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Fu Y, Han YT, Xie JL, Liu RQ, Zhao B, Zhang XL, Zhang J, Zhang J. Mesenchymal stem cell exosomes enhance the development of hair follicle to ameliorate androgenetic alopecia. World J Stem Cells 2025; 17:102088. [PMID: 40160691 PMCID: PMC11947894 DOI: 10.4252/wjsc.v17.i3.102088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/21/2025] [Accepted: 02/26/2025] [Indexed: 03/21/2025] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) and their secretome have significant potential in promoting hair follicle development. However, the effects of MSC therapy have been reported to vary due to their heterogeneous characteristics. Different sources of MSCs or culture systems may cause heterogeneity of exosomes. AIM To define the potential of human adipose-derived MSC exosomes (hADSC-Exos) and human umbilical cord-derived MSC exosomes (hUCMSC-Exos) for improving dermal papillary cell proliferation in androgenetic alopecia. METHODS We conducted liquid chromatography-mass spectrometry proteomic analysis of hADSC-Exos and hUCMSC-Exos. Liquid chromatography-mass spectrometry suggested that hADSC-Exos were related to metabolism and immunity. Additionally, the hADSC-Exo proteins regulated the cell cycle and other 9 functional groups. RESULTS We verified that hADSC-Exos inhibited glycogen synthase kinase-3β expression by activating the Wnt/β-catenin signaling pathway via cell division cycle protein 42, and enhanced dermal papillary cell proliferation and migration. Excess dihydrotestosterone caused androgenetic alopecia by shortening the hair follicle growth phase, but hADSC-Exos reversed these effects. CONCLUSION This study indicated that hair development is influenced by hADSC-Exo-mediated cell-to-cell communication via the Wnt/β-catenin pathway.
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Affiliation(s)
- Yu Fu
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Yao-Ting Han
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jun-Ling Xie
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Rong-Qi Liu
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Bo Zhao
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Xing-Liao Zhang
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jun Zhang
- Tongji Lifeng Institute of Regenerative Medicine, Tongji University, Shanghai 200092, China
- Research Center for Translational Medicine at East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jing Zhang
- Tongji Lifeng Institute of Regenerative Medicine, Tongji University, Shanghai 200092, China
- Research Center for Translational Medicine at East Hospital, School of Life Science, Tongji University, Shanghai 200092, China.
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Jin W, Li Y, Yu M, Ren D, Han C, Guo S. Advances of exosomes in diabetic wound healing. BURNS & TRAUMA 2025; 13:tkae078. [PMID: 39980588 PMCID: PMC11836438 DOI: 10.1093/burnst/tkae078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 06/11/2024] [Accepted: 11/09/2024] [Indexed: 02/22/2025]
Abstract
Poor wound healing is a refractory process that places an enormous medical and financial burden on diabetic patients. Exosomes have recently been recognized as crucial players in the healing of diabetic lesions. They have excellent stability, homing effects, biocompatibility, and reduced immunogenicity as novel cell-free therapies. In addition to transporting cargos to target cells to enhance intercellular communication, exosomes are beneficial in nearly every phase of diabetic wound healing. They participate in modulating the inflammatory response, accelerating proliferation and reepithelization, increasing angiogenesis, and regulating extracellular matrix remodeling. Accumulating evidence indicates that hydrogels or dressings in conjunction with exosomes can prolong the duration of exosome residency in diabetic wounds. This review provides an overview of the mechanisms, delivery, clinical application, engineering, and existing challenges of the use of exosomes in diabetic wound repair. We also propose future directions for biomaterials incorporating exosomes: 2D or 3D scaffolds, biomaterials loaded with wound healing-promoting gases, intelligent biomaterials, and the prospect of systematic application of exosomes. These findings may might shed light on future treatments and enlighten some studies to improve quality of life among diabetes patients.
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Affiliation(s)
- Weixue Jin
- Department of Plastic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, 1511 Jiang Hong Road, Binjiang District, Hangzhou 310009, Zhejiang, China
| | - Yi Li
- Department of Plastic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, 1511 Jiang Hong Road, Binjiang District, Hangzhou 310009, Zhejiang, China
| | - Meirong Yu
- Center for Basic and Translational Research, Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jie Fang Road, Shangcheng District, Hangzhou 310009, Zhejiang, China
| | - Danyang Ren
- Department of Plastic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, 1511 Jiang Hong Road, Binjiang District, Hangzhou 310009, Zhejiang, China
| | - Chunmao Han
- Department of Burns and Wound Repair, Second Affiliated Hospital Zhejiang University School of Medicine, 88 Jie Fang Road, Shangcheng District, Hangzhou 310009, Zhejiang, China
- Zhejiang Key Laboratory of Trauma, Burn, and Medical Rescue, 88 Jie Fang Road, Shangcheng District, Hangzhou 310009, Zhejiang, China
| | - Songxue Guo
- Department of Plastic Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, 1511 Jiang Hong Road, Binjiang District, Hangzhou 310009, Zhejiang, China
- Zhejiang Key Laboratory of Trauma, Burn, and Medical Rescue, 88 Jie Fang Road, Shangcheng District, Hangzhou 310009, Zhejiang, China
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Li AN, Sun JH, Saidin S, Cheah JS, Kuo CH, Li L, Li JS, Bai RY, Diao Y, Wang HMD. Regenerative Potential Nanomedicine of Adipocyte Stem Cell-Derived Exosomes in Senescent Skin Tissue. Int J Nanomedicine 2024; 19:13149-13163. [PMID: 39660280 PMCID: PMC11628318 DOI: 10.2147/ijn.s470225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 11/05/2024] [Indexed: 12/12/2024] Open
Abstract
Introduction Skin is the first-line barrier defense against infection, irradiation, and toxins, but is prone to natural aging (intrinsic aging) and environmental factors (extrinsic aging). Hence, there is an increasing urgency to explore an effective treatment for aging skin. This study was focused on testing the potential of utilizing adipocyte stem cell derived exosomal as nanomedicine to regenerate the dermal layer and counteract signs of skin aging. Methods The harvested stem cells from adipose tissues were isolated, cultured, and then starved. The centrifugation of cell cultures medium yielded the human adipose-derived stem cells conditional medium (HADSCs-CM). Collagen secretion and fibroblast viability of human fibroblasts (Hs68) were measured in the presence of HADSCs-CM. The dermal layer, vascular endothelial growth factor (VEGF), and collagen levels were evaluated on the mice animal models between the treatments with and without HADSCs-CM. Results Western blotting, transmission electron microscopy (TEM), and dynamic light scattering (DLS) confirmed that the functional particles in HADSCs-CM were exosomes. When Hs68 fibroblasts were treated with HADSCs-CM, both cell viability and collagen secretion increased in a dose-dependent manner. Following the post-ultraviolet A (post-UVA) exposure, the mice exposed to the HADSCs-CM have decreased dermal thickness and VEGF expression and increased collagen volume compared to the non-HADSCs-CM exposed mice (control group). Conclusion HADSCs-CM significantly alleviated signs of skin senescence, including reduced dermal thickness, decreased VEGF expression, and enhanced collagen production. Exosomes, identified in the HADSCs-CM, are the functional component of these regenerative effects. This study highlights that the exosomal nanomedicine found in HADSCs-CM could regenerate skin, boost collagen production, improve fibroblast cell viability, and contain functional exosomes.
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Affiliation(s)
- An-Na Li
- School of Medicine, Huaqiao University, Quanzhou, Fujian, 362021, People’s Republic of China
| | - Jing-Hua Sun
- School of Medicine, Huaqiao University, Quanzhou, Fujian, 362021, People’s Republic of China
- Hebei Key Laboratory of Basic Medicine for Diabetes, Shijiazhuang Second Hospital, Shijiazhuang, Hebei, 050000, People’s Republic of China
| | - Syafiqah Saidin
- IJN-UTM Cardiovascular Engineering Centre, Institute of Human Centered Engineering, Universiti Teknologi Malaysia, Johor Bahru, Johor, 81310, Malaysia
- Department of Biomedical Engineering & Health Sciences, Faculty of Electrical Engineering, Universiti Teknologi Malaysia, Johor Bahru, Johor, 81310, Malaysia
| | - Jee Syuen Cheah
- Department of Biomedical Engineering & Health Sciences, Faculty of Electrical Engineering, Universiti Teknologi Malaysia, Johor Bahru, Johor, 81310, Malaysia
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, Taiwan, Republic of China
| | - Chia-Hung Kuo
- Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan, Republic of China
| | - Ling Li
- School of Medicine, Huaqiao University, Quanzhou, Fujian, 362021, People’s Republic of China
| | - Jia-Shen Li
- School of Medicine, Huaqiao University, Quanzhou, Fujian, 362021, People’s Republic of China
| | - Ru-Yu Bai
- School of Medicine, Huaqiao University, Quanzhou, Fujian, 362021, People’s Republic of China
| | - Yong Diao
- School of Medicine, Huaqiao University, Quanzhou, Fujian, 362021, People’s Republic of China
| | - Hui-Min David Wang
- Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, Taiwan, Republic of China
- Regenerative Medicine and Cell Therapy Research Center; and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan, Republic of China
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan, Republic of China
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Sharma Y, Ghatak S, Sen CK, Mohanty S. Emerging technologies in regenerative medicine: The future of wound care and therapy. J Mol Med (Berl) 2024; 102:1425-1450. [PMID: 39358606 DOI: 10.1007/s00109-024-02493-x] [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: 03/08/2024] [Revised: 09/10/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
Wound healing, an intricate biological process, comprises orderly phases of simple biological processed including hemostasis, inflammation, angiogenesis, cell proliferation, and ECM remodeling. The regulation of the shift in these phases can be influenced by systemic or environmental conditions. Any untimely transitions between these phases can lead to chronic wounds and scarring, imposing a significant socio-economic burden on patients. Current treatment modalities are largely supportive in nature and primarily involve the prevention of infection and controlling inflammation. This often results in delayed healing and wound complications. Recent strides in regenerative medicine and tissue engineering offer innovative and patient-specific solutions. Mesenchymal stem cells (MSCs) and their secretome have gained specific prominence in this regard. Additionally, technologies like tissue nano-transfection enable in situ gene editing, a need-specific approach without the requirement of complex laboratory procedures. Innovating approaches like 3D bioprinting and ECM bioscaffolds also hold the potential to address wounds at the molecular and cellular levels. These regenerative approaches target common healing obstacles, such as hyper-inflammation thereby promoting self-recovery through crucial signaling pathway stimulation. The rationale of this review is to examine the benefits and limitations of both current and emerging technologies in wound care and to offer insights into potential advancements in the field. The shift towards such patient-centric therapies reflects a paradigmatic change in wound care strategies.
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Affiliation(s)
- Yashvi Sharma
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, Delhi, 110029, India
| | - Subhadip Ghatak
- Indiana Center for Regenerative Medicine and Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- McGowan Institute of Regenerative Medicine, Department of Surgery, University of Pittsburgh, 419 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA, 15219, USA
| | - Chandan K Sen
- Indiana Center for Regenerative Medicine and Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- McGowan Institute of Regenerative Medicine, Department of Surgery, University of Pittsburgh, 419 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA, 15219, USA.
| | - Sujata Mohanty
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, Delhi, 110029, India.
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Li S, Li Y, Zhu K, He W, Guo X, Wang T, Gong S, Zhu Z. Exosomes from mesenchymal stem cells: Potential applications in wound healing. Life Sci 2024; 357:123066. [PMID: 39306326 DOI: 10.1016/j.lfs.2024.123066] [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: 02/09/2024] [Revised: 07/08/2024] [Accepted: 09/16/2024] [Indexed: 09/26/2024]
Abstract
Wound healing is a continuous and complex process regulated by multiple factors, which has become an intractable clinical burden. Mesenchymal stem cell-derived exosomes (MSC-exos) possess low immunogenicity, easy preservation, and potent bioactivity, which is a mirror to their parental cells MSC-exos are important tools for regulating the biological behaviors of wound healing-associated cells, including fibroblasts, keratinocytes, immune cells, and endothelial cells. MSC-exos accelerate the wound healing process at cellular and animal levels by modulating inflammatory responses, promoting collagen deposition and vascularization. MSC-exos accelerate wound healing at the cellular and animal levels by modulating inflammatory responses and promoting collagen deposition and vascularization. This review summarizes the roles and mechanisms of MSC-exos originating from various sources in promoting the healing efficacy of general wounds, diabetic wounds, burn wounds, and healing-related scars. It also discusses the limitations and perspectives of MSC-exos in wound healing, in terms of exosome acquisition, mechanistic complexity, and exosome potentiation modalities. A deeper understanding of the properties and functions of MSC-exos is beneficial to advance the therapeutic approaches for achieving optimal wound healing.
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Affiliation(s)
- Sicheng Li
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Yichuan Li
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Keyu Zhu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wenlin He
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Xingjun Guo
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ting Wang
- Department of Medical Ultrasound, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
| | - Song Gong
- Department of Emergency and Traumatic Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Zhanyong Zhu
- Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
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Soltani S, Zahedi A, Vergara AJS, Noli M, Soltysik FM, Pociot F, Yarani R. Preclinical Therapeutic Efficacy of Extracellular Vesicles Derived from Adipose-Derived Mesenchymal Stromal/Stem Cells in Diabetic Wounds: a Systematic Review and Meta-Analysis. Stem Cell Rev Rep 2024; 20:2016-2031. [PMID: 38970763 DOI: 10.1007/s12015-024-10753-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2024] [Indexed: 07/08/2024]
Abstract
Extracellular vesicles isolated from adipose tissue-derived mesenchymal stromal/stem cells (ADSC-EVs) have demonstrated promising potential in wound healing treatment. To determine the therapeutic efficacy of ADSC-EVs for diabetic wounds in preclinical models, we performed a meta-analysis of available studies. PubMed and Embase were searched (to April 23, 2023). All full-text articles describing the therapeutic application of ADSC-EVs in diabetic wounds were included. Study outcomes were pooled using a random effects meta-analysis, including wound closure, angiogenesis, and collagen deposition. Other outcomes were only discussed descriptively. Seventy unique records were identified from our search; 20 full-text articles were included for qualitative analysis. Twelve studies were eligible for quantitative meta-analysis. The results showed that ADSC-EVs accelerated diabetic wound healing compared to controls with a large effect (standardized mean difference (SMD) 4.22, 95% confidence interval (CI) 3.07 to 5.36). The administration of ADSC-EVs also improved neovascularization (SMD 9.27, 95% CI 4.70 to 13.83) and collagen deposition (SMD 2.19, 95% CI 0.94 to 3.44), with a large effect. The risk of bias was unclear in all included studies. Conclusively, ADSC-EV is an effective treatment for diabetic wounds in preclinical trials, and it appears justified for transfer into the clinical field.
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Affiliation(s)
- Setareh Soltani
- Clinical Research Development Center, Taleghani and Imam Ali Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ahora Zahedi
- Department of Artificial Intelligence in Medical Sciences, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - April Joy S Vergara
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Marta Noli
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Fumie Mitani Soltysik
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark.
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Liu S, Zhao H, Jiang T, Wan G, Yan C, Zhang C, Yang X, Chen Z. The Angiogenic Repertoire of Stem Cell Extracellular Vesicles: Demystifying the Molecular Underpinnings for Wound Healing Applications. Stem Cell Rev Rep 2024; 20:1795-1812. [PMID: 39001965 DOI: 10.1007/s12015-024-10762-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2024] [Indexed: 07/15/2024]
Abstract
Stem cells-derived extracellular vesicles (SC-EVs) have emerged as promising therapeutic agents for wound repair, recapitulating the biological effects of parent cells while mitigating immunogenic and tumorigenic risks. These EVs orchestrate wound healing processes, notably through modulating angiogenesis-a critical event in tissue revascularization and regeneration. This study provides a comprehensive overview of the multifaceted mechanisms underpinning the pro-angiogenic capacity of EVs from various stem cell sources within the wound microenvironment. By elucidating the molecular intricacies governing their angiogenic prowess, we aim to unravel the mechanistic repertoire underlying their remarkable potential to accelerate wound healing. Additionally, methods to enhance the angiogenic effects of SC-EVs, current limitations, and future perspectives are highlighted, emphasizing the significant potential of this rapidly advancing field in revolutionizing wound healing strategies.
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Affiliation(s)
- Shuoyuan Liu
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Huayuan Zhao
- Department of Urology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tao Jiang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Gui Wan
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Chengqi Yan
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chi Zhang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaofan Yang
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Zhenbing Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Fu Y, Xie JL, Zhang WT, Zhang XL, Zhang XM, Xu MM, Han YT, Liu RQ, Xie GM, Zhang J, Zhang J. Synergistic delivery of hADSC-Exos and antioxidants has inhibitory effects on UVB-induced skin photoaging. Heliyon 2024; 10:e34321. [PMID: 39144947 PMCID: PMC11320485 DOI: 10.1016/j.heliyon.2024.e34321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/08/2024] [Accepted: 07/08/2024] [Indexed: 08/16/2024] Open
Abstract
Ultraviolet B (UVB) light exposure accelerates skin photoaging. Human adipose-derived stem cell exosomes (hADSC-Exos) and some antioxidants may have anti-photoaging effects. However, it is unknown whether the combination of hADSC-Exos and antioxidants plays a synergistic role in anti-photoaging. In cellular and 3D skin models, we showed that vitamin E (VE) and hADSC-Exos were optimal anti-photoaging combinations. In vivo, VE and hADSC-Exos increased skin tightening and elasticity in UVB-induced photoaging mice Combined treatment with VE and hADSC-Exos inhibited SIRT1/NF-κB pathway. These findings contribute to the understanding of hADSC-Exos in conjunction with other antioxidants, thereby providing valuable insights for the future pharmaceutical and cosmetic industries.
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Affiliation(s)
- Yu Fu
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Jun-ling Xie
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Wan-ting Zhang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shangha, 200010, China
| | - Xing-liao Zhang
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Xin-Min Zhang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shangha, 200010, China
| | - Meng-meng Xu
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Yao-ting Han
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shangha, 200010, China
| | - Rong-qi Liu
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shangha, 200010, China
| | - Guang-ming Xie
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Jing Zhang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shangha, 200010, China
- Tongji Lifeng Institute of Regenerative Medicine, Tongji University, Shanghai, 200092, China
| | - Jun Zhang
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
- Tongji Lifeng Institute of Regenerative Medicine, Tongji University, Shanghai, 200092, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200092, China
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9
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Zhou B, Chen Q, Zhang Q, Tian W, Chen T, Liu Z. Therapeutic potential of adipose-derived stem cell extracellular vesicles: from inflammation regulation to tissue repair. Stem Cell Res Ther 2024; 15:249. [PMID: 39113098 PMCID: PMC11304935 DOI: 10.1186/s13287-024-03863-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 07/27/2024] [Indexed: 08/10/2024] Open
Abstract
Inflammation is a key pathological feature of many diseases, disrupting normal tissue structure and resulting in irreversible damage. Despite the need for effective inflammation control, current treatments, including stem cell therapies, remain insufficient. Recently, extracellular vesicles secreted by adipose-derived stem cells (ADSC-EVs) have garnered attention for their significant anti-inflammatory properties. As carriers of bioactive substances, these vesicles have demonstrated potent capabilities in modulating inflammation and promoting tissue repair in conditions such as rheumatoid arthritis, osteoarthritis, diabetes, cardiovascular diseases, stroke, and wound healing. Consequently, ADSC-EVs are emerging as promising alternatives to conventional ADSC-based therapies, offering advantages such as reduced risk of immune rejection, enhanced stability, and ease of storage and handling. However, the specific mechanisms by which ADSC-EVs regulate inflammation under pathological conditions are not fully understood. This review discusses the role of ADSC-EVs in inflammation control, their impact on disease prognosis, and their potential to promote tissue repair. Additionally, it provides insights into future clinical research focused on ADSC-EV therapies for inflammatory diseases, which overcome some limitations associated with cell-based therapies.
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Affiliation(s)
- Bohuai Zhou
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Qiuyu Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Qiuwen Zhang
- The Affiliated Stomatological Hospital Southwest Medical University, Luzhou, 646000, China
| | - Weidong Tian
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Tian Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Zhi Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
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10
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Sun Y, Zhang S, Shen Y, Lu H, Zhao X, Wang X, Wang Y, Wang T, Liu B, Yao L, Wen J. Therapeutic application of mesenchymal stem cell-derived exosomes in skin wound healing. Front Bioeng Biotechnol 2024; 12:1428793. [PMID: 39161350 PMCID: PMC11330766 DOI: 10.3389/fbioe.2024.1428793] [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: 05/08/2024] [Accepted: 07/25/2024] [Indexed: 08/21/2024] Open
Abstract
Wound healing is a complicated obstacle, especially for chronic wounds. Mesenchymal stem cell-derived exosomes may be a promising cell-free approach for treating skin wound healing. Exosomes can accelerate wound healing by attenuating inflammation, promoting angiogenesis, cell proliferation, extracellular matrix production and remodeling. However, many issues, such as off-target effects and high degradation of exosomes in wound sites need to be addressed before applying into clinical therapy. Therefore, the bioengineering technology has been introduced to modify exosomes with greater stability and specific therapeutic property. To prolong the function time and the local concentration of exosomes in the wound bed, the use of biomaterials to load exosomes emerges as a promising strategy. In this review, we summarize the biogenesis and characteristics of exosomes, the role of exosomes in wound healing, and the therapeutic applications of modified-exosomes in wound healing. The challenges and prospects of exosomes in wound healing are also discussed.
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Affiliation(s)
- Yunhan Sun
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Shun Zhang
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yukai Shen
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Haoyang Lu
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xincan Zhao
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xin Wang
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yongkai Wang
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Taiping Wang
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Bing Liu
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Lan Yao
- Eye Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Jie Wen
- School of Stomatology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
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11
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Yue G, Li Y, Liu Z, Yu S, Cao Y, Wang X. Efficacy of MSC-derived small extracellular vesicles in treating type II diabetic cutaneous wounds: a systematic review and meta-analysis of animal models. Front Endocrinol (Lausanne) 2024; 15:1375632. [PMID: 39076515 PMCID: PMC11284036 DOI: 10.3389/fendo.2024.1375632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 06/25/2024] [Indexed: 07/31/2024] Open
Abstract
Background Small extracellular vesicles derived from mesenchymal stem cells (MSC-sEVs) have emerged as a promising therapy for treating type II diabetic cutaneous wounds. Currently, the evidence supporting the use of MSC-sEVs for treating diabetic skin wounds remains inconclusive and is limited to preclinical studies. To facilitate the clinical translation of cell-free therapy, conducting a comprehensive systematic review of preclinical studies assessing the efficacy of MSC-sEVs is imperative. Methods A systematic search was conducted on PubMed, Web of Science, Embase, and Cochrane Library databases until June 14, 2023, to identify studies that met our pre-established inclusion criteria. The outcome indicators comprised wound closure rate (primary outcome), neovascular density, re-epithelialization rate, collagen deposition, and inflammatory factors (secondary Outcomes). A fixed-effects model was employed in instances of low heterogeneity (I2<50%), while a random-effects model was utilized for high heterogeneity (I2≥50%). The risk of bias in animal studies was assessed using the SYRCLE tool. Results Twenty-one studies were included in this meta-analysis. Compared with the control group, MSC-sEVs were found to significantly facilitate the healing of cutaneous wounds in type II diabetic patients (standardized mean difference [SMD]=3.16, 95% confidence interval [CI]: 2.65 to 3.66, P<0.00001, I2 = 39%). Conclusions According to the meta-analysis of preclinical studies, MSC-sEVs show promising applications in promoting type II diabetic wound healing. As a result, translating these findings into clinical applications appears warranted. Systematic review registration https://www.crd.york.ac.uk/prospero, identifier CRD42023375467.
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Affiliation(s)
- Guangren Yue
- Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yu Li
- Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Zheng Liu
- Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuying Yu
- Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yilin Cao
- Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, Shanghai, China
| | - Ximei Wang
- Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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12
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Hushmandi K, Saadat SH, Raei M, Aref AR, Reiter RJ, Nabavi N, Taheriazam A, Hashemi M. The science of exosomes: Understanding their formation, capture, and role in cellular communication. Pathol Res Pract 2024; 259:155388. [PMID: 38850846 DOI: 10.1016/j.prp.2024.155388] [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: 03/05/2024] [Revised: 05/06/2024] [Accepted: 06/01/2024] [Indexed: 06/10/2024]
Abstract
Extracellular vesicles (EVs) serve as a crucial method for transferring information among cells, which is vital in multicellular organisms. Among these vesicles, exosomes are notable for their small size, ranging from 20 to 150 nm, and their role in cell-to-cell communication. They carry lipids, proteins, and nucleic acids between cells. The creation of exosomes begins with the inward budding of the cell membrane, which then encapsulates various macromolecules as cargo. Once filled, exosomes are released into the extracellular space and taken up by target cells via endocytosis and similar processes. The composition of exosomal cargo varies, encompassing diverse macromolecules with specific functions. Because of their significant roles, exosomes have been isolated from various cell types, including cancer cells, endothelial cells, macrophages, and mesenchymal cells, with the aim of harnessing them for therapeutic applications. Exosomes influence cellular metabolism, and regulate lipid, glucose, and glutamine pathways. Their role in pathogenesis is determined by their cargo, which can manipulate processes such as apoptosis, proliferation, inflammation, migration, and other molecular pathways in recipient cells. Non-coding RNA transcripts, a common type of cargo, play a pivotal role in regulating disease progression. Exosomes are implicated in numerous biological and pathological processes, including inflammation, cancer, cardiovascular diseases, diabetes, wound healing, and ischemic-reperfusion injury. As a result, they hold significant potential in the treatment of both cancerous and non-cancerous conditions.
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Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Seyed Hassan Saadat
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mehdi Raei
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran; Department of Epidemiology and Biostatistics, School of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Reza Aref
- Department of Translational Sciences, Xsphera Biosciences Inc. Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, Long School of Medicine, San Antonio, TX, USA
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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13
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Zhang B, Bi Y, Wang K, Guo X, Liu Z, Li J, Wu M. Stem Cell-Derived Extracellular Vesicles: Promising Therapeutic Opportunities for Diabetic Wound Healing. Int J Nanomedicine 2024; 19:4357-4375. [PMID: 38774027 PMCID: PMC11108067 DOI: 10.2147/ijn.s461342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/10/2024] [Indexed: 05/24/2024] Open
Abstract
Wound healing is a sophisticated and orderly process of cellular interactions in which the body restores tissue architecture and functionality following injury. Healing of chronic diabetic wounds is difficult due to impaired blood circulation, a reduced immune response, and disrupted cellular repair mechanisms, which are often associated with diabetes. Stem cell-derived extracellular vesicles (SC-EVs) hold the regenerative potential, encapsulating a diverse cargo of proteins, RNAs, and cytokines, presenting a safe, bioactivity, and less ethical issues than other treatments. SC-EVs orchestrate multiple regenerative processes by modulating cellular communication, increasing angiogenesis, and promoting the recruitment and differentiation of progenitor cells, thereby potentiating the reparative milieu for diabetic wound healing. Therefore, this review investigated the effects and mechanisms of EVs from various stem cells in diabetic wound healing, as well as their limitations and challenges. Continued exploration of SC-EVs has the potential to revolutionize diabetic wound care.
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Affiliation(s)
- Boyu Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Yajun Bi
- Department of Pediatrics, Dalian Municipal Women and Children’s Medical Center (Group), Dalian Medical University, Dalian, Liaoning Province, 116011, People’s Republic of China
| | - Kang Wang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Xingjun Guo
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China
| | - Zeming Liu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Jia Li
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Min Wu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
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14
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He Z, Zhu Y, Ma H, Shen Q, Chen X, Wang X, Shao H, Wang Y, Yang S. Hydrogen sulfide regulates macrophage polarization and necroptosis to accelerate diabetic skin wound healing. Int Immunopharmacol 2024; 132:111990. [PMID: 38574702 DOI: 10.1016/j.intimp.2024.111990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/06/2024]
Abstract
Hydrogen sulfide (H2S), recognized as the third gasotransmitter, plays a pivotal role in the pathophysiological processes of various diseases. Cystathionine γ-lyase (CSE) is the main enzyme for H2S production in the skin. However, effects and mechanisms of H2S in diabetic skin wound healing remain unclear. Our findings revealed a decrease in plasma H2S content in diabetic patients with skin wounds. CSE knockout (KO) diabetic mice resulted in delayed wound healing, reduced blood perfusion, and CD31 expression around the wounds. It also led to increased infiltration of inflammatory cells and M1-type macrophages, decreased collagen levels, α-smooth muscle actin (α-SMA), and proliferating cell nuclear antigen (PCNA) expression. Additionally, there were enhanced expressions of necroptosis related proteins, including receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain like protein (MLKL). In comparison, sodium hydrosulfide (NaHS), H2S donor, accelerated skin wound healing in leptin receptor deficiency (db/db) mice. This acceleration was accompanied by increased blood perfusion and CD31 expression, reduced infiltration of inflammatory cells and M1-type macrophages, elevated collagen levels, α-SMA, and PCNA expressions, and decreased necroptosis-related protein expressions together with nuclear factor-κB (NF-κB) p65 phosphorylation. In conclusion, H2S regulates macrophage polarization and necroptosis, contributing to the acceleration of diabetic skin wound healing. These findings offer a novel strategy for the treatment of diabetic skin wounds.
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Affiliation(s)
- Ziying He
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yue Zhu
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Haojie Ma
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Qiyan Shen
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Xudong Chen
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Xin Wang
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Hongmei Shao
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yuqin Wang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu Province, China
| | - Shengju Yang
- Department of Dermatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China.
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15
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Sun T, Li M, Liu Q, Yu A, Cheng K, Ma J, Murphy S, McNutt PM, Zhang Y. Insights into optimizing exosome therapies for acute skin wound healing and other tissue repair. Front Med 2024; 18:258-284. [PMID: 38216854 PMCID: PMC11283324 DOI: 10.1007/s11684-023-1031-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 09/15/2023] [Indexed: 01/14/2024]
Abstract
Exosome therapy holds great promise as a novel approach to improve acute skin wound healing. This review provides a comprehensive overview of the current understanding of exosome biology and its potential applications in acute skin wound healing and beyond. Exosomes, small extracellular vesicles secreted by various stem cells, have emerged as potent mediators of intercellular communication and tissue repair. One advantage of exosome therapy is its ability to avoid potential risks associated with stem cell therapy, such as immune rejection or stem cells differentiating into unwanted cell types. However, further research is necessary to optimize exosome therapy, not only in the areas of exosome isolation, characterization, and engineering, but also in determining the optimal dose, timing, administration, and frequency of exosome therapy. Thus, optimization of exosome therapy is critical for the development of more effective and safer exosome-based therapies for acute skin wound healing and other diseases induced by cancer, ischemia, or inflammation. This review provides valuable insights into the potential of exosome therapy and highlights the need for further research to optimize exosome therapy for clinical use.
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Affiliation(s)
- Tianjing Sun
- Department of Emergency, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, China
| | - Mo Li
- Department of Emergency, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, China
| | - Qi Liu
- Department of Nephrology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, China.
| | - Anyong Yu
- Department of Emergency, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, China.
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, 64108, USA
| | - Jianxing Ma
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Sean Murphy
- Wake Forest Institute of Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27109, USA
| | - Patrick Michael McNutt
- Wake Forest Institute of Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27109, USA
| | - Yuanyuan Zhang
- Wake Forest Institute of Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27109, USA.
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16
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Fu Y, Zhang YL, Liu RQ, Xu MM, Xie JL, Zhang XL, Xie GM, Han YT, Zhang XM, Zhang WT, Zhang J, Zhang J. Exosome lncRNA IFNG-AS1 derived from mesenchymal stem cells of human adipose ameliorates neurogenesis and ASD-like behavior in BTBR mice. J Nanobiotechnology 2024; 22:66. [PMID: 38368393 PMCID: PMC10874555 DOI: 10.1186/s12951-024-02338-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 02/09/2024] [Indexed: 02/19/2024] Open
Abstract
BACKGROUND The transplantation of exosomes derived from human adipose-derived mesenchymal stem cells (hADSCs) has emerged as a prospective cellular-free therapeutic intervention for the treatment of neurodevelopmental disorders (NDDs), as well as autism spectrum disorder (ASD). Nevertheless, the efficacy of hADSC exosome transplantation for ASD treatment remains to be verified, and the underlying mechanism of action remains unclear. RESULTS The exosomal long non-coding RNAs (lncRNAs) from hADSC and human umbilical cord mesenchymal stem cells (hUCMSC) were sequenced and 13,915 and 729 lncRNAs were obtained, respectively. The lncRNAs present in hADSC-Exos encompass those found in hUCMSC-Exos and are associated with neurogenesis. The biodistribution of hADSC-Exos in mouse brain ventricles and organoids was tracked, and the cellular uptake of hADSC-Exos was evaluated both in vivo and in vitro. hADSC-Exos promote neurogenesis in brain organoid and ameliorate social deficits in ASD mouse model BTBR T + tf/J (BTBR). Fluorescence in situ hybridization (FISH) confirmed lncRNA Ifngas1 significantly increased in the prefrontal cortex (PFC) of adult mice after hADSC-Exos intraventricular injection. The lncRNA Ifngas1 can act as a molecular sponge for miR-21a-3p to play a regulatory role and promote neurogenesis through the miR-21a-3p/PI3K/AKT axis. CONCLUSION We demonstrated hADSC-Exos have the ability to confer neuroprotection through functional restoration, attenuation of neuroinflammation, inhibition of neuronal apoptosis, and promotion of neurogenesis both in vitro and in vivo. The hADSC-Exos-derived lncRNA IFNG-AS1 acts as a molecular sponge and facilitates neurogenesis via the miR-21a-3p/PI3K/AKT signaling pathway, thereby exerting a regulatory effect. Our findings suggest a potential therapeutic avenue for individuals with ASD.
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Affiliation(s)
- Yu Fu
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Yuan-Lin Zhang
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
- Department of Pathology, Air Force Medical Center, Beijing, 100142, China
| | - Rong-Qi Liu
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200010, China
| | - Meng-Meng Xu
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Jun-Ling Xie
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Xing-Liao Zhang
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Guang-Ming Xie
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China
| | - Yao-Ting Han
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200010, China
| | - Xin-Min Zhang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200010, China
| | - Wan-Ting Zhang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200010, China
| | - Jing Zhang
- Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200010, China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200092, China.
| | - Jun Zhang
- Research Center for Translational Medicine at East Hospital, School of Medicine, Tongji University, Shanghai, 200010, China.
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200092, China.
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Liu W, Liu T, Zhao Q, Ma J, Jiang J, Shi H. Adipose Tissue-Derived Extracellular Vesicles: A Promising Biomarker and Therapeutic Strategy for Metabolic Disorders. Stem Cells Int 2023; 2023:9517826. [PMID: 38169960 PMCID: PMC10761228 DOI: 10.1155/2023/9517826] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/23/2023] [Accepted: 11/25/2023] [Indexed: 01/05/2024] Open
Abstract
Adipose tissue plays an important role in systemic energy metabolism, and its dysfunction can lead to severe metabolic disorders. Various cells in adipose tissue communicate with each other to maintain metabolic homeostasis. Extracellular vesicles (EVs) are recognized as novel medium for remote intercellular communication by transferring various bioactive molecules from parental cells to distant target cells. Increasing evidence suggests that the endocrine functions of adipose tissue and even the metabolic homeostasis are largely affected by different cell-derived EVs, such as insulin signaling, lipolysis, and metabolically triggered inflammation regulations. Here, we provide an overview focused on the role of EVs released by different cell types of adipose tissue in metabolic diseases and their possible molecular mechanisms and highlight the potential applications of EVs as biomarkers and therapeutic targets. Moreover, the current EVs-based therapeutic strategies have also been discussed. This trial is registered with NCT05475418.
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Affiliation(s)
- Wenhui Liu
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou 215600, Jiangsu, China
- Zhenjiang Key Laboratory of High Technology Research on sEVs Foundation and Transformation Application, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu, China
| | - Tianyan Liu
- Center of Laboratory Medicine, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou 215600, Jiangsu, China
| | - Qingyu Zhao
- Department of Nephrology, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou 215600, Jiangsu, China
| | - Junqiu Ma
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou 215600, Jiangsu, China
- Center of Laboratory Medicine, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou 215600, Jiangsu, China
| | - Jiajia Jiang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou 215600, Jiangsu, China
- Center of Laboratory Medicine, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou 215600, Jiangsu, China
| | - Hui Shi
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Zhangjiagang, Suzhou 215600, Jiangsu, China
- Zhenjiang Key Laboratory of High Technology Research on sEVs Foundation and Transformation Application, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu, China
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18
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Wang Y, Shen X, Song S, Chen Y, Wang Y, Liao J, Chen N, Zeng L. Mesenchymal stem cell-derived exosomes and skin photoaging: From basic research to practical application. PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE 2023; 39:556-566. [PMID: 37605539 DOI: 10.1111/phpp.12910] [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: 02/20/2023] [Revised: 06/25/2023] [Accepted: 08/01/2023] [Indexed: 08/23/2023]
Abstract
BACKGROUND Skin photoaging is a condition caused by long-term exposure to ultraviolet irradiation, resulting in a variety of changes in the skin, such as capillary dilation, increased or absent pigmentation, dryness, sagging, and wrinkles. Stem cells possess a remarkable antioxidant capacity and the ability to proliferate, differentiate, and migrate, and their main mode of action is through paracrine secretion, with exosomes being the primary form of secretion. Stem cell-derived exosomes contain a variety of growth factors and cytokines and may have great potential to promote skin repair and delay skin ageing. METHODS This review focuses on the mechanisms of UV-induced skin photoaging, the research progress of stem cell exosomes against skin photoaging, emerging application approaches and limitations in the application of exosome therapy. RESULT Exosomes derived from various stem cells have the potential to prevent skin photoaging. CONCLUSION The combination with novel materials may be a key step for their practical application, which could be an important direction for future basic research and practical applications.
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Affiliation(s)
- Yihao Wang
- Center of Burn & Plastic and Wound Healing Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Xu Shen
- Center of Burn & Plastic and Wound Healing Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Shenghua Song
- Center of Burn & Plastic and Wound Healing Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Yan Chen
- Center of Burn & Plastic and Wound Healing Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Yiping Wang
- Center of Burn & Plastic and Wound Healing Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Junlin Liao
- Center of Burn & Plastic and Wound Healing Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Nian Chen
- Center of Burn & Plastic and Wound Healing Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Li Zeng
- Center of Burn & Plastic and Wound Healing Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, China
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19
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Satyadev N, Rivera MI, Nikolov NK, Fakoya AOJ. Exosomes as biomarkers and therapy in type 2 diabetes mellitus and associated complications. Front Physiol 2023; 14:1241096. [PMID: 37745252 PMCID: PMC10515224 DOI: 10.3389/fphys.2023.1241096] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most prevalent metabolic disorders worldwide. However, T2DM still remains underdiagnosed and undertreated resulting in poor quality of life and increased morbidity and mortality. Given this ongoing burden, researchers have attempted to locate new therapeutic targets as well as methodologies to identify the disease and its associated complications at an earlier stage. Several studies over the last few decades have identified exosomes, small extracellular vesicles that are released by cells, as pivotal contributors to the pathogenesis of T2DM and its complications. These discoveries suggest the possibility of novel detection and treatment methods. This review provides a comprehensive presentation of exosomes that hold potential as novel biomarkers and therapeutic targets. Additional focus is given to characterizing the role of exosomes in T2DM complications, including diabetic angiopathy, diabetic cardiomyopathy, diabetic nephropathy, diabetic peripheral neuropathy, diabetic retinopathy, and diabetic wound healing. This study reveals that the utilization of exosomes as diagnostic markers and therapies is a realistic possibility for both T2DM and its complications. However, the majority of the current research is limited to animal models, warranting further investigation of exosomes in clinical trials. This review represents the most extensive and up-to-date exploration of exosomes in relation to T2DM and its complications.
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Affiliation(s)
- Nihal Satyadev
- Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
| | - Milagros I. Rivera
- University of Medicine and Health Sciences, Basseterre, St. Kitts and Nevis
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20
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Ni H, Xi J, Tang J, Yan Y, Chu Y, Zhou J. Therapeutic Potential of Extracellular Vesicles from Different Stem Cells in Chronic Wound Healing. Stem Cell Rev Rep 2023; 19:1596-1614. [PMID: 37178227 DOI: 10.1007/s12015-023-10540-2] [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: 03/31/2023] [Indexed: 05/15/2023]
Abstract
Wound healing has long been a complex problem, especially in chronic wounds. Although debridement, skin grafting, and antimicrobial dressings have been used to treat chronic wounds, their treatment period is long, expensive, and has specific rejection reactions. The poor treatment results of traditional methods have caused psychological stress to patients and a substantial economic burden to society. Extracellular vesicles (EVs) are nanoscale vesicles secreted by cells. They play an essential role in intercellular communication. Numerous studies have confirmed that stem cell-derived extracellular vesicles (SC-EVs) can inhibit overactive inflammation, induce angiogenesis, promote re-epithelization, and reduce scar formation. Therefore, SC-EVs are expected to be a novel cell-free strategy for chronic wound treatment. We first summarize the pathological factors that hinder wound healing and discuss how SC-EVs accelerate chronic wound repair. And then, we also compare the advantages and disadvantages of different SC-EVs for chronic wound treatment. Finally, we discuss the limitations of SC-EVs usage and provide new thoughts for future SC-EVs research in chronic wound treatment.
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Affiliation(s)
- Haoxi Ni
- School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Jianbo Xi
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
| | - Jianjun Tang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
- Department of General Surgery, Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China
| | - Yongmin Yan
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
| | - Ying Chu
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China.
| | - Jing Zhou
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China.
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21
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Jia Q, Zhao H, Wang Y, Cen Y, Zhang Z. Mechanisms and applications of adipose-derived stem cell-extracellular vesicles in the inflammation of wound healing. Front Immunol 2023; 14:1214757. [PMID: 37520532 PMCID: PMC10376705 DOI: 10.3389/fimmu.2023.1214757] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 06/26/2023] [Indexed: 08/01/2023] Open
Abstract
Wound healing is a sophisticated process consisting of serial phases with overlaps, including hemostasis, inflammation, proliferation, and remodeling. The inflammation response is an early response that plays a crucial role in eliminating microbes and clearing damaged cell debris. However, in some pathological circumstances, such as diabetes mellitus, ischemia, trauma, deep burn, etc., abnormal inflammation can cause impaired wound healing. Adipose-derived stem cells (ADSCs) belong to the mesenchymal stem cell (MSC) family and exhibit prospective applications in tissue regeneration and dermatological repairs. ADSC-secreted extracellular vesicles (ADSC-EVs) mimic the functions of ADSCs without the concerns of cell survival, immune response, or ethical issues. Studies have revealed that ADSC-EVs can inhibit abnormal inflammation responses and accelerate wound healing through various mechanisms. Moreover, some studies explored modifications in the cargo components of ADSC-EVs to enhance their therapeutic efficacy. Given the increasing studies focusing on the potential of ADSC-EVs in wound healing, how they interfere with different phases of this process has been investigated in pieces. In this review, we summarized all up-to-date evidence to map a clearer picture of the underlying mechanisms of ADSC-EVs in inflammation response. The applications of ADSC-EVs aiming at inflammation in the healing process were also reviewed to provide therapeutic strategies for future investigators.
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Affiliation(s)
- Qingyi Jia
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hanxing Zhao
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yixi Wang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ying Cen
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhenyu Zhang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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22
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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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23
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Sheng W, Song Q, Su X, Lu Y, Bai Y, Ji F, Zhang L, Yang R, Fu X. Sodium alginate/gelatin hydrogels loaded with adipose-derived mesenchymal stem cells promote wound healing in diabetic rats. J Cosmet Dermatol 2023; 22:1670-1679. [PMID: 36718822 DOI: 10.1111/jocd.15631] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/25/2022] [Accepted: 01/03/2023] [Indexed: 02/01/2023]
Abstract
BACKGROUND Chronic refractory wounds are a common complication in diabetic patients. Adipose-derived mesenchymal stem cells (ASCs) have been shown to play an essential role in diabetic wound repair. AIMS To determine whether a composite of ASCs and sodium alginate/gelatin (Gel-Al) hydrogel can promote diabetic wound healing. METHODS Full-thickness cutaneous wounds were created in streptozotocin-induced diabetic rats prior to treatment with Gel-Al hydrogels loaded with ASCs. Hydrogel biocompatibility and wound healing were analyzed. Hematoxylin and eosin staining, Masson staining, immunofluorescence, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time PCR were performed for the assessment of cellular responses. RESULTS Compared to the control group or Gel-Al alone group, the combination of Gel-Al and ASCs promoted wound closure, facilitated granulation tissue regeneration and collagen deposition, and upregulated the expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and endothelial cell marker CD31. Moreover, the combination of Gel-Al and ASCs decreased interleukin-6 (IL-6) and interleukin-1β (IL-1β) expression, increased transforming growth factor beta1 (TGFβ1), interleukin-10 (IL-10), interleukin-4 (IL-4) and interleukin-13 (IL-13) expression, and increased M2 macrophage polarization. CONCLUSIONS Gel-Al hydrogels loaded with ASCs accelerate diabetic wound healing. The Gel-Al hydrogel-based ASC system therefore represents an innovative therapeutic strategy for diabetic wound repair.
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Affiliation(s)
- Wei Sheng
- Medical School of Chinese PLA, Beijing, China.,Department of Tissue Repair and Regeneration, The First Medical Center, Chinese PLA General Hospital, Beijing, China.,Medical Innovation Research Department, Chinese PLA General Hospital, Beijing, China
| | - Qi Song
- Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - XiangZheng Su
- Department of Tissue Repair and Regeneration, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yao Lu
- Department of Tissue Repair and Regeneration, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - YuZhe Bai
- Department of Tissue Repair and Regeneration, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - FengKun Ji
- Department of Tissue Repair and Regeneration, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Li Zhang
- Department of Rehabilitation Medicine, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - RunGong Yang
- Department of Tissue Repair and Regeneration, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaobing Fu
- Key Laboratory of Tissue Repair and Regeneration, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Chinese PLA General Hospital, Beijing, China
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24
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Liu WS, Liu Y, Gao J, Zheng H, Lu ZM, Li M. Biomembrane-Based Nanostructure- and Microstructure-Loaded Hydrogels for Promoting Chronic Wound Healing. Int J Nanomedicine 2023; 18:385-411. [PMID: 36703725 PMCID: PMC9871051 DOI: 10.2147/ijn.s387382] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/20/2022] [Indexed: 01/20/2023] Open
Abstract
Wound healing is a complex and dynamic process, and metabolic disturbances in the microenvironment of chronic wounds and the severe symptoms they cause remain major challenges to be addressed. The inherent properties of hydrogels make them promising wound dressings. In addition, biomembrane-based nanostructures and microstructures (such as liposomes, exosomes, membrane-coated nanostructures, bacteria and algae) have significant advantages in the promotion of wound healing, including special biological activities, flexible drug loading and targeting. Therefore, biomembrane-based nanostructure- and microstructure-loaded hydrogels can compensate for their respective disadvantages and combine the advantages of both to significantly promote chronic wound healing. In this review, we outline the loading strategies, mechanisms of action and applications of different types of biomembrane-based nanostructure- and microstructure-loaded hydrogels in chronic wound healing.
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Affiliation(s)
- Wen-Shang Liu
- Department of Dermatology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China
| | - Yu Liu
- Department of Gastroenterology, Jinling Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of China
| | - Jie Gao
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China
| | - Hao Zheng
- Department of General Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China
| | - Zheng-Mao Lu
- Department of General Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China,Zheng-Mao Lu, Department of General Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China, Tel +086-13651688596, Fax +086-021-31161589, Email
| | - Meng Li
- Department of Dermatology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China,Correspondence: Meng Li, Department of Dermatology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China, Tel +086-15000879978, Fax +086-021-23271699, Email
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25
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Zhao H, Li Z, Wang Y, Zhou K, Li H, Bi S, Wang Y, Wu W, Huang Y, Peng B, Tang J, Pan B, Wang B, Chen Z, Zhang Z. Bioengineered MSC-derived exosomes in skin wound repair and regeneration. Front Cell Dev Biol 2023; 11:1029671. [PMID: 36923255 PMCID: PMC10009159 DOI: 10.3389/fcell.2023.1029671] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 02/16/2023] [Indexed: 03/02/2023] Open
Abstract
Refractory skin defects such as pressure ulcers, diabetic ulcers, and vascular ulcers represent a challenge for clinicians and researchers in many aspects. The treatment strategies for wound healing have high cost and limited efficacy. To ease the financial and psychological burden on patients, a more effective therapeutic approach is needed to address the chronic wound. MSC-derived exosomes (MSC-exosomes), the main bioactive extracellular vesicles of the paracrine effect of MSCs, have been proposed as a new potential cell-free approach for wound healing and skin regeneration. The benefits of MSC-exosomes include their ability to promote angiogenesis and cell proliferation, increase collagen production, regulate inflammation, and finally improve tissue regenerative capacity. However, poor targeting and easy removability of MSC-exosomes from the wound are major obstacles to their use in clinical therapy. Thus, the concept of bioengineering technology has been introduced to modify exosomes, enabling higher concentrations and construction of particles of greater stability with specific therapeutic capability. The use of biomaterials to load MSC-exosomes may be a promising strategy to concentrate dose, create the desired therapeutic efficacy, and maintain a sustained release effect. The beneficial role of MSC-exosomes in wound healing is been widely accepted; however, the potential of bioengineering-modified MSC-exosomes remains unclear. In this review, we attempt to summarize the therapeutic applications of modified MSC-exosomes in wound healing and skin regeneration. The challenges and prospects of bioengineered MSC-exosomes are also discussed.
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Affiliation(s)
- Hanxing Zhao
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China.,Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Zhengyong Li
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China.,Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Yixi Wang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Kai Zhou
- Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Hairui Li
- Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Siwei Bi
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yudong Wang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Wenqing Wu
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yeqian Huang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Peng
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China.,Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Jun Tang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China.,Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Bo Pan
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Baoyun Wang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China.,Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Zhixing Chen
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China.,Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
| | - Zhenyu Zhang
- Department of Plastic and Burn Surgery, West China Hospital, Sichuan University, Chengdu, China.,Department of Plastic Reconstructive and Aesthetic Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, China
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26
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Wu J, Chen LH, Sun SY, Li Y, Ran XW. Mesenchymal stem cell-derived exosomes: The dawn of diabetic wound healing. World J Diabetes 2022; 13:1066-1095. [PMID: 36578867 PMCID: PMC9791572 DOI: 10.4239/wjd.v13.i12.1066] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/04/2022] [Accepted: 11/23/2022] [Indexed: 12/15/2022] Open
Abstract
Chronic wound healing has long been an unmet medical need in the field of wound repair, with diabetes being one of the major etiologies. Diabetic chronic wounds (DCWs), especially diabetic foot ulcers, are one of the most threatening chronic complications of diabetes. Although the treatment strategies, drugs, and dressings for DCWs have made great progress, they remain ineffective in some patients with refractory wounds. Stem cell-based therapies have achieved specific efficacy in various fields, with mesenchymal stem cells (MSCs) being the most widely used. Although MSCs have achieved good feedback in preclinical studies and clinical trials in the treatment of cutaneous wounds or other situations, the potential safety concerns associated with allogeneic/autologous stem cells and unknown long-term health effects need further attention and supervision. Recent studies have reported that stem cells mainly exert their trauma repair effects through paracrine secretion, and exosomes play an important role in intercellular communication as their main bioactive component. MSC-derived exosomes (MSC-Exos) inherit the powerful inflammation and immune modulation, angiogenesis, cell proliferation and migration promotion, oxidative stress alleviation, collagen remodeling imbalances regulation of their parental cells, and can avoid the potential risks of direct stem cell transplantation to a large extent, thus demonstrating promising performance as novel "cell-free" therapies in chronic wounds. This review aimed to elucidate the potential mechanism and update the progress of MSC-Exos in DCW healing, thereby providing new therapeutic directions for DCWs that are difficult to be cured using conventional therapy.
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Affiliation(s)
- Jing Wu
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Hong Chen
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shi-Yi Sun
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Li
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xing-Wu Ran
- Innovation Center for Wound Repair, Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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27
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Clément V, Roy V, Paré B, Goulet CR, Deschênes LT, Berthod F, Bolduc S, Gros-Louis F. Tridimensional cell culture of dermal fibroblasts promotes exosome-mediated secretion of extracellular matrix proteins. Sci Rep 2022; 12:19786. [PMID: 36396670 PMCID: PMC9672399 DOI: 10.1038/s41598-022-23433-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 10/31/2022] [Indexed: 11/19/2022] Open
Abstract
Extracellular matrix (ECM) secretion, deposition and assembly are part of a whole complex biological process influencing the microenvironment and other cellular behaviors. Emerging evidence is attributing a significant role to extracellular vesicles (EVs) and exosomes in a plethora of ECM-associated functions, but the role of dermal fibroblast-derived EVs in paracrine signalling is yet unclear. Herein, we investigated the effect of exosomes isolated from stimulated human dermal fibroblasts. We report that tridimensional (3D) cell culture of dermal fibroblasts promotes secretion of exosomes carrying a large quantity of proteins involved in the formation, organisation and remodelling of the ECM. In our 3D model, gene expression was highly modulated and linked to ECM, cellular migration and proliferation, as well as inflammatory response. Mass spectrometry analysis of exosomal proteins, isolated from 3D cultured fibroblast-conditioned media, revealed ECM protein enrichment, of which many were associated with the matrisome. We also show that the cytokine interleukin 6 (IL-6) is predicted to be central to the signalling pathways related to ECM formation and contributing to cell migration and proliferation. Overall, our data suggest that dermal fibroblast-derived EVs participate in many steps of the establishment of dermis's ECM.
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Affiliation(s)
- Vincent Clément
- grid.23856.3a0000 0004 1936 8390Department of Surgery, Faculty of Medicine, Laval University, Québec, QC Canada ,grid.23856.3a0000 0004 1936 8390Division of Regenerative Medicine, Laval University Experimental Organogenesis Research Center/LOEX, CHU de Québec Research Center – Enfant-Jésus Hospital, Québec, QC Canada
| | - Vincent Roy
- grid.23856.3a0000 0004 1936 8390Department of Surgery, Faculty of Medicine, Laval University, Québec, QC Canada ,grid.23856.3a0000 0004 1936 8390Division of Regenerative Medicine, Laval University Experimental Organogenesis Research Center/LOEX, CHU de Québec Research Center – Enfant-Jésus Hospital, Québec, QC Canada
| | - Bastien Paré
- grid.23856.3a0000 0004 1936 8390Department of Surgery, Faculty of Medicine, Laval University, Québec, QC Canada ,grid.23856.3a0000 0004 1936 8390Division of Regenerative Medicine, Laval University Experimental Organogenesis Research Center/LOEX, CHU de Québec Research Center – Enfant-Jésus Hospital, Québec, QC Canada
| | - Cassandra R. Goulet
- grid.23856.3a0000 0004 1936 8390Department of Surgery, Faculty of Medicine, Laval University, Québec, QC Canada ,grid.23856.3a0000 0004 1936 8390Division of Regenerative Medicine, Laval University Experimental Organogenesis Research Center/LOEX, CHU de Québec Research Center – Enfant-Jésus Hospital, Québec, QC Canada
| | - Lydia Touzel Deschênes
- grid.23856.3a0000 0004 1936 8390Department of Surgery, Faculty of Medicine, Laval University, Québec, QC Canada ,grid.23856.3a0000 0004 1936 8390Division of Regenerative Medicine, Laval University Experimental Organogenesis Research Center/LOEX, CHU de Québec Research Center – Enfant-Jésus Hospital, Québec, QC Canada
| | - François Berthod
- grid.23856.3a0000 0004 1936 8390Department of Surgery, Faculty of Medicine, Laval University, Québec, QC Canada ,grid.23856.3a0000 0004 1936 8390Division of Regenerative Medicine, Laval University Experimental Organogenesis Research Center/LOEX, CHU de Québec Research Center – Enfant-Jésus Hospital, Québec, QC Canada
| | - Stéphane Bolduc
- grid.23856.3a0000 0004 1936 8390Department of Surgery, Faculty of Medicine, Laval University, Québec, QC Canada ,grid.23856.3a0000 0004 1936 8390Division of Regenerative Medicine, Laval University Experimental Organogenesis Research Center/LOEX, CHU de Québec Research Center – Enfant-Jésus Hospital, Québec, QC Canada
| | - François Gros-Louis
- grid.23856.3a0000 0004 1936 8390Department of Surgery, Faculty of Medicine, Laval University, Québec, QC Canada ,grid.23856.3a0000 0004 1936 8390Division of Regenerative Medicine, Laval University Experimental Organogenesis Research Center/LOEX, CHU de Québec Research Center – Enfant-Jésus Hospital, Québec, QC Canada
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Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapy for Diabetes Mellitus and Diabetic Complications. Pharmaceutics 2022; 14:pharmaceutics14102208. [PMID: 36297643 PMCID: PMC9607185 DOI: 10.3390/pharmaceutics14102208] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/10/2022] [Accepted: 10/13/2022] [Indexed: 12/02/2022] Open
Abstract
As a novel cell-free strategy, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) inherit the therapeutic potential of donor cells, and are widely used for the treatment of many diseases. Increasing studies have shown that MSC-EVs transfer various bioactive molecules to create a beneficial microenvironment, thus exerting protective roles in diabetic mellitus (DM) and diabetic complications. To overcome the limitations of natural MSC-EVs such as heterogeneity and insufficient function, several modification methods have been established for constructing engineered MSC-EVs with elevated repairing efficiency. In this review, the PubMed library was searched from inception to August 2022, using a combination of Medical Subject Headings (MeSH) and keywords related to MSC-EVs, DM, and diabetic complications. We provide an overview of the major characteristics of MSC-EVs and summarize the recent advances of MSC-EV-based therapy for hyperglycemia-induced tissue damage with an emphasis on MSC-EV-mediated delivery of functional components. Moreover, the potential applications of engineered MSC-EVs in DM-related diseases therapy are discussed by presenting examples, and the opportunities and challenges for the clinical translation of MSC-EVs, especially engineered MSC-EVs, are evaluated.
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Tong S, Li Q, Liu Q, Song B, Wu J. Recent advances of the nanocomposite hydrogel as a local drug delivery for diabetic ulcers. Front Bioeng Biotechnol 2022; 10:1039495. [PMID: 36267448 PMCID: PMC9577098 DOI: 10.3389/fbioe.2022.1039495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic ulcer is a serious complication of diabetes. Compared with that of healthy people, the skin of patients with a diabetic ulcer is more easily damaged and difficult to heal. Without early intervention, the disease will become increasingly serious, often leading to amputation or even death. Most current treatment methods cannot achieve a good wound healing effect. Numerous studies have shown that a nanocomposite hydrogel serves as an ideal drug delivery method to promote the healing of a diabetic ulcer because of its better drug loading capacity and stability. Nanocomposite hydrogels can be loaded with one or more drugs for application to chronic ulcer wounds to promote rapid wound healing. Therefore, this paper reviews the latest progress of delivery systems based on nanocomposite hydrogels in promoting diabetic ulcer healing. Through a review of the recent literature, we put forward the shortcomings and improvement strategies of nanocomposite hydrogels in the treatment of diabetic ulcers.
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Affiliation(s)
- Sen Tong
- School of Basic Medical, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Qingyu Li
- School of Medicine, Jianghan University, Wuhan, China
| | - Qiaoyan Liu
- School of Basic Medical, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
| | - Bo Song
- School of Basic Medical, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
- *Correspondence: Bo Song, ; Junzi Wu,
| | - Junzi Wu
- School of Basic Medical, Yunnan University of Chinese Medicine, Kunming, Yunnan, China
- *Correspondence: Bo Song, ; Junzi Wu,
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Long C, Wang J, Gan W, Qin X, Yang R, Chen X. Therapeutic potential of exosomes from adipose-derived stem cells in chronic wound healing. Front Surg 2022; 9:1030288. [PMID: 36248361 PMCID: PMC9561814 DOI: 10.3389/fsurg.2022.1030288] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic wound healing remains a challenging medical problem affecting society, which urgently requires anatomical and functional solutions. Adipose-derived stem cells (ADSCs), mesenchymal stem cells with self-renewal and multiple differentiation ability, play essential roles in wound healing and tissue regeneration. The exosomes from ADSCs (ADSC-EXOs) are extracellular vesicles that are essential for communication between cells. ADSC-EXOs release various bioactive molecules and subsequently restore tissue homeostasis and accelerate wound healing, by promoting various stages of wound repair, including regulating the inflammatory response, promoting wound angiogenesis, accelerating cell proliferation, and modulating wound remodeling. Compared with ADSCs, ADSC-EXOs have the advantages of avoiding ethical issues, being easily stored, and having high stability. In this review, a literature search of PubMed, Medline, and Google Scholar was performed for articles before August 1, 2022 focusing on exosomes from ADSCs, chronic wound repair, and therapeutic potential. This review aimed to provide new therapeutic strategies to help investigators explore how ADSC-EXOs regulate intercellular communication in chronic wounds.
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Affiliation(s)
- Chengmin Long
- Guangdong Medical University, Zhanjiang, China
- Department of Burn Surgery and Skin Regeneration, the First People’s Hospital of Foshan, Foshan, China
| | - Jingru Wang
- Department of Burn Surgery and Skin Regeneration, the First People’s Hospital of Foshan, Foshan, China
- Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University, Guangzhou, China
| | - Wenjun Gan
- Guangdong Medical University, Zhanjiang, China
- Department of Burn Surgery and Skin Regeneration, the First People’s Hospital of Foshan, Foshan, China
| | - Xinchi Qin
- Department of Burn Surgery and Skin Regeneration, the First People’s Hospital of Foshan, Foshan, China
- Zunyi Medical University, Zhuhai, China
| | - Ronghua Yang
- Guangdong Medical University, Zhanjiang, China
- Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
- Correspondence: Xiaodong Chen Ronghua Yang a_hwa991316 @163.com
| | - Xiaodong Chen
- Guangdong Medical University, Zhanjiang, China
- Department of Burn Surgery and Skin Regeneration, the First People’s Hospital of Foshan, Foshan, China
- Correspondence: Xiaodong Chen Ronghua Yang a_hwa991316 @163.com
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Teng L, Maqsood M, Zhu M, Zhou Y, Kang M, Zhou J, Chen J. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Accelerate Diabetic Wound Healing via Promoting M2 Macrophage Polarization, Angiogenesis, and Collagen Deposition. Int J Mol Sci 2022; 23:ijms231810421. [PMID: 36142334 PMCID: PMC9498995 DOI: 10.3390/ijms231810421] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 11/16/2022] Open
Abstract
Some scholars have suggested that the clinical application of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) might represent a novel strategy to improve diabetic wound healing. However, the mechanisms underlying the effects of hucMSCs-exo on wound healing remain poorly understood. This study aimed to identify the mechanism of hucMSCs-exo in treating diabetic wounds. HucMSCs-exo were isolated from human umbilical cord mesenchymal stem cells (hucMSCs) and subcutaneously injected into full-thickness wounds in diabetic rats. Wound healing closure rates and histological analysis were performed. The levels of tumor necrosis factor-α (TNF-α), macrophage mannose receptor (MMR/CD206), platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. The degree of collagen deposition was examined using Masson’s trichrome staining. Gross evaluation of wound healing was carried out from day 0 to 14 post-surgery, and the wound site was harvested for histology on days 3, 7, and 14 post-wounding. HucMSCs-exo transplantation increased diabetic wound healing. In vitro, hucMSCs-exo promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and NIH-3T3 cells. In vivo, hucMSCs-exo reduced wound area and inflammatory infiltration and increased collagen fibers. In addition, wound tissues in the hucMSCs-exo group had higher CD206, CD31, and VEGF expressions and lower TNF-α levels than those in the control group on day 14. Our results demonstrated that hucMSCs-exo facilitated diabetic wound repair by inducing anti-inflammatory macrophages and promoting angiogenesis and collagen deposition.
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Affiliation(s)
- Liping Teng
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Maria Maqsood
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
| | - Min Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
| | - Yuting Zhou
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
| | - Mingzhu Kang
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
| | - Juan Zhou
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
| | - Jinghua Chen
- School of Life Sciences and Heath Engineering, Jiangnan University, Wuxi 214122, China
- Correspondence:
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Exosomes from human adipose-derived mesenchymal stromal/stem cells accelerate angiogenesis in wound healing: implication of the EGR-1/lncRNA-SENCR/DKC1/VEGF-A axis. Hum Cell 2022; 35:1375-1390. [PMID: 35751795 DOI: 10.1007/s13577-022-00732-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 05/30/2022] [Indexed: 11/04/2022]
Abstract
Exosomes (Exos) extracted from human adipose mesenchymal stromal/stem cells (hAD-MSCs) have been reported as therapeutic tools for tissue repair, but how they regulate angiogenesis of endothelial cells remains unknown. In this study, hAD-MSCs were isolated, and early growth response factor-1, Smooth muscle and endothelial cell enriched migration/differentiation-associated long-noncoding RNA (lncRNA-SENCR), and vascular endothelial growth factor-A (VEGF-A) overexpression or knockdown was achieved. Exos extracted from hAD-MSCs (hADSC-Exos) were co-cultured with human umbilical vein endothelial cells (HUVECs) to detect the effects of EGR-1, lncRNA-SENCR, and VEGF-A on angiogenesis and the relationships between EGR-1, lncRNA-SENCR, Dyskerin pseudouridine synthase 1 (DKC1), and VEGF-A. An in vivo experiment verified the effect of hADSC-Exos on the wound healing process. hADSC-Exos substantially promoted the proliferation, migration, and angiogenesis of HUVECs, which could be reversed by short-hairpin RNA SENCR (shSENCR) transfection. hADSC-Exos had elevated expression of EGR-1, which bound to the lncRNA-SENCR promoter. The suppressive effect of Exo-shEGR1 on HUVECs was counteracted by SENCR overexpression. LncRNA-SENCR was shown to interact with DKC1. Overexpression of DKC1 or lncRNA-SENCR maintained stable VEGF-A expression. Overexpression of VEGF-A reversed the suppressive effect of shSENCR on HUVECs. Consistent results were obtained in mice in vivo. Overall, hADSC-Exo EGR-1 upregulates lncRNA-SENCR expression to activate the DKC1/VEGF-A axis, facilitating the wound-healing process by increasing angiogenesis.
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Dong Y, Zhu W, Lei X, Luo X, Xiang Q, Zhu X, Pan Q, Jin P, Cheng B. Treatment of Acute Wounds With Recombinant Human-Like Collagen and Recombinant Human-Like Fibronectin in C57BL/6 Mice Individually or in Combination. Front Bioeng Biotechnol 2022; 10:908585. [PMID: 35662842 PMCID: PMC9160431 DOI: 10.3389/fbioe.2022.908585] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 04/25/2022] [Indexed: 11/22/2022] Open
Abstract
Wound repair is accomplished by the interaction between the cells involved in the repair and the extracellular matrix (ECM). Collagen is the main component of ECM, which is involved in transduction of signal, transportation of growth factors and cytokines. Fibronectin (FN) is also an important ECM, which participates in the initiation of fibroblast cell (FC) and promotes adhesion, migration, proliferation and differentiation of target cells. Compared with natural protein, the recombinant protein prepared by artificial method has the advantages of poor immunogenicity, wide range of sources, low cost and high activity. In this study, we used recombinant human-like collagen (RHC) and recombinant human-like fibronectin (rhFN) to treat acute wounds in C57BL/6 mice individually or in combination, and explored their effects on wound healing. Our study confirmed that these two recombinant proteins could effectively promote the proliferation, migration and adhesion of FCs. Meanwhile, it could positively regulate the healing speed and quality of acute wounds, re-epithelialization, collagen deposition, inflammation and angiogenesis. Moreover, we proved that the combination of the two was better than the treatment alone. Consequently, it has a good prospect as a new tissue material in the field of skin repair.
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Affiliation(s)
- Yunqing Dong
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou, China
| | - Weidong Zhu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou, China
| | - Xiaoxuan Lei
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou, China
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Center for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam, Amsterdam Movement Science, Amsterdam, Netherlands
| | - Xin Luo
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Qi Xiang
- Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Xuanru Zhu
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou, China
| | - Qiao Pan
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou, China
| | - Panshi Jin
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou, China
| | - Biao Cheng
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of PLA, Guangzhou, China
- *Correspondence: Biao Cheng,
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Chen J, Liu R, Huang T, Sun H, Jiang H. Adipose stem cells-released extracellular vesicles as a next-generation cargo delivery vehicles: a survey of minimal information implementation, mass production and functional modification. Stem Cell Res Ther 2022; 13:182. [PMID: 35505389 PMCID: PMC9062865 DOI: 10.1186/s13287-022-02849-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 04/12/2022] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES To investigate current situation of minimal information implementation highlighted by minimal information for studies of extracellular vesicles 2018 (MISEV2018) guidelines, and explore technological advances towards mass production and functional modification in aesthetic, plastic and reconstructive surgery. METHODS Original articles on extracellular vesicles (EVs) of adipose stem cells (ASCs) were identified. Statistics upon minimal information for EVs research, such as species, cell types, culture conditions, conditioned media harvesting parameters, EVs isolation/storage/identification/quantification, functional uptake and working concentration, were analyzed. RESULTS The items of cell culture conditions such as passage number, seeding density, conditioned media harvesting time, functional uptake and working concentration were poorly documented, with a reporting percentage of 47.13%, 54.02%, 29.89%, 62.07% and 36.21%, respectively. However, there were some studies not reporting information of ASCs origin, culture medium, serum, EVs isolation methods, quantification and identification of EVs, accounting for 3.45%, 10.34%, 6.90%, 3.45%, 18.39% and 4.02%, respectively. Serum deprivation and trophic factors stimuli were attempted for EVs mass production. Several technological advances towards functional modification included hypoxia pre-condition, engineering EVs and controlled release. Presently, ASCs EVs have been applied in multiple fields, including diabetic/non-diabetic wound healing, angiogenesis, inflammation modulation, fat grafting, hair regeneration, antiaging, and healing and regeneration of cartilage/bone/peripheral nerve/tendon. CONCLUSION Our results highlight normative reporting of ASCs EVs in functional studies to increase reliability and reproducibility of scientific publications. The advances towards mass production and functional modification of ASCs EVs are also recommended to enhance therapeutic effects.
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Affiliation(s)
- Jianguo Chen
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Badachu Road, Shijingshan District, Beijing, 100144, People's Republic of China
| | - Ruiquan Liu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Badachu Road, Shijingshan District, Beijing, 100144, People's Republic of China
| | - Tianyu Huang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Badachu Road, Shijingshan District, Beijing, 100144, People's Republic of China
| | - Hengyun Sun
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Badachu Road, Shijingshan District, Beijing, 100144, People's Republic of China
| | - Haiyue Jiang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 33 Badachu Road, Shijingshan District, Beijing, 100144, People's Republic of China.
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35
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Jiang YL, Wang ZL, Fan ZX, Wu MJ, Zhang Y, Ding W, Huang YZ, Xie HQ. Human adipose-derived stem cell-loaded small intestinal submucosa as a bioactive wound dressing for the treatment of diabetic wounds in rats. BIOMATERIALS ADVANCES 2022; 136:212793. [PMID: 35929325 DOI: 10.1016/j.bioadv.2022.212793] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 03/29/2022] [Accepted: 04/02/2022] [Indexed: 06/15/2023]
Abstract
Chronic nonhealing wounds are one of the most common and serious complications of diabetes, which can lead to disability of patients. Adipose-derived stem cells (ADSCs) have emerged as a promising tool for skin wound healing, but the therapeutic potential depends considerably on the cell delivery system. Small intestinal submucosa (SIS) is an extracellular matrix-based membranous scaffold with outstanding repair potential for skin wounds. In this study, we first fabricated a bioactive wound dressing, termed the SIS+ADSCs composite, by using human ADSCs as the seed cell and porcine SIS as the cell delivery vehicle. Then, we systematically investigated, for the first time, the healing potential of this wound dressing in a rat model of type 2 diabetes. In vitro studies revealed that SIS provided a favorable microenvironment for ADSCs and significantly promoted the expression of growth factors critical for chronic wound healing. After implantation in the full-thickness skin wounds of diabetic rats, the SIS+ADSCs composite showed a higher wound healing rate and wound healing quality than those in the PBS, ADSCs, and SIS groups. Along with the ability to modulate the polarization of macrophages in vivo, the SIS+ADSCs composite was potent at promoting wound angiogenesis, reepithelialization, and skin appendage regeneration. Taken together, these results indicate that the SIS+ADSCs composite has good therapeutic potential and high translational value for diabetic wound treatment.
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Affiliation(s)
- Yan-Lin Jiang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
| | - Zhu-Le Wang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
| | - Zhao-Xin Fan
- Neo-life Stem Cell Biotech INC, Chengdu, Sichuan 610037, China
| | - Ming-Jun Wu
- Neo-life Stem Cell Biotech INC, Chengdu, Sichuan 610037, China
| | - Yi Zhang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
| | - Wei Ding
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
| | - Yi-Zhou Huang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
| | - Hui-Qi Xie
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
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Krawczenko A, Klimczak A. Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Contribution to Angiogenic Processes in Tissue Regeneration. Int J Mol Sci 2022; 23:ijms23052425. [PMID: 35269568 PMCID: PMC8910401 DOI: 10.3390/ijms23052425] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/17/2022] [Accepted: 02/21/2022] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are widely described in the context of their regenerative and immunomodulatory activity. MSCs are isolated from various tissues and organs. The most frequently described sources are bone marrow and adipose tissue. As stem cells, MSCs are able to differentiate into other cell lineages, but they are usually reported with respect to their paracrine potential. In this review, we focus on MSCs derived from adipose tissue (AT-MSCs) and their secretome in regeneration processes. Special attention is given to the contribution of AT-MSCs and their derivatives to angiogenic processes described mainly in the context of angiogenic dysfunction. Finally, we present clinical trials registered to date that concern the application of AT-MSCs and their secretome in various medical conditions.
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Yang M, Chen J, Chen L. The roles of mesenchymal stem cell-derived exosomes in diabetes mellitus and its related complications. Front Endocrinol (Lausanne) 2022; 13:1027686. [PMID: 36339446 PMCID: PMC9633677 DOI: 10.3389/fendo.2022.1027686] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes mellitus is a type of metabolic disease characterized by hyperglycemia, primarily caused by defects in insulin secretion, insulin action, or both. Long-term chronic hyperglycemia can lead to diabetes-related complications, causing damage, dysfunction, and failure of different organs. However, traditional insulin and oral drug therapy can only treat the symptoms but not delay the progressive failure of pancreatic beta cells or prevent the emergence of diabetic complications. Mesenchymal stem cells have received extensive attention due to their strong immunoregulatory functions and regeneration effects. Mesenchymal stem cell-derived exosomes (MSC-Exos) have been proposed as a novel treatment for diabetic patients as they have demonstrated superior efficiency to mesenchymal stem cells. This review summarizes the therapeutic effects, mechanisms, challenges, and future prospects of MSC-Exos in treating diabetes mellitus and its related complications. This review supports the potential use of MSC-Exos in future regenerative medicine to overcome the current difficulties in clinical treatment, particularly in treating diabetes.
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Affiliation(s)
- Mengmeng Yang
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
| | - Jun Chen
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
- *Correspondence: Jun Chen, ; Li Chen,
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
- *Correspondence: Jun Chen, ; Li Chen,
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Burgess JL, Wyant WA, Abdo Abujamra B, Kirsner RS, Jozic I. Diabetic Wound-Healing Science. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1072. [PMID: 34684109 PMCID: PMC8539411 DOI: 10.3390/medicina57101072] [Citation(s) in RCA: 299] [Impact Index Per Article: 74.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022]
Abstract
Diabetes mellitus is an increasingly prevalent chronic metabolic disease characterized by prolonged hyperglycemia that leads to long-term health consequences. It is estimated that impaired healing of diabetic wounds affects approximately 25% of all patients with diabetes mellitus, often resulting in lower limb amputation, with subsequent high economic and psychosocial costs. The hyperglycemic environment promotes the formation of biofilms and makes diabetic wounds difficult to treat. In this review, we present updates regarding recent advances in our understanding of the pathophysiology of diabetic wounds focusing on impaired angiogenesis, neuropathy, sub-optimal chronic inflammatory response, barrier disruption, and subsequent polymicrobial infection, followed by current and future treatment strategies designed to tackle the various pathologies associated with diabetic wounds. Given the alarming increase in the prevalence of diabetes, and subsequently diabetic wounds, it is imperative that future treatment strategies target multiple causes of impaired healing in diabetic wounds.
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Affiliation(s)
| | | | | | - Robert S. Kirsner
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (J.L.B.); (W.A.W.); (B.A.A.)
| | - Ivan Jozic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA; (J.L.B.); (W.A.W.); (B.A.A.)
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