy using extracellular vesicles (EVs) from adipose-derived mesenchymal stromal/stem cells (ASCs) seems to be a safe and effective therapeutic option to support tissue and organ regeneration. The application of EVs requires particles with a maximum regenerative capability and hypoxic culture conditions as an in vitro preconditioning regimen has been shown to alter the molecular composition of released EVs. Nevertheless, the EV cargo after hypoxic preconditioning has not yet been comprehensively examined. The aim of the present study was the characterization of EVs from hypoxic preconditioned ASCs. We investigated the EV proteome and their effects on renal tubular epithelial cells in vitro. While no effect of hypoxia was observed on the number of released EVs and their protein content, the cargo of the proteins was altered. Proteomic analysis showed 41 increased or decreased proteins, 11 in a statistically significant manner. Furthermore, the uptake of EVs in epithelial cells and a positive effect on oxidative stress in vitro were observed. In conclusion, culture of ASCs under hypoxic conditions was demonstrated to be a promising in vitro preconditioning regimen, which alters the protein cargo and increases the anti-oxidative potential of EVs. These properties may provide new potential therapeutic options for regenerative medicine.
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Affiliation(s)
- Alec Geßner
- Division of Nephrology, Department of Internal Medicine III, University Hospital, Goethe-University, 60596 Frankfurt/M., Germany; (A.G.); (B.K.); (S.F.); (H.G.)
| | - Benjamin Koch
- Division of Nephrology, Department of Internal Medicine III, University Hospital, Goethe-University, 60596 Frankfurt/M., Germany; (A.G.); (B.K.); (S.F.); (H.G.)
| | - Kevin Klann
- Institute of Biochemistry II, Faculty of Medicine, Goethe-University, 60596 Frankfurt/M., Germany; (K.K.); (C.M.)
| | - Dominik C. Fuhrmann
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany;
| | - Samira Farmand
- Division of Nephrology, Department of Internal Medicine III, University Hospital, Goethe-University, 60596 Frankfurt/M., Germany; (A.G.); (B.K.); (S.F.); (H.G.)
| | - Ralf Schubert
- Division of Allergology, Pneumology and Cystic Fibrosis, Department for Children and Adolescents, University Hospital, Goethe-University, 60596 Frankfurt/M., Germany;
| | - Christian Münch
- Institute of Biochemistry II, Faculty of Medicine, Goethe-University, 60596 Frankfurt/M., Germany; (K.K.); (C.M.)
| | - Helmut Geiger
- Division of Nephrology, Department of Internal Medicine III, University Hospital, Goethe-University, 60596 Frankfurt/M., Germany; (A.G.); (B.K.); (S.F.); (H.G.)
| | - Patrick C. Baer
- Division of Nephrology, Department of Internal Medicine III, University Hospital, Goethe-University, 60596 Frankfurt/M., Germany; (A.G.); (B.K.); (S.F.); (H.G.)
- Correspondence: ; Tel.: +49-6301-5554
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Nakao Y, Fukuda T, Zhang Q, Sanui T, Shinjo T, Kou X, Chen C, Liu D, Watanabe Y, Hayashi C, Yamato H, Yotsumoto K, Tanaka U, Taketomi T, Uchiumi T, Le AD, Shi S, Nishimura F. Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss. Acta Biomater 2021; 122:306-324. [PMID: 33359765 PMCID: PMC7897289 DOI: 10.1016/j.actbio.2020.12.046] [Citation(s) in RCA: 277] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/25/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cell (MSC)-derived exosome plays a central role in the cell-free therapeutics involving MSCs and the contents can be customized under disease-associated microenvironments. However, optimal MSC-preconditioning to enhance its therapeutic potential is largely unknown. Here, we show that preconditioning of gingival tissue-derived MSCs (GMSCs) with tumor necrosis factor-alpha (TNF-α) is ideal for the treatment of periodontitis. TNF-α stimulation not only increased the amount of exosome secreted from GMSCs, but also enhanced the exosomal expression of CD73, thereby inducing anti-inflammatory M2 macrophage polarization. The effect of GMSC-derived exosomes on inflammatory bone loss were examined by ligature-induced periodontitis model in mice. Local injection of GMSC-derived exosomes significantly reduced periodontal bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and these effects were further enhanced by preconditioning of GMSCs with TNF-α. Thus, GMSC-derived exosomes also exhibited anti-osteoclastogenic activity. Receptor activator of NF-κB ligand (RANKL) expression was regulated by Wnt5a in periodontal ligament cells (PDLCs), and exosomal miR-1260b was found to target Wnt5a-mediated RANKL pathway and inhibit its osteoclastogenic activity. These results indicate that significant ability of the TNF-α-preconditioned GMSC-derived exosomes to regulate inflammation and osteoclastogenesis paves the way for establishment of a therapeutic approach for periodontitis.
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Affiliation(s)
- Yuki Nakao
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Takao Fukuda
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan; Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA
| | - Qunzhou Zhang
- Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, PA, USA
| | - Terukazu Sanui
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Takanori Shinjo
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Xiaoxing Kou
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA; South China Center of Craniofacial Stem Cell Research, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong, China
| | - Chider Chen
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA; Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, PA, USA
| | - Dawei Liu
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA; Department of Orthodontics, Peking University School and Stomatology, Peking, China
| | - Yukari Watanabe
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Chikako Hayashi
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Hiroaki Yamato
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Karen Yotsumoto
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Urara Tanaka
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Takaharu Taketomi
- Dental and Oral Medical Center, Kurume University School of Medicine, Fukuoka, Japan
| | - Takeshi Uchiumi
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Anh D Le
- Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine, PA, USA
| | - Songtao Shi
- Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, USA; South China Center of Craniofacial Stem Cell Research, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong, China
| | - Fusanori Nishimura
- Department of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
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Kahmini FR, Shahgaldi S. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles as novel cell-free therapy for treatment of autoimmune disorders. Exp Mol Pathol 2021; 118:104566. [PMID: 33160961 DOI: 10.1016/j.yexmp.2020.104566] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 10/24/2020] [Accepted: 11/03/2020] [Indexed: 02/08/2023]
Abstract
Over the past decades, new light has been shed on the efficiency of Mesenchymal Stem Cells (MSCs) in the treatment of autoimmune diseases. The therapeutic functions of MSCs partly stem from their well-recognized ability to efficiently modulate immune responses and it is well substantiated that MSC secretory components, in particular extracellular vesicles (EVs), play a critical role in this immunomodulation. In fact, almost any cell type can generate and release EVs under both pathological and physiological conditions and these nano-sized particles are believed to greatly contribute to homeostasis and cell-cell communication through transportation of a wide variety of biomolecules including nucleic acid, signaling lipids, regulatory proteins, transcription factors, cytokines, and growth factors. Lamentably, despite exhibiting promising results in both animal experiments and clinical trials, MSC therapy is still largely restricted to the experimental stage due to its critical pitfalls and drawbacks such as safety issues, poor cell survival, immune rejection and high cost. On the other hand, MSC-derived EVs, which ideally reflect the exact biophysical features of MSCs, are considered to be much safer and more effective than MSCs themselves. Therefore, introducing alternative approaches based on MSC-derived EVs can offer appreciable promise in overcoming the limitations and practical challenges observed in cell-based therapy and thus the extracellular vesicles of MSCs may also provide a far more potent therapeutic strategy for immune-related disorders. In this review, we first focus on the properties of MSC-derived EVs and then we shall provide valuable insight regarding their beneficial therapeutic opportunities to further compare this alternative approach with conventional MSC therapy. Finally, we will attempt to summarize the current findings on the influences of MSC-derived EVs on autoimmune disorders, offering a potential alternative avenue towards treatment of autoimmune diseases.
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Affiliation(s)
- Fatemeh Rezaei Kahmini
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Shahab Shahgaldi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Herrmann M, Diederichs S, Melnik S, Riegger J, Trivanović D, Li S, Jenei-Lanzl Z, Brenner RE, Huber-Lang M, Zaucke F, Schildberg FA, Grässel S. Extracellular Vesicles in Musculoskeletal Pathologies and Regeneration. Front Bioeng Biotechnol 2021; 8:624096. [PMID: 33553127 PMCID: PMC7855463 DOI: 10.3389/fbioe.2020.624096] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022] Open
Abstract
The incidence of musculoskeletal diseases is steadily increasing with aging of the population. In the past years, extracellular vesicles (EVs) have gained attention in musculoskeletal research. EVs have been associated with various musculoskeletal pathologies as well as suggested as treatment option. EVs play a pivotal role in communication between cells and their environment. Thereby, the EV cargo is highly dependent on their cellular origin. In this review, we summarize putative mechanisms by which EVs can contribute to musculoskeletal tissue homeostasis, regeneration and disease, in particular matrix remodeling and mineralization, pro-angiogenic effects and immunomodulatory activities. Mesenchymal stromal cells (MSCs) present the most frequently used cell source for EV generation for musculoskeletal applications, and herein we discuss how the MSC phenotype can influence the cargo and thus the regenerative potential of EVs. Induced pluripotent stem cell-derived mesenchymal progenitor cells (iMPs) may overcome current limitations of MSCs, and iMP-derived EVs are discussed as an alternative strategy. In the last part of the article, we focus on therapeutic applications of EVs and discuss both practical considerations for EV production and the current state of EV-based therapies.
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Affiliation(s)
- Marietta Herrmann
- Interdisciplinary Center for Clinical Research (IZKF) Group Tissue Regeneration in Musculoskeletal Diseases, University Hospital Würzburg, Würzburg, Germany
- Bernhard-Heine-Centrum for Locomotion Research, University of Würzburg, Würzburg, Germany
| | - Solvig Diederichs
- Research Centre for Experimental Orthopaedics, Centre for Orthopaedics, Trauma Surgery and Paraplegiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Svitlana Melnik
- Research Centre for Experimental Orthopaedics, Centre for Orthopaedics, Trauma Surgery and Paraplegiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Jana Riegger
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, University of Ulm, Ulm, Germany
| | - Drenka Trivanović
- Interdisciplinary Center for Clinical Research (IZKF) Group Tissue Regeneration in Musculoskeletal Diseases, University Hospital Würzburg, Würzburg, Germany
- Bernhard-Heine-Centrum for Locomotion Research, University of Würzburg, Würzburg, Germany
| | - Shushan Li
- Department of Orthopedic Surgery, Experimental Orthopedics, Centre for Medical Biotechnology (ZMB), University of Regensburg, Regensburg, Germany
| | - Zsuzsa Jenei-Lanzl
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim, Frankfurt, Germany
| | - Rolf E. Brenner
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, University of Ulm, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany
| | - Frank Zaucke
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim, Frankfurt, Germany
| | - Frank A. Schildberg
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| | - Susanne Grässel
- Department of Orthopedic Surgery, Experimental Orthopedics, Centre for Medical Biotechnology (ZMB), University of Regensburg, Regensburg, Germany
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Lou P, Liu S, Xu X, Pan C, Lu Y, Liu J. Extracellular vesicle-based therapeutics for the regeneration of chronic wounds: current knowledge and future perspectives. Acta Biomater 2021; 119:42-56. [PMID: 33161186 DOI: 10.1016/j.actbio.2020.11.001] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/20/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023]
Abstract
Chronic wounds are still an intractable medical problem for both clinicians and researchers and cause a substantial social and medical burden. Current clinical approaches can only manage wounds but have limited capacity to promote the regeneration of chronic wounds. As a type of natural nanovesicle, extracellular vesicles (EVs) from multiple cell types (e.g., stem cells, immune cells, and skin cells) have been shown to participate in all stages of skin wound healing including inflammation, proliferation, and remodeling, and display beneficial roles in promoting wound repair. Moreover, EVs can be further re-engineered with genetic/chemical or scaffold material-based strategies for enhanced skin regeneration. In this review, we provide an overview of EV biology and discuss the current findings regarding the roles of EVs in chronic wound healing, particularly in immune regulation, cell proliferation and migration, angiogenesis, and extracellular matrix remodeling, as well as the therapeutic effects of EVs on chronic wounds by genetic modification, in combination with functionalized biomaterials, and as drug carriers. We also discuss the challenges and perspectives of translating EV-based therapies into clinical wound care in the future.
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Mesenchymal Stem Cell-derived Extracellular Vesicles for Skin Wound Healing. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1310:495-507. [PMID: 33834447 DOI: 10.1007/978-981-33-6064-8_18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Skin is vulnerable to various external insults such as burn, severe injury, or inflammation, which necessitates a better strategy for wound repair. Mesenchymal stem cells (MSCs) can self-renew and differentiate into various supporting tissues including cartilage, bone, muscle, and adipose tissue. Along with their unique multipotent capacity, they secrete various paracrine mediators such as growth factors, cytokines, and membrane-enclosed particles called extracellular vesicles (EVs). Herein, we discussed the general traits of EVs such as cell-to-cell communicator, and highlighted the recent preclinical outcomes, with a focus on the application of MSC-derived EVs in wound repair. This chapter provides insights into developing novel strategies for skin wound healing in a cell-free manner.
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