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Li X, Hayashi R, Imaizumi T, Harrington J, Kudo Y, Takayanagi H, Baba K, Nishida K. Extracellular vesicles from adipose-derived mesenchymal stem cells promote colony formation ability and EMT of corneal limbal epithelial cells. PLoS One 2025; 20:e0321579. [PMID: 40257992 PMCID: PMC12011229 DOI: 10.1371/journal.pone.0321579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 03/07/2025] [Indexed: 04/23/2025] Open
Abstract
Corneal diseases are a leading cause of visual impairment, and their treatment remains challenging. Corneal epithelial stem cells exist in the limbus, the peripheral region of the cornea, and play an important role in corneal regeneration. Here, we evaluated the effects of extracellular vesicles from human adipose-derived mesenchymal stem cells (AdMSC-EVs) on limbal epithelial cells (LECs). Colony formation assays showed that the colony-forming efficiency of LECs significantly increased in the presence of AdMSC-EVs. We next demonstrated that AdMSC-EVs accelerated the migration of LECs in a scratch assay, whereas the proliferation of LECs was decreased by AdMSC-EVs in the cell proliferation assay. RNA sequencing analysis of LECs indicated that AdMSC-EVs maintained their stem cell properties and improved epithelial-mesenchymal transition (EMT). Furthermore, after identifying the six most abundant microRNAs (miRNAs) in AdMSC-EVs, LEC transfection with miRNA mimics indicated that miR-25, miR-191, and miR-335 were the most probable miRNA factors within AdMSC-EVs at improving colony formation ability and EMT. Taken together, our findings indicated that AdMSC-EVs enhanced the colony formation ability and EMT of LECs, and the effects of AdMSC-EVs were in-part mediated by the miRNAs within the AdMSC-EVs.
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Affiliation(s)
- Xiaoqin Li
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryuhei Hayashi
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan
| | - Tsutomu Imaizumi
- Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Basic Research Development Division, ROHTO Pharmaceutical, Ikuno-ku, Osaka, Japan
| | - Jodie Harrington
- Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Faculty of Health, Medicine and Social Care, Medical Technology Research Centre, Anglia Ruskin University, Chelmsford Campus, England, United Kingdom
| | - Yuji Kudo
- Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Basic Research Development Division, ROHTO Pharmaceutical, Ikuno-ku, Osaka, Japan
| | - Hiroshi Takayanagi
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Research, Development and Production Department of RAYMEI Inc, Suita, Osaka, Japan
| | - Koichi Baba
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Advanced Device Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Visual Regenerative Medicine, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kohji Nishida
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka, Japan
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Song P, Liang Q, Ge X, Zhou D, Yuan M, Chu W, Xu J. Adipose-Derived Stem Cell Exosomes Promote Scar-Free Healing of Diabetic Wounds via miR-204-5p/TGF- β1/Smad Pathway. Stem Cells Int 2025; 2025:6344844. [PMID: 40018015 PMCID: PMC11865461 DOI: 10.1155/sci/6344844] [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: 06/27/2024] [Accepted: 01/18/2025] [Indexed: 03/01/2025] Open
Abstract
Numerous researches have demonstrated the therapeutic potential of adipose-derived stem cell exosomes (ADSC-Exos) in promoting wound healing. In this study, we aimed to investigate the impact of ADSC-Exos on diabetic wound fibroblasts and elucidate its possible mechanisms. CCK-8, Edu, cell scratch, and Transwell tests were used to evaluate the function of ADSC-Exos on rat skin fibroblasts (RSFs) in high-glucose (HG) medium. The targeting effect of ADSC-Exo-derived microRNA (miRNA) and TGF-β1 was assessed using bioinformatic analysis and then confirmed with western blot and dual luciferase reporter assays. ADSC-Exos, miR-204-5p mimic, and anti-miR-204-5p mimic were used to stimulate RSFs, and the levels of TGF-β1/Smad pathway were analyzed by western blot. In vivo, digital photo and tissue section staining were used to evaluate the therapeutic effect of ADSC-Exos on diabetic wounds. The data showed that ADSC-Exos enhance the proliferation and migration of fibroblasts under HG conditions, reduce excessive myofibroblast differentiation and collagen deposition, and promote scarless healing of diabetic wounds. Additionally, miR-204-5p in ADSC-Exos targets TGF-β1 to inhibit p-Smad2/3, Col I, and alpha-smooth muscle actin (α-SMA), thereby reducing fibrosis. These findings suggest that ADSC-Exos have potential prospects for promoting diabetic wound healing.
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Affiliation(s)
- Peijun Song
- Department of Plastic Surgery and Burn, The First Affiliated Hospital of Bengbu Medical University, Bengbu City 233000, Anhui Province, China
| | - Qiu Liang
- Department of Plastic Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou City 225000, Jiangsu Province, China
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical University, Bengbu City 233000, Anhui Province, China
| | - Xiuyu Ge
- Department of Plastic Surgery and Burn, The First Affiliated Hospital of Bengbu Medical University, Bengbu City 233000, Anhui Province, China
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical University, Bengbu City 233000, Anhui Province, China
| | - Danlian Zhou
- Department of Plastic Surgery and Burn, The First Affiliated Hospital of Bengbu Medical University, Bengbu City 233000, Anhui Province, China
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical University, Bengbu City 233000, Anhui Province, China
| | - Mei Yuan
- Department of Plastic Surgery and Burn, The First Affiliated Hospital of Bengbu Medical University, Bengbu City 233000, Anhui Province, China
| | - Weiwei Chu
- Department of Plastic Surgery and Burn, The First Affiliated Hospital of Bengbu Medical University, Bengbu City 233000, Anhui Province, China
| | - Jing Xu
- Department of Plastic Surgery and Burn, The First Affiliated Hospital of Bengbu Medical University, Bengbu City 233000, Anhui Province, China
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Sheikhi K, Ghaderi S, Firouzi H, Rahimibarghani S, Shabani E, Afkhami H, Yarahmadi A. Recent advances in mesenchymal stem cell therapy for multiple sclerosis: clinical applications and challenges. Front Cell Dev Biol 2025; 13:1517369. [PMID: 39963155 PMCID: PMC11830822 DOI: 10.3389/fcell.2025.1517369] [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: 10/25/2024] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
Multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system (CNS), is characterized by inflammation, demyelination, and neurodegeneration, leading to diverse clinical manifestations such as fatigue, sensory impairment, and cognitive dysfunction. Current pharmacological treatments primarily target immune modulation but fail to arrest disease progression or entirely reverse CNS damage. Mesenchymal stem cell (MSC) therapy offers a promising alternative, leveraging its immunomodulatory, neuroprotective, and regenerative capabilities. This review provides an in-depth analysis of MSC mechanisms of action, including immune system regulation, promotion of remyelination, and neuroregeneration. It examines preclinical studies and clinical trials evaluating the efficacy, safety, and limitations of MSC therapy in various MS phenotypes. Special attention is given to challenges such as delivery routes, dosing regimens, and integrating MSCs with conventional therapies. By highlighting advancements and ongoing challenges, this review underscores the potential of MSCs to revolutionize MS treatment, paving the way for personalized and combinatory therapeutic approaches.
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Affiliation(s)
- Kamran Sheikhi
- Kurdistan University of Medical Sciences, Kurdistan, Iran
| | | | - Hassan Firouzi
- Department of Medical Laboratory, Faculty of Medicine, Sari Branch, Islamic Azad University, Sari, Iran
| | - Sarvenaz Rahimibarghani
- Department of Physical Medicine and Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Shabani
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
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Liu X, Wang B. Adipose stem cell-derived exosomes promote wound healing by regulating the let-7i-5p/GAS7 axis. J Cosmet Dermatol 2024; 23:2279-2287. [PMID: 38429909 DOI: 10.1111/jocd.16267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 03/03/2024]
Abstract
BACKGROUND Injury to skin tissue is devastating for human health, making it imperative to devise strategies for hastening wound healing. Normal wound healing is a complex process comprising overlapping steps, including hemostasis, inflammatory response, proliferation, and matrix remodeling. This study investigated the effects of adipose stem cell-derived exosomes (ADSC-exos) on wound healing and the underlying mechanisms. METHODS In vitro hydrogen peroxide (H2O2)-treated human keratinocyte (HaCaT) cell lines and in vivo animal wound models were established for this purpose. The cell migration was assessed using transwell and wound healing assays, while exosome biomarker expressions were studied using western blot. Moreover, adipose stem cells were identified using flow cytometry, alizarin red S and oil red O staining, and transmission electron microscopy. RESULTS Results indicated that H2O2 treatment inhibited the cell viability and migration of HaCaT cells while being promoted by ADSC-exos. Mechanistic investigations revealed that microRNA-let-7i-5p (let-7i-5p) in ADSC-exos was carried into the HaCaT cells, inhibiting the expression of growth arrest-specific-7 (GAS7). Rescue experiments further verified these results, which indicated that GAS7 overexpression reversed the effect of let-7i-5p on the viability and migration of HaCaT cells, suggesting ADSC-exos promoted wound healing via the let-7i-5p/GAS7 axis. CONCLUSION Adipose stem cell-derived-exos enhanced the viability and migration of HaCaT via carrying let-7i-5p and targeting GAS7, ultimately promoting wound healing in rats.
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Affiliation(s)
- Xiaosong Liu
- Department of Surgery, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Biao Wang
- Department of Surgery, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Dong L, Li X, Leng W, Guo Z, Cai T, Ji X, Xu C, Zhu Z, Lin J. Adipose stem cells in tissue regeneration and repair: From bench to bedside. Regen Ther 2023; 24:547-560. [PMID: 37854632 PMCID: PMC10579872 DOI: 10.1016/j.reth.2023.09.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 09/21/2023] [Accepted: 09/28/2023] [Indexed: 10/20/2023] Open
Abstract
ADSCs are a large number of mesenchymal stem cells in Adipose tissue, which can be applied to tissue engineering. ADSCs have the potential of multi-directional differentiation, and can differentiate into bone tissue, cardiac tissue, urothelial cells, skin tissue, etc. Compared with other mesenchymal stem cells, ADSCs have a multitude of promising advantages, such as abundant number, accessibility in cell culture, stable function, and less immune rejection. There are two main methods to use ADSCs for tissue repair and regeneration. One is to implant the "ADSCs-scaffold composite" into the injured site to promote tissue regeneration. The other is cell-free therapy: using ADSC-exos or ADSC-CM alone to release a large number of miRNAs, cytokines and other bioactive substances to promote tissue regeneration. The tissue regeneration potential of ADSCs is regulated by a variety of cytokines, signaling molecules, and external environment. The differentiation of ADSCs into different tissues is also induced by growth factors, ions, hormones, scaffold materials, physical stimulation, and other factors. The specific mechanisms are complex, and most of the signaling pathways need to be further explored. This article reviews and summarizes the mechanism and clinical application of ADSCs in tissue injury repair so far, and puts forward further problems that need to be solved in this field, hoping to provide directions for further research in this field.
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Affiliation(s)
- Lei Dong
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
| | - Xiaoyu Li
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
| | - Wenyuan Leng
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
| | - Zhenke Guo
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
| | - Tianyu Cai
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
| | - Xing Ji
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
| | - Chunru Xu
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
| | - Zhenpeng Zhu
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
| | - Jian Lin
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
- Institute of Urology, Peking University, Beijing, 100034, China
- National Urological Cancer Center, Beijing, 100034, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China
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Finocchio L, Zeppieri M, Gabai A, Spadea L, Salati C. Recent Advances of Adipose-Tissue-Derived Mesenchymal Stem Cell-Based Therapy for Retinal Diseases. J Clin Med 2023; 12:7015. [PMID: 38002628 PMCID: PMC10672618 DOI: 10.3390/jcm12227015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/29/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
With the rapid development of stem cell research in modern times, stem cell-based therapy has opened a new era of tissue regeneration, becoming one of the most promising strategies for currently untreatable retinal diseases. Among the various sources of stem cells, adipose tissue-derived mesenchymal stem cells (ADSCs) have emerged as a promising therapeutic modality due to their characteristics and multiple functions, which include immunoregulation, anti-apoptosis of neurons, cytokine and growth factor secretion, and antioxidative activities. Studies have shown that ADSCs can facilitate the replacement of dying cells, promote tissue remodeling and regeneration, and support the survival and growth of retinal cells. Recent studies in this field have provided numerous experiments using different preclinical models. The aim of our review is to provide an overview of the therapeutic strategies, modern-day clinical trials, experimental models, and potential clinical use of this fascinating class of cells in addressing retinal disorders and diseases.
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Affiliation(s)
- Lucia Finocchio
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Andrea Gabai
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
| | - Leopoldo Spadea
- Eye Clinic, Policlinico Umberto I, La Sapienza University of Rome, 00142 Rome, Italy
| | - Carlo Salati
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy; (L.F.)
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Wang L, Zhang JJ, Wang SS, Li L. Mechanism of adipose-derived mesenchymal stem cell exosomes in the treatment of heart failure. World J Stem Cells 2023; 15:897-907. [PMID: 37900939 PMCID: PMC10600745 DOI: 10.4252/wjsc.v15.i9.897] [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: 07/27/2023] [Revised: 08/16/2023] [Accepted: 09/12/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND Heart failure (HF) is a global health problem characterized by impaired heart function. Cardiac remodeling and cell death contribute to the development of HF. Although treatments such as digoxin and angiotensin receptor blocker drugs have been used, their effectiveness in reducing mortality is uncertain. Researchers are exploring the use of adipose-derived mesenchymal stem cell (ADMSC) exosomes (Exos) as a potential therapy for HF. These vesicles, secreted by cells, may aid in tissue repair and regulation of inflammation and immune responses. However, further investigation is needed to understand the specific role of these vesicles in HF treatment. AIM To investigate the mechanism of extracellular vesicles produced by ADMSC s in the treatment of HF. METHODS Exogenous surface markers of ADMSCs were found, and ADMSCs were cultured. RESULTS The identification of surface markers showed that the surface markers CD44 and CD29 of adipose-derived stem cells (ADSCs) were well expressed, while the surface markers CD45 and CD34 of ADSCs were negative, so the cultured cells were considered ADSCs. Western blotting detected the Exo surface marker protein, which expressed CD63 protein but did not express calnexin protein, indicating that ADSC-derived Exos were successfully extracted. CONCLUSION The secretion of MSCs from adipose tissue can increase ATP levels, block cardiomyocyte apoptosis, and enhance the heart function of animals susceptible to HF. The inhibition of Bax, caspase-3 and p53 protein expression may be related to this process.
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Affiliation(s)
- Lei Wang
- Department of Geriatric Medicine, Fourth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Jin-Jin Zhang
- Department of Geriatric Medicine, Fourth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Sha-Sha Wang
- Department of Geriatric Medicine, Fourth Medical Center of PLA General Hospital, Beijing 100048, China
| | - Liang Li
- Department of Geriatric Medicine, Fourth Medical Center of PLA General Hospital, Beijing 100048, China.
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Koh HB, Kim HJ, Kang SW, Yoo TH. Exosome-Based Drug Delivery: Translation from Bench to Clinic. Pharmaceutics 2023; 15:2042. [PMID: 37631256 PMCID: PMC10459753 DOI: 10.3390/pharmaceutics15082042] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Exosome-based drug delivery is emerging as a promising field with the potential to revolutionize therapeutic interventions. Exosomes, which are small extracellular vesicles released by various cell types, have attracted significant attention due to their unique properties and natural ability to transport bioactive molecules. These nano-sized vesicles, ranging in size from 30 to 150 nm, can effectively transport a variety of cargoes, including proteins, nucleic acids, and lipids. Compared to traditional drug delivery systems, exosomes exhibit unique biocompatibility, low immunogenicity, and reduced toxicity. In addition, exosomes can be designed and tailored to improve targeting efficiency, cargo loading capacity, and stability, paving the way for personalized medicine and precision therapy. However, despite the promising potential of exosome-based drug delivery, its clinical application remains challenging due to limitations in exosome isolation and purification, low loading efficiency of therapeutic cargoes, insufficient targeted delivery, and rapid elimination in circulation. This comprehensive review focuses on the transition of exosome-based drug delivery from the bench to clinic, highlighting key aspects, such as exosome structure and biogenesis, cargo loading methods, surface engineering techniques, and clinical applications. It also discusses challenges and prospects in this emerging field.
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Affiliation(s)
- Hee Byung Koh
- Division of Nephrology, Department of Internal Medicine, International Saint Mary’s Hospital, College of Medicine, Catholic Kwandong University, Seo-gu, Incheon 22711, Republic of Korea;
| | - Hyo Jeong Kim
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, College of Medicine, Yonsei University, Gangnam-gu, Seoul 06273, Republic of Korea;
| | - Shin-Wook Kang
- Department of Internal Medicine, Institute of Kidney Disease Research, College of Medicine, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Tae-Hyun Yoo
- Department of Internal Medicine, Institute of Kidney Disease Research, College of Medicine, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea
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Baldassarro VA, Perut F, Cescatti M, Pinto V, Fazio N, Alastra G, Parziale V, Bassotti A, Fernandez M, Giardino L, Baldini N, Calzà L. Intra-individual variability in the neuroprotective and promyelinating properties of conditioned culture medium obtained from human adipose mesenchymal stromal cells. Stem Cell Res Ther 2023; 14:128. [PMID: 37170115 PMCID: PMC10173531 DOI: 10.1186/s13287-023-03344-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 04/13/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Greater knowledge of mesenchymal stromal cell (MSC)-based therapies is driving the research into their secretome, identified as the main element responsible for their therapeutic effects. The aim of this study is to characterize the individual variability of the secretome of adipose tissue-derived MSCs (adMSCs) with regard to potential therapeutical applications in neurology. METHODS adMSCs were isolated from the intact adipose tissue of ten subjects undergoing abdominal plastic surgery or reduction mammoplasty. Two commercial lines were also included. We analyzed the expansion rate, production, and secretion of growth factors of interest for neurological applications (VEGF-A, BDNF, PDGF-AA and AA/BB, HGF, NGF, FGF-21, GDNF, IGF-I, IGF-II, EGF and FGF-2). To correlate these characteristics with the biological effects on the cellular targets, we used individual media conditioned with adMSCs from the various donors on primary cultures of neurons/astrocytes and oligodendrocyte precursor cells (OPCs) exposed to noxious stimuli (oxygen-glucose deprivation, OGD) to evaluate their protective and promyelinating properties, using MSC medium as a control group. RESULTS The MSC secretome showed significant individual variability within the considered population with regard to PDGF-AA, PDGF-AB/BB, VEGF-A and BDNF. None of the MSC-derived supernatants affected neuron viability in normoxia, while substantial protection by high BDNF-containing conditioned MSC medium was observed in neuronal cultures exposed to OGD conditions. In OPC cultures, the MSC-derived supernatants protected cells from OGD-induced cell death, also increasing the differentiation in mature oligodendrocytes. Neuroprotection showed a positive correlation with VEGF-A, BDNF and PDGF-AA concentrations in the culture supernatants, and an inverse correlation with HGF, while OPC differentiation following OGD was positively correlated to PDGF-AA concentration. CONCLUSIONS Despite the limited number of adMSC donors, this study showed significant individual variability in the biological properties of interest for neurological applications for adMSC secretome, an under-researched aspect which may represent an important step in the translation of MSC-derived acellular products to clinical practice. We also showed the potential protection capability of MSC conditioned medium on neuronal and oligodendroglial lineages exposed to oxygen-glucose deprivation. These effects are directly correlated to the concentration of specific growth factors, and indicate that the remyelination should be included as a primary target in MSC-based therapies.
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Affiliation(s)
- Vito Antonio Baldassarro
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Via Tolara Di Sopra 50, 40064, Ozzano Dell'Emilia, Bologna, Italy
- Health Science and Technologies, Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara Di Sopra 50, 40064, Ozzano Dell'Emilia, Bologna, Italy
| | - Francesca Perut
- Biomedical Science and Technologies and Nanobiotechnology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136, Bologna, Italy
| | - Maura Cescatti
- IRET Foundation, Via Tolara Di Sopra 41/E, 40064, Ozzano Dell'Emilia, Bologna, Italy
| | - Valentina Pinto
- Division of Plastic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Nicola Fazio
- Biomedical Science and Technologies and Nanobiotechnology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136, Bologna, Italy
| | - Giuseppe Alastra
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Via Tolara Di Sopra 50, 40064, Ozzano Dell'Emilia, Bologna, Italy
| | - Valentina Parziale
- Biomedical Science and Technologies and Nanobiotechnology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136, Bologna, Italy
| | - Alessandra Bassotti
- Biomedical Science and Technologies and Nanobiotechnology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136, Bologna, Italy
| | - Mercedes Fernandez
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Via Tolara Di Sopra 50, 40064, Ozzano Dell'Emilia, Bologna, Italy
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy
| | - Luciana Giardino
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Via Tolara Di Sopra 50, 40064, Ozzano Dell'Emilia, Bologna, Italy
- Health Science and Technologies, Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara Di Sopra 50, 40064, Ozzano Dell'Emilia, Bologna, Italy
| | - Nicola Baldini
- Biomedical Science and Technologies and Nanobiotechnology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136, Bologna, Italy
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Di Barbiano 1/10, 40136, Bologna, Italy
| | - Laura Calzà
- Health Science and Technologies, Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Via Tolara Di Sopra 50, 40064, Ozzano Dell'Emilia, Bologna, Italy.
- Pharmacology and Biotecnology Department (FaBiT), University of Bologna, Via San Donato, 15, 40127, Bologna, Italy.
- Monetecatone Rehabilitation Institute (MRI), Via Montecatone, 37, 40026, Imola, Bologna, Italy.
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Lischer M, di Summa PG, Petrou IG, Schaefer DJ, Guzman R, Kalbermatten DF, Madduri S. Mesenchymal Stem Cells in Nerve Tissue Engineering: Bridging Nerve Gap Injuries in Large Animals. Int J Mol Sci 2023; 24:ijms24097800. [PMID: 37175506 PMCID: PMC10177884 DOI: 10.3390/ijms24097800] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Cell-therapy-based nerve repair strategies hold great promise. In the field, there is an extensive amount of evidence for better regenerative outcomes when using tissue-engineered nerve grafts for bridging severe gap injuries. Although a massive number of studies have been performed using rodents, only a limited number involving nerve injury models of large animals were reported. Nerve injury models mirroring the human nerve size and injury complexity are crucial to direct the further clinical development of advanced therapeutic interventions. Thus, there is a great need for the advancement of research using large animals, which will closely reflect human nerve repair outcomes. Within this context, this review highlights various stem cell-based nerve repair strategies involving large animal models such as pigs, rabbits, dogs, and monkeys, with an emphasis on the limitations and strengths of therapeutic strategy and outcome measurements. Finally, future directions in the field of nerve repair are discussed. Thus, the present review provides valuable knowledge, as well as the current state of information and insights into nerve repair strategies using cell therapies in large animals.
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Affiliation(s)
- Mirko Lischer
- Center for Bioengineering and Regenerative Medicine, Department of Biomedical Engineering, University of Basel, 4123 Allschwil, Switzerland
| | - Pietro G di Summa
- Department of Plastic, Reconstructive and Hand Surgery, University Hospital of Lausanne and University of Lausanne, 1015 Lausanne, Switzerland
| | - Ilias G Petrou
- Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, University Hospitals and University of Geneva, 1205 Geneva, Switzerland
| | - Dirk J Schaefer
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
| | - Raphael Guzman
- Department of Neurosurgery, University Hospital Basel, 4031 Basel, Switzerland
| | - Daniel F Kalbermatten
- Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, University Hospitals and University of Geneva, 1205 Geneva, Switzerland
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
| | - Srinivas Madduri
- Center for Bioengineering and Regenerative Medicine, Department of Biomedical Engineering, University of Basel, 4123 Allschwil, Switzerland
- Plastic, Reconstructive and Aesthetic Surgery, Department of Surgery, University Hospitals and University of Geneva, 1205 Geneva, Switzerland
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
- Bioengineering and Neuroregeneration, Department of Surgery, Geneva University Hospitals and University of Geneva, 1205 Geneva, Switzerland
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11
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Therapeutic role of adipose-derived mesenchymal stem cells-derived extracellular vesicles in rats with obstructive sleep apnea hypopnea syndrome. Regen Ther 2023; 22:210-223. [PMID: 36926469 PMCID: PMC10011058 DOI: 10.1016/j.reth.2023.01.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/03/2023] [Accepted: 01/12/2023] [Indexed: 03/06/2023] Open
Abstract
Background Obstructive sleep apnea hypopnea syndrome (OSAHS) is an underestimated sleep disorder that leads to multiple organ damages, including lung injury (LI). This paper sought to analyze the molecular mechanism of extracellular vesicles (EVs) from adipose-derived mesenchymal stem cells (ADSCs) in OSAHS-induced lung injury (LI) via the miR-22-3p/histone lysine demethylase 6 B (KDM6B)/high mobility group AT-hook 2 (HMGA2) axis. Methods ADSCs and ADSCs-EVs were separated and characterized. Chronic intermittent hypoxia (CIH) was used to mimic OSAHS-LI, followed by ADSCs-EVs treatment and hematoxylin and eosin staining, TUNEL, ELISA, and assays of inflammation and oxidative stress (MPO/ROS/MDA/SOD). The CIH cell model was established and treated with ADSCs-EVs. Cell injury was assessed by the assays of MTT, TUNEL, ELISA, and others. Levels of miR-22-3p, KDM6B, histone H3 trimethylation at lysine 27 (H3K27me3), and HMGA2 were determine by RT-qPCR or Western blot analysis. The transfer of miR-22-3p by ADSCs-EVs was observed by fluorescence microscopy. Gene interactions were analyzed by dual-luciferase assay or chromatin immunoprecipitation. Results ADSCs-EVs effectively alleviated OSAHS-LI by reducing lung tissue injury, apoptosis, oxidative stress, and inflammation. In vitro, ADSCs-EVs increased cell viability and reduced apoptosis, inflammation and oxidative stress. ADSCs-EVs delivered enveloped miR-22-3p into pneumonocytes to upregulate miR-22-3p expression, inhibit KDM6B expression, increase H3K27me3 levels on the HMGA2 promoter, and decrease HMGA2 mRNA levels. Overexpression of KDM6B or HMGA2 attenuated the protective role of ADSCs-EVs in OSAHS-LI. Conclusion ADSCs-EVs transferred miR-22-3p to pneumonocytes and reduced apoptosis, inflammation, and oxidative stress through KDM6B/HMGA2, mitigating OSAHS-LI progression.
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12
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Lai F, Dai S, Zhao Y, Sun Y. Combination of PDGF-BB and adipose-derived stem cells accelerated wound healing through modulating PTEN/AKT pathway. Injury 2023:S0020-1383(23)00123-7. [PMID: 37028952 DOI: 10.1016/j.injury.2023.02.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/01/2023] [Accepted: 02/10/2023] [Indexed: 04/09/2023]
Abstract
Adipose-derived stem cells (ADSCs) have been widely proven to facilitate wound healing. Our study aimed to estimate the influence of combined ADSCs and platelet-derived growth factor-BB (PDGF-BB) on wound healing. We utilized 4 healthy SD rats to isolate ADSCs. Platelet-rich plasma (PRP) was acquired utilizing a two-step centrifugation technology. The role of PRP, PDGF-BB, and PDGF-BB combined with a PI3k inhibitor LY294002 on the viability, migration, and PTEN/AKT pathway in ADSCs were examined utilizing CCK-8, Transwell, and western blot assays. Then, we constructed an open trauma model in SD rats. Effects of ADSCs treated with PDGF-BB on pathological changes, CD31, and PTEN/AKT pathway of wound closure were assessed by hematoxylin & eosin (H&E) staining, Masson staining, immunohistochemical, and western blot assays, respectively. PRP and PDGF-BB intensified the viability and migration of ADSCs by modulating the PTEN/AKT pathway. Interestingly, LY294002 reversed the role of PDGF-BB on ADSCs. In vivo experiments, combined intervention with ADSCs plus PDGF-BB/PRP facilitated wound closure and ameliorated histological injury. Moreover, combined intervention with ADSCs and PDGF-BB attenuated the PTEN level and elevated the CD31 level as well as the ratio of p-AKT/AKT in the skin tissues. A combination of ADSCs and PDGF-BB facilitated wound healing might associate with the regulation of the PTEN/AKT pathway.
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Affiliation(s)
- Fangyuan Lai
- Center for Plastic & Reconstructive Surgery, Department of Plastic & Reconstructive Surgery, Zhejiang Provincial People's Hospital （Affiliated People's Hospital, Hangzhou Medical College）, Hangzhou, Zhejiang, China
| | - Shijie Dai
- College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Ye Zhao
- Center for Plastic & Reconstructive Surgery, Department of Plastic & Reconstructive Surgery, Zhejiang Provincial People's Hospital （Affiliated People's Hospital, Hangzhou Medical College）, Hangzhou, Zhejiang, China
| | - Yi Sun
- Center for Plastic & Reconstructive Surgery, Department of Plastic & Reconstructive Surgery, Zhejiang Provincial People's Hospital （Affiliated People's Hospital, Hangzhou Medical College）, Hangzhou, Zhejiang, China.
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13
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Review of Technological Challenges in Personalised Medicine and Early Diagnosis of Neurodegenerative Disorders. Int J Mol Sci 2023; 24:ijms24043321. [PMID: 36834733 PMCID: PMC9968142 DOI: 10.3390/ijms24043321] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
Neurodegenerative disorders are characterised by progressive neuron loss in specific brain areas. The most common are Alzheimer's disease and Parkinson's disease; in both cases, diagnosis is based on clinical tests with limited capability to discriminate between similar neurodegenerative disorders and detect the early stages of the disease. It is common that by the time a patient is diagnosed with the disease, the level of neurodegeneration is already severe. Thus, it is critical to find new diagnostic methods that allow earlier and more accurate disease detection. This study reviews the methods available for the clinical diagnosis of neurodegenerative diseases and potentially interesting new technologies. Neuroimaging techniques are the most widely used in clinical practice, and new techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have significantly improved the diagnosis quality. Identifying biomarkers in peripheral samples such as blood or cerebrospinal fluid is a major focus of the current research on neurodegenerative diseases. The discovery of good markers could allow preventive screening to identify early or asymptomatic stages of the neurodegenerative process. These methods, in combination with artificial intelligence, could contribute to the generation of predictive models that will help clinicians in the early diagnosis, stratification, and prognostic assessment of patients, leading to improvements in patient treatment and quality of life.
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14
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Yang X, Xia H, Liu C, Wu Y, Liu X, Cheng Y, Wang Y, Xia Y, Yue Y, Cheng X, Jia R. The novel delivery-exosome application for diagnosis and treatment of rheumatoid arthritis. Pathol Res Pract 2023; 242:154332. [PMID: 36696804 DOI: 10.1016/j.prp.2023.154332] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/15/2023] [Accepted: 01/20/2023] [Indexed: 01/22/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic degenerative disease characterized by persistent systemic synovitis, with a high risk of stiffness, pain, and swelling. It may affect the other extra-articular tissues. There is no ideal treatment for this disease at present, and it can only be controlled by medication to alleviate the prognosis. Exosomes are small vesicles secreted by various cells in the organism under normal or pathological conditions, and play a role in immune response, antigen presentation, cell migration, cell differentiation, tumor invasion and so on. Due to the adverse effects of conventional drugs and treatments in the treatment of RA, exosomes, as a nanocarrier with many advantages, can have a great impact on the loading of drugs for the treatment of RA. This article reviews the role of exosomes in the pathogenesis of RA and the progress of exosome-based therapy for RA.
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Affiliation(s)
- Xinying Yang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Hongmei Xia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China.
| | - Chang Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yifang Wu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Xinyi Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yongfeng Cheng
- Clinical College of Anhui Medical University, Hefei 230031, People's Republic of China; School of Life Science, University of Science and Technology of China, Hefei 230027, People's Republic of China
| | - Yu Wang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Ying Xia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yan Yue
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Xiaoman Cheng
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Ruoyang Jia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
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15
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Everts PA, Panero AJ. Basic Science of Autologous Orthobiologics. Phys Med Rehabil Clin N Am 2023; 34:25-47. [DOI: 10.1016/j.pmr.2022.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Ghasempour E, Hesami S, Movahed E, keshel SH, Doroudian M. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy in the brain tumors. Stem Cell Res Ther 2022; 13:527. [PMID: 36536420 PMCID: PMC9764546 DOI: 10.1186/s13287-022-03212-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Brain tumors are one of the most mortal cancers, leading to many deaths among kids and adults. Surgery, chemotherapy, and radiotherapy are available options for brain tumor treatment. However, these methods are not able to eradicate cancer cells. The blood-brain barrier (BBB) is one of the most important barriers to treat brain tumors that prevents adequate drug delivery to brain tissue. The connection between different brain parts is heterogeneous and causes many challenges in treatment. Mesenchymal stem cells (MSCs) migrate to brain tumor cells and have anti-tumor effects by delivering cytotoxic compounds. They contain very high regenerative properties, as well as support the immune system. MSCs-based therapy involves cell replacement and releases various vesicles, including exosomes. Exosomes receive more attention due to their excellent stability, less immunogenicity and toxicity compare to cells. Exosomes derived from MSCs can develop a powerful therapeutic strategy for different diseases and be a hopeful candidate for cell-based and cell-free regenerative medicine. These nanoparticles contain nucleic acid, proteins, lipids, microRNAs, and other biologically active substances. Many studies show that each microRNA can prevent angiogenesis, migration, and metastasis in glioblastoma. These exosomes can-act as a suitable nanoparticle carrier for therapeutic applications of brain tumors by passing through the BBB. In this review, we discuss potential applications of MSC and their produced exosomes in the treatment of brain tumors.
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Affiliation(s)
- Elham Ghasempour
- grid.411600.2Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shilan Hesami
- grid.411600.2Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elaheh Movahed
- grid.238491.50000 0004 0367 6866Wadsworth Center, New York State Department of Health, Albany, NY USA
| | - Saeed Heidari keshel
- grid.411600.2Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Doroudian
- grid.412265.60000 0004 0406 5813Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
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Ebrahim N, El-Halim HEA, Helal OK, El-Azab NEE, Badr OAM, Hassouna A, Saihati HAA, Aborayah NH, Emam HT, El-Wakeel HS, Aljasir M, El-Sherbiny M, Sarg NAS, Shaker GA, Mostafa O, Sabry D, Fouly MAK, Forsyth NR, Elsherbiny NM, Salim RF. Effect of bone marrow mesenchymal stem cells-derived exosomes on diabetes-induced retinal injury: Implication of Wnt/ b-catenin signaling pathway. Biomed Pharmacother 2022; 154:113554. [PMID: 35987163 DOI: 10.1016/j.biopha.2022.113554] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 08/01/2022] [Accepted: 08/14/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus. Mesenchymal stem cells are currently studied as therapeutic strategy for management of DR. Exosomes, considered as a promising cell-free therapy option, display biological functions similar to those of their parent cells. In retinal development, Wnt/b-catenin signaling provides key cues for functional progression. The present study aimed to evaluate the potential efficacy of bone marrow-derived mesenchymal stem cell-derived exosomes (BM-MSCs-Ex) in diabetes-induced retinal injury via modulation of the Wnt/ b-catenin signaling pathway. METHODS Eighty-one rats were allocated into 6 groups (control, DR, DR + DKK1, DR + exosomes, DR + Wnt3a and DR + exosomes+Wnt3a). Evaluation of each group was via histopathological examination, assessment of gene and/or protein expression concerned with oxidative stress (SOD1, SOD2, Nox2, Nox4, iNOS), inflammation (TNF-α, ICAM-1, NF-κB) and angiogenesis (VEGF, VE-cadherin). RESULTS Results demonstrated that exosomes blocked the wnt/b-catenin pathway in diabetic retina concomitant with significant reduction of features of DR as shown by downregulation of retinal oxidants, upregulation of antioxidant enzymes, suppression of retinal inflammatory and angiogenic markers. These results were further confirmed by histopathological results, fundus examination and optical coherence tomography. Additionally, exosomes ameliorative effects abrogated wnt3a-triggered retinal injury in DR. CONCLUSION Collectively, these data demonstrated that exosomes ameliorated diabetes-induced retinal injury via suppressing Wnt/ b-catenin signaling with subsequent reduction of oxidative stress, inflammation and angiogenesis.
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Affiliation(s)
- Nesrine Ebrahim
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Egypt; Stem Cell Unit, Faculty of Medicine, Benha University, Egypt.
| | | | - Omayma Kamel Helal
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Egypt
| | | | - Omnia A M Badr
- Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Egypt.
| | - Amira Hassouna
- School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, AUT University, Auckland, New Zealand.
| | - Hajir A Al Saihati
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Albatin, Saudi Arabia.
| | | | - Hanan Tawfeek Emam
- Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Egypt.
| | - Hend S El-Wakeel
- Department of Physiology, Faculty of Medicine, Benha University, Egypt.
| | - Mohammad Aljasir
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia.
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia; Department of Anatomy, Mansoura Faculty of Medicine, Mansoura University, Egypt.
| | - Naglaa A S Sarg
- Department of Anatomy, Benha Faculty of Medicine, Benha University, Egypt.
| | - Gehan Ahmed Shaker
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Ola Mostafa
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Egypt.
| | - Dina Sabry
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Egypt; Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Badr University, Cairo 11562, Egypt.
| | | | - Nicholas Robert Forsyth
- Guy Hilton Research Laboratories, School of Pharmacy and Bioengineering, Faculty of Medicine and Health Sciences, Keele University, Newcastle ST5 5BG, UK.
| | - Nehal M Elsherbiny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia; Biochemistry department, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt.
| | - Rabab F Salim
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Egypt.
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Lebeau G, Ah-Pine F, Daniel M, Bedoui Y, Vagner D, Frumence E, Gasque P. Perivascular Mesenchymal Stem/Stromal Cells, an Immune Privileged Niche for Viruses? Int J Mol Sci 2022; 23:ijms23148038. [PMID: 35887383 PMCID: PMC9317325 DOI: 10.3390/ijms23148038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/16/2022] [Accepted: 07/20/2022] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) play a critical role in response to stress such as infection. They initiate the removal of cell debris, exert major immunoregulatory activities, control pathogens, and lead to a remodeling/scarring phase. Thus, host-derived ‘danger’ factors released from damaged/infected cells (called alarmins, e.g., HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (LPS, single strand RNA) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of growth factors and chemoattractant molecules that influence immune cell recruitment and stem cell mobilization. MSC, in an ultimate contribution to tissue repair, may also directly trans- or de-differentiate into specific cellular phenotypes such as osteoblasts, chondrocytes, lipofibroblasts, myofibroblasts, Schwann cells, and they may somehow recapitulate their neural crest embryonic origin. Failure to terminate such repair processes induces pathological scarring, termed fibrosis, or vascular calcification. Interestingly, many viruses and particularly those associated to chronic infection and inflammation may hijack and polarize MSC’s immune regulatory activities. Several reports argue that MSC may constitute immune privileged sanctuaries for viruses and contributing to long-lasting effects posing infectious challenges, such as viruses rebounding in immunocompromised patients or following regenerative medicine therapies using MSC. We will herein review the capacity of several viruses not only to infect but also to polarize directly or indirectly the functions of MSC (immunoregulation, differentiation potential, and tissue repair) in clinical settings.
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Affiliation(s)
- Grégorie Lebeau
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Franck Ah-Pine
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Service Anatomo-Pathologie, CHU de la Réunion, 97400 Saint-Denis, France
| | - Matthieu Daniel
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Yosra Bedoui
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Damien Vagner
- Service de Médecine Interne, CHU de la Réunion, 97400 Saint-Denis, France;
| | - Etienne Frumence
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Philippe Gasque
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
- Correspondence:
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Fan Z, Jiang C, Wang Y, Wang K, Marsh J, Zhang D, Chen X, Nie L. Engineered extracellular vesicles as intelligent nanosystems for next-generation nanomedicine. NANOSCALE HORIZONS 2022; 7:682-714. [PMID: 35662310 DOI: 10.1039/d2nh00070a] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Extracellular vesicles (EVs), as natural carriers of bioactive cargo, have a unique micro/nanostructure, bioactive composition, and characteristic morphology, as well as fascinating physical, chemical and biochemical features, which have shown promising application in the treatment of a wide range of diseases. However, native EVs have limitations such as lack of or inefficient cell targeting, on-demand delivery, and therapeutic feedback. Recently, EVs have been engineered to contain an intelligent core, enabling them to (i) actively target sites of disease, (ii) respond to endogenous and/or exogenous signals, and (iii) provide treatment feedback for optimal function in the host. These advances pave the way for next-generation nanomedicine and offer promise for a revolution in drug delivery. Here, we summarise recent research on intelligent EVs and discuss the use of "intelligent core" based EV systems for the treatment of disease. We provide a critique about the construction and properties of intelligent EVs, and challenges in their commercialization. We compare the therapeutic potential of intelligent EVs to traditional nanomedicine and highlight key advantages for their clinical application. Collectively, this review aims to provide a new insight into the design of next-generation EV-based theranostic platforms for disease treatment.
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Affiliation(s)
- Zhijin Fan
- School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China.
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P. R. China
| | - Cheng Jiang
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen 518172, China
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Yichao Wang
- Department of Clinical Laboratory Medicine, Tai Zhou Central Hospital (Taizhou University Hospital), Taizhou 318000, P. R. China
| | - Kaiyuan Wang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China
| | - Jade Marsh
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | - Da Zhang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China.
| | - Xin Chen
- School of Chemical Engineering and Technology, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, Xi'an Jiao Tong University, Xi'an 710049, P. R. China.
| | - Liming Nie
- Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P. R. China
- School of Medicine, South China University of Technology, Guangzhou 510006, P. R. China.
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Lyu K, Liu T, Chen Y, Lu J, Jiang L, Liu X, Liu X, Li Y, Li S. A “cell-free treatment” for tendon injuries: adipose stem cell-derived exosomes. Eur J Med Res 2022; 27:75. [PMID: 35643543 PMCID: PMC9148514 DOI: 10.1186/s40001-022-00707-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/13/2022] [Indexed: 11/10/2022] Open
Abstract
AbstractTendon injuries are widespread and chronic disorders of the musculoskeletal system, frequently caused by overload of the tendons. Currently, the most common treatment for tendon injuries is "cell-free therapy", of which exosomes, which can treat a host of diseases, including immune disorders, musculoskeletal injuries and cardiovascular diseases, are one kind. Among the many sources of exosomes, adipose-derived stem cell exosomes (ASC-Exos) have better efficacy. This is attributed not only to the ease of isolation of adipose tissue, but also to the high differentiation capacity of ASCs, their greater paracrine function, and immunomodulatory capacity compared to other exosomes. ASC-Exos promote tendon repair by four mechanisms: promoting angiogenesis under hypoxic conditions, reducing the inflammatory response, promoting tendon cell migration and proliferation, and accelerating collagen synthesis, thus accelerating tendon healing. This review focuses on describing studies of preclinical experiments with various exosomes, the characteristics of ASC-Exos and their mechanisms of action in tendon healing, as well as elaborating the limitations of ASC-Exos in clinical applications.
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21
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Sharun K, Musa TH, Musa HH, Kumar R, Pawde AM, Chandra V, Tuli HS, Dhama K, Amarpal, Sharma GT. Mapping global trends in adipose-derived mesenchymal stem cell research: A bibliometric analysis using scopus database. Ann Med Surg (Lond) 2022; 77:103542. [PMID: 35638047 PMCID: PMC9142410 DOI: 10.1016/j.amsu.2022.103542] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 03/25/2022] [Indexed: 11/08/2022] Open
Abstract
Background and objective Adipose-derived mesenchymal stem cells (AdMSC) are multipotent adult mesenchymal cells isolated and cultured from the stromal vascular fraction derived from adipose tissue. The present study was conducted to analyze the global trends in AdMSC research using bibliometric and visual analysis tools. Methods The literature search was done on February 13, 2022, using appropriate keywords and inclusion-exclusion criteria from the Scopus database. The extracted data were retrospectively analyzed and visualized using Bibliometrics and R packages and VOSviewer. Results Preliminary analysis identified 1569 documents from the Scopus database published between 2005 and 2021. The average citations received per document was 26.51, whereas the average citations per year per document was 3.347. In addition, the selected documents had an h-index value of 90. China was the most productive country, whereas Seoul National University (South Korea) was identified as the most productive institute/university in AdMSC research. In addition, the National Natural Science Foundation of China funded the most research studies in AdMSC research. Conclusion The findings from this study indicate a progressive increase in interest among the research community towards AdMSC, suggesting promising prospects in the coming years.
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Affiliation(s)
- Khan Sharun
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Taha Hussein Musa
- Biomedical Research Institute, Darfur University College, Nyala, Sudan
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, Jiangsu Province, China
| | - Hassan Hussein Musa
- Faculty of Medical Laboratory Science, University of Khartoum, Khartoum, Sudan
| | - Rohit Kumar
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - A M Pawde
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Vikash Chandra
- Division of Physiology and Climatology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, 133207, Haryana, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - Amarpal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India
| | - G Taru Sharma
- National Institute of Animal Biotechnology, Hyderabad, 500032, India
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22
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Li C, An Y, Sun Y, Yang F, Xu Q, Wang Z. Adipose Mesenchymal Stem Cell-Derived Exosomes Promote Wound Healing Through the WNT/β-catenin Signaling Pathway in Dermal Fibroblasts. Stem Cell Rev Rep 2022; 18:2059-2073. [PMID: 35471485 PMCID: PMC9391246 DOI: 10.1007/s12015-022-10378-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2022] [Indexed: 11/28/2022]
Abstract
The differentiation, migration, and proliferation of skin fibroblasts are identified as key factors in cutaneous wound healing. Adipose-derived mesenchymal stem cells (ADMSCs) and their exosomes (ADMSC-Exos) have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms on cutaneous wound healing are still not well understood. In this study, we successfully obtained ADMSC-Exos and found ADMSC-Exos significantly promoted the migration and proliferation of fibroblasts in a dose-dependent manner in vitro. The expression levels of COL-I and COL-III in fibroblasts treated with ADMSC-Exos were significantly increased, while the expression level of α-SMA was decreased. In addition, the enhanced protein expression of WNT2b and β-catenin confirmed the activation of the WNT/β-catenin signaling pathway and the WNT/β-catenin inhibitor (XAV939) reversed the promoting effect of ADMSC-Exos on wound healing and the β-catenin expression. Taken together, our study partially elucidates the mechanism of ADMSC-Exos in wound healing, illustrating the potential of ADMSC-Exos as a new therapeutic approach to promote skin wound healing.
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Affiliation(s)
- Cong Li
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong Province, 266021, People's Republic of China
| | - Yu An
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong Province, 266021, People's Republic of China
| | - Yu Sun
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong Province, 266021, People's Republic of China
| | - Fan Yang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong Province, 266021, People's Republic of China
| | - Quanchen Xu
- Department of Stomatology, the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong Province, 266021, People's Republic of China.
| | - Zhiguo Wang
- Department of Burn and Plastic Surgery, the Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong Province, 266021, People's Republic of China.
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23
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Zhou Y, Xu W, Hou J, Hou C, Zhang J. Application of Free Skin Flap Transplantation in Skin Malignant Tumor Resection. JOURNAL OF ONCOLOGY 2022; 2022:7510330. [PMID: 35479963 PMCID: PMC9038399 DOI: 10.1155/2022/7510330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/09/2022] [Accepted: 01/20/2022] [Indexed: 11/21/2022]
Abstract
One of the most important surgical approaches for restoring cutaneous abnormalities caused by tumor resection is the insertion of a skin flap. Flap transplantation has been used to cover and fill different deficiencies after tumor removal. However, distal necrosis is among the most prevalent postsurgical consequences for skin flaps, particularly when treating large regions. Blood circulation failure causes flap necrosis, which may lead to serious problems, particularly in patients undergoing body cavity reconstruction following tumor excision. ADSCs (adipose-derived stem cells) are a kind of stem cell separated from the adipose tissue that has multilineage differentiation, simple availability, high proliferation capability, and self-renewal capabilities. This paper uses human adipose-derived stem cell (ADSC) therapy for skin flap transplantation in skin malignant tumor resection. ADSC-based therapy is an applicable technique for assisting flap transplantation. The isolation of ADSC is performed using different trypsin concentrations, and then, the population doubling time is determined. The isolated ADSCs are differentiated and then employed for the skin flap model. The performance of the suggested method is analyzed using various assays. The usage of adipose-derived stem cells to boost the vitality of the skin flaps proved successful.
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Affiliation(s)
- Yue Zhou
- Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weili Xu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jue Hou
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Chunsheng Hou
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jufang Zhang
- The Affiliated Hangzhou Hospital of Nanjing Medical University, Nanjing, Zhejiang, China
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24
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Han L, Zhao Z, Yang K, Xin M, Zhou L, Chen S, Zhou S, Tang Z, Ji H, Dai R. Application of exosomes in the diagnosis and treatment of pancreatic diseases. Stem Cell Res Ther 2022; 13:153. [PMID: 35395948 PMCID: PMC8994331 DOI: 10.1186/s13287-022-02826-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/22/2022] [Indexed: 12/20/2022] Open
Abstract
Pancreatic diseases, a serious threat to human health, have garnered considerable research interest, as they are associated with a high mortality rate. However, owing to the uncertain etiology and complex pathophysiology, the treatment of pancreatic diseases is a challenge for clinicians and researchers. Exosomes, carriers of intercellular communication signals, play an important role in the diagnosis and treatment of pancreatic diseases. Exosomes are involved in multiple stages of pancreatic disease development, including apoptosis, immune regulation, angiogenesis, cell migration, and cell proliferation. Thus, extensive alterations in the quantity and variety of exosomes may be indicative of abnormal biological behaviors of pancreatic cells. This phenomenon could be exploited for the development of exosomes as a new biomarker or target of new treatment strategies. Several studies have demonstrated the diagnostic and therapeutic effects of exosomes in cancer and inflammatory pancreatic diseases. Herein, we introduce the roles of exosomes in the diagnosis and treatment of pancreatic diseases and discuss directions for future research and perspectives of their applications.
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Affiliation(s)
- Li Han
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, China
| | - Zhirong Zhao
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, China
| | - Ke Yang
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
- Department of Cardiovascular Surgery, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
| | - Mei Xin
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
- Department of Cardiovascular Surgery, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
| | - Lichen Zhou
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Siping Chen
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, China
| | - Shibo Zhou
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Zheng Tang
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Hua Ji
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China
| | - Ruiwu Dai
- General Surgery Center, General Hospital of Western Theater Command, Chengdu, 610083, Sichuan Province, China.
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, China.
- College of Clinical Medicine Southwest, Medical University, Luzhou, 646000, Sichuan Province, China.
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25
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Rao D, Huang D, Sang C, Zhong T, Zhang Z, Tang Z. Advances in Mesenchymal Stem Cell-Derived Exosomes as Drug Delivery Vehicles. Front Bioeng Biotechnol 2022; 9:797359. [PMID: 35186913 PMCID: PMC8854766 DOI: 10.3389/fbioe.2021.797359] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
Exosomes are tiny vesicles with a double membrane structure that cells produce. They range in diameter from 40 to 150 nm and may contain a variety of biomolecules including proteins and nucleic acids. Exosomes have low toxicity, low immunogenicity, and the ability to encapsulate a wide variety of substances, making them attractive drug delivery vehicles. MSCs secrete large amounts of exosomes and hence serve as an excellent source of exosomes. MSCs-derived exosomes have regenerative and tissue repair functions comparable to MSCs and can circumvent the risks of immune rejection and infection associated with MSC transplantation, indicating that they may be a viable alternative to MSCs' biological functions. In this review, we summarized the drug delivery methods and advantages of exosomes, as well as the advancement of MSC exosomes as drug carriers. The challenges and prospects of using exosomes as drug delivery vectors are presented.
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Affiliation(s)
- Dingyu Rao
- The First Clinical College, Gannan Medical University, Ganzhou, China
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Ganna Medical University, Ganzhou, China
| | - Defa Huang
- The First Clinical College, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Chengpeng Sang
- The First Clinical College, Gannan Medical University, Ganzhou, China
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Ganna Medical University, Ganzhou, China
| | - Tianyu Zhong
- The First Clinical College, Gannan Medical University, Ganzhou, China
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Zuxiong Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Ganna Medical University, Ganzhou, China
| | - Zhixian Tang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Ganna Medical University, Ganzhou, China
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26
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Deng H, Chen Y. The role of adipose-derived stem cells-derived extracellular vesicles in the treatment of diabetic foot ulcer: Trends and prospects. Front Endocrinol (Lausanne) 2022; 13:902130. [PMID: 35966086 PMCID: PMC9363610 DOI: 10.3389/fendo.2022.902130] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic foot ulcer(DFU) is one of the most severe chronic complications of type 2 diabetes mellitus, which is mainly caused by peripheral vascular occlusion with various degrees of infection. Treatment of DFU is difficult, and ulcer formation in lower limbs and deep-tissue necrosis might lead to disability or even death. Insulin resistance is the major mechanism of type 2 diabetes mellitus development, largely caused by adipose tissue dysfunction. However, adipose tissue was recently identified as an important endocrine organ that secretes bio-active factors, such as adipokines and extracellular vesicles(EVs). And adipose tissue-derived stem cells(ADSCs) are abundant in adipose tissue and have become a hot topic in the tissue engineering field. In particular, EVs derived from ADSCs contain abundant biomarkers and mediators. These EVs exert significant effects on distant cells and organs, contributing to metabolic homeostasis. In this review, we aim to elaborate on the mechanisms of diabetic non-healing wound development and the role of ADSCs-EVs in wound repair, which might provide a new therapy for treating DFU.
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Affiliation(s)
- Hongyan Deng
- Division of Endocrinology, Internal Medicine, Tongji Hospital, Huazhong University of Science & Technology, Wuhan, China
- Laboratory of Endocrinology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan, China
| | - Yong Chen
- Division of Endocrinology, Internal Medicine, Tongji Hospital, Huazhong University of Science & Technology, Wuhan, China
- Laboratory of Endocrinology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
- *Correspondence: Yong Chen,
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27
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Shi H, Wang M, Sun Y, Yang D, Xu W, Qian H. Exosomes: Emerging Cell-Free Based Therapeutics in Dermatologic Diseases. Front Cell Dev Biol 2021; 9:736022. [PMID: 34722517 PMCID: PMC8553038 DOI: 10.3389/fcell.2021.736022] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/20/2021] [Indexed: 12/17/2022] Open
Abstract
Exosomes are lipid bilayer vesicles released by multiple cell types. These bioactive vesicles are gradually becoming a leading star in intercellular communication involving in various pathological and physiological process. Exosomes convey specific and bioactive transporting cargos, including lipids, nucleic acids and proteins which can be reflective of their parent cells, rendering them attractive in cell-free therapeutics. Numerous findings have confirmed the crucial role of exosomes in restraining scars, burning, senescence and wound recovery. Moreover, the biology research of exosomes in cutting-edge studies are emerging, allowing for the development of particular guidelines and quality control methodology, which favor their possible application in the future. In this review, we discussed therapeutic potential of exosomes in different relevant mode of dermatologic diseases, as well as the various molecular mechanisms. Furthermore, given the advantages of favorable biocompatibility and transporting capacity, the bioengineering modification of exosomes is also involved.
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Affiliation(s)
- Hui Shi
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yaoxiang Sun
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Dakai Yang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Wenrong Xu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
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28
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Adipose Mesenchymal Stem Cell-Derived Exosomes Enhance PC12 Cell Function through the Activation of the PI3K/AKT Pathway. Stem Cells Int 2021; 2021:2229477. [PMID: 34691190 PMCID: PMC8536463 DOI: 10.1155/2021/2229477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 07/20/2021] [Accepted: 09/09/2021] [Indexed: 11/18/2022] Open
Abstract
Transplantation of mesenchymal stem cells has been considered as an auspicious treatment for repairing nerve injuries. The rat adrenal pheochromocytoma cell line (PC12) is one of the traditional models for the study of neuronal differentiation and neuroregeneration in vitro. However, the effects of adipose mesenchymal stem cell-derived exosomes (ADSC-exo) on PC12 cells remain unclear and to be elucidated. In our study, the effects of ADSC-exo on PC12 cells were investigated. ADSC-exo were isolated by ultracentrifugation and characterized by transmission electron microscopy, flow nanoanalysis, and western blot. The effects of ADSC-exo on PC12 cell proliferation, migration, apoptosis, and the protein levels were analyzed using CCK-8 assay and EdU incorporation assay, transwell migration assay and scratch wound assay, flow cytometry, and western blot, respectively. We successfully isolated and purified exosomes from ADSC supernatant and found that ADSC-exo treatment significantly promoted PC12 cell proliferation and migration, inhibited their apoptosis, and activated the PI3K/AKT pathway, while PI3K/AKT signaling repression using LY294002 exhibited the opposite effects. The results showed that ADSC-exo promoted proliferation and migration and inhibited apoptosis of PC12 through the activation of the PI3K/AKT pathway. Thus, the effect of ADSC-exo on PC12 cells may suggest ADSC-exo may be a promising therapeutic for nerve damage.
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29
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Wang SZ, Jia J, Chen CH. lncRNA-KCNQ1OT1: A Potential Target in Exosomes Derived from Adipose-Derived Stem Cells for the Treatment of Osteoporosis. Stem Cells Int 2021; 2021:7690006. [PMID: 34712334 PMCID: PMC8548139 DOI: 10.1155/2021/7690006] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/21/2021] [Accepted: 09/29/2021] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Osteoporosis is a worldwide medical and socioeconomic burden characterized by systemic impairment of bone strength and microstructure. Exosomes derived from adipose-derived stem cells (ADSCs-Exos) have been confirmed to play effective roles in the repair of various tissues and organs. This study was aimed at investigating the role of ADSCs-Exos and a novel long noncoding RNA KCNQ1OT1 played in osteoporosis as well as the underlying mechanism. METHODS Primary osteoblasts were treated with different doses of tumor necrosis factor-α (TNF-α) (0, 1, 2.5, 5, and 10 ng/ml) and then cocultured with ADSCs-Exos or exosome-derived from lnc-KCNQ1OT1-modified ADSCs (KCNQ1OT1-Exos). The expression of miRNA-141-5p (miR-141-5p) and lnc-KCNQ1OT1 was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of cleaved-caspase-3, caspase-3, and Bax was determined by Western blot. Cell viability and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) and flow cytometry analysis, respectively. The binding sites between KCNQ1OT1 and miR-141-5p were validated by dual-luciferase reporter assay. RESULTS TNF-α dose-dependently increased miR-141-5p expression, inhibited viability, and promoted apoptosis of osteoblasts. However, miR-141-5p silencing or cocultured with ADSCs-Exos attenuated these effects. In addition, KCNQ1OT1-Exos could more significantly attenuate the induced cytotoxicity and apoptosis compared to ADSCs-Exos. Moreover, miR-141-5p was confirmed as the target of KCNQ1OT1 by luciferase reporter assay. CONCLUSIONS ADSCs-Exos can attenuate cytotoxicity and apoptosis of TNF-α-induced primary osteoblasts. KCNQ1OT1-Exos have a more significant inhibitory effect compared to ADSCs-Exos by the function of sponging miR-141-5p, suggesting that KCNQ1OT1-Exos can be promising agents in osteoporosis treatment.
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Affiliation(s)
- Shan-zheng Wang
- Department of Orthopaedics, Zhongda Hospital, Medical School of Southeast University, 87 Ding Jia Qiao Road, Nanjing, Jiangsu 210009, China
| | - Jun Jia
- Department of Orthopaedics, The 904th Hospital of Joint Logistic Support Force, PLA, 101 Xingyuan North Road, Wuxi, Jiangsu 214000, China
| | - Chang-hong Chen
- Department of Orthopaedics, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, 130 Renmin Middle Road, Jiangyin, Jiangsu 214400, China
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Abstract
Scar is a common way of healing after tissue injury. The poor scar healing will not only cause dysfunction of tissues and organs but also affect the appearance of the patients’ body surface, which causes the pressure of life and spirit to the patients. However, the formation of scar tissue is an extremely complex process and its mechanism is not fully understood. At present, there is no treatment method to eliminate scars completely. Fibroblasts are the most abundant cells in the dermis, which have the ability to synthesize and remodel extracellular matrix (ECM). Myofibroblasts actively participate in the wound healing process and influence the outcome. Therefore, both of them play important roles in wound healing and scar formation. Adipose tissue-derived stem cells (ADSCs) are pluripotent stem cells that can act on target cells by paracrine. Adipose tissue stem cell-derived exosomes (ADSC-Exos) are important secretory substances of ADSCs. They are nanomembrane vesicles that can transport a variety of cellular components and fuse with target cells. In this review, we will discuss the effects of ADSCs and ADSC-Exos on the behavior of fibroblasts and myofibroblasts during wound healing and scarring stage in combination with recent studies.
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31
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Dinescu S, Dobranici A, Tecucianu R, Selaru A, Balahura R, Ignat S, Costache M. Exosomes as Part of the Human Adipose-Derived Stem Cells Secretome- Opening New Perspectives for Cell-Free Regenerative Applications. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1312:139-163. [PMID: 32986128 DOI: 10.1007/5584_2020_588] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Human adipose-derived stem cells (hASCs) represent a great resource for regenerative medicine based on their accessibility, self-renewal potential, low immunogenicity, high proliferative rate and potential to differentiate on multiple lineages. Their secretome is rich in chemokines, cytokines and protein growth factors that are actively involved in regeneration processes. In addition, part of this secretome are also the exosomes (hASC-exos), which display high content in proteins, messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs). Due to their content, exosomes promote tissue regeneration by different mechanisms, either by activating or inhibiting several signaling pathways involved in wound healing, extracellular matrix remodeling, immunomodulation, angiogenesis, anti-apoptotic activity and cell migration, proliferation and differentiation. The use of hASC-exos may provide an improved alternative to standard therapies used in regenerative medicine, as a cell-free new approach with multiple possibilities to be modulated according to the patient needs. This review offers an updated overview on the functions and applications of hASC-exos in all areas of tissue regeneration, aiming to highlight to the reader the benefits of using hASCs in modern tissue engineering and regenerative medicine applications.
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Affiliation(s)
- Sorina Dinescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania. .,The Research Institute of the University of Bucharest, Bucharest, Romania.
| | - Alexandra Dobranici
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Ramona Tecucianu
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Aida Selaru
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania.,Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Roxana Balahura
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania.,Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Simona Ignat
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania.,The Research Institute of the University of Bucharest, Bucharest, Romania
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Barik P, Shibu MA, Hsieh DJY, Day CH, Chen RJ, Kuo WW, Chang YM, Padma VV, Ho TJ, Huang CY. Cardioprotective effects of transplanted adipose-derived stem cells under Ang II stress with Danggui administration augments cardiac function through upregulation of insulin-like growth factor 1 receptor in late-stage hypertension rats. ENVIRONMENTAL TOXICOLOGY 2021; 36:1466-1475. [PMID: 33881220 DOI: 10.1002/tox.23145] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/18/2021] [Accepted: 04/02/2021] [Indexed: 06/12/2023]
Abstract
In aging hypertensive conditions, deterioration of insulin-like growth factor 1 receptor (IGF1R) cause a pathological impact on hypertensive hearts with an increased Ang II level. Recovering these adverse conditions through transplanted adipose-derived stem cells is a challenging approach. Moreover, Danggui, a Traditional Chinese medicine (TCM), is used for the treatment of cardioprotective effects. In this study, to evaluate whether the combined effect of MSCs and TCM can recover the cardiac function in late-stage hypertension rats. We observed that lower dose of Danggui crude extract treatment showed an increased level of cell viability with maintained stemness properties and growth rate in rat adipose-derived stem cells (rADSCs). Further, we cocultured the H9c2 cells with rADSCs and the results revealed that Danggui-treated MSCs enhanced the IGF1R expression and attenuated the hypertrophy in H9c2 cells against Ang II challenge by immunoblot and rhodamine-phalloidin staining. In addition, Danggui crude extract was also quantified and characterized by HPLC and LC-MS analysis. Furthermore, the in vivo study was performed by considering 11 months old rats (n = 7). Importantly, the oral administration of Danggui crude extract with stem cells intravenous injection in SHR-D-ADSCs group showed a combination effect to augment the cardiac function through enhancement of ejection fraction, fractional shortening, contractility function in the late-stage hypertension conditions. We have also observed a decreased apoptosis rate in the heart tissue of SHR-D-ADSCs group. Taken together, these results indicate that the combinatorial effects of Danggui crude extract and stem cell therapy enhanced cardiac function in late-stage SHR rats.
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Affiliation(s)
- Parthasarathi Barik
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Marthandam Asokan Shibu
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Dennis Jine-Yuan Hsieh
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
- Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
| | | | - Ray-Jade Chen
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Yung-Ming Chang
- The School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan
| | - V Vijaya Padma
- Department of Biotechnology, Bharathiar University, Coimbatore, India
| | - Tsung-Jung Ho
- Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
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You DG, Lim GT, Kwon S, Um W, Oh BH, Song SH, Lee J, Jo DG, Cho YW, Park JH. Metabolically engineered stem cell–derived exosomes to regulate macrophage heterogeneity in rheumatoid arthritis. SCIENCE ADVANCES 2021; 7:7/23/eabe0083. [PMID: 34078596 PMCID: PMC8172131 DOI: 10.1126/sciadv.abe0083] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 04/16/2021] [Indexed: 05/02/2023]
Abstract
Despite the remarkable advances in therapeutics for rheumatoid arthritis (RA), a large number of patients still lack effective countermeasures. Recently, the reprogramming of macrophages to an immunoregulatory phenotype has emerged as a promising therapeutic strategy for RA. Here, we report metabolically engineered exosomes that have been surface-modified for the targeted reprogramming of macrophages. Qualified exosomes were readily harvested from metabolically engineered stem cells by tangential flow filtration at a high yield while maintaining their innate immunomodulatory components. When systemically administered into mice with collagen-induced arthritis, these exosomes effectively accumulated in the inflamed joints, inducing a cascade of anti-inflammatory events via macrophage phenotype regulation. The level of therapeutic efficacy obtained with bare exosomes was achievable with the engineered exosomes of 10 times less dose. On the basis of the boosted nature to reprogram the synovial microenvironment, the engineered exosomes display considerable potential to be developed as a next-generation drug for RA.
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Affiliation(s)
- Dong Gil You
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
| | - Gyeong Taek Lim
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
| | - Seunglee Kwon
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
| | - Wooram Um
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
| | - Byeong Hoon Oh
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
| | - Seok Ho Song
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
| | - Jungmi Lee
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
| | - Dong-Gyu Jo
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
- School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
- ExoStemTech Inc., 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
| | - Yong Woo Cho
- ExoStemTech Inc., 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
- Department of Chemical Engineering, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
| | - Jae Hyung Park
- School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
- Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea
- ExoStemTech Inc., 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 15588, Republic of Korea
- Corresponding author.
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Ghodrat S, Hoseini SJ, Asadpour S, Nazarnezhad S, Alizadeh Eghtedar F, Kargozar S. Stem cell-based therapies for cardiac diseases: The critical role of angiogenic exosomes. Biofactors 2021; 47:270-291. [PMID: 33606893 DOI: 10.1002/biof.1717] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 01/25/2021] [Indexed: 12/26/2022]
Abstract
Finding effective treatments for cardiac diseases is among the hottest subjects in medicine; cell-based therapies have brought great promises for managing a broad range of life-threatening heart complications such as myocardial infarction. After clarifying the critical role of angiogenesis in tissue repair and regeneration, various stem/progenitor cell were utilized to accelerate the healing of injured cardiac tissue. Embryonic, fetal, adult, and induced pluripotent stem cells have shown the appropriate proangiogenic potential for tissue repair strategies. The capability of stem cells for differentiating into endothelial lineages was initially introduced as the primary mechanism involved in improving angiogenesis and accelerated heart tissue repair. However, recent studies have demonstrated the leading role of paracrine factors secreted by stem cells in advancing neo-vessel formation. Genetically modified stem cells are also being applied for promoting angiogenesis regarding their ability to considerably overexpress and secrete angiogenic bioactive molecules. Yet, conducting further research seems necessary to precisely identify molecular mechanisms behind the proangiogenic potential of stem cells, including the signaling pathways and regulatory molecules such as microRNAs. In conclusion, stem cells' pivotal roles in promoting angiogenesis and consequent improved cardiac healing and remodeling processes should not be ignored, especially in the case of stem cell-derived extracellular vesicles.
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Affiliation(s)
- Sara Ghodrat
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Javad Hoseini
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shiva Asadpour
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Simin Nazarnezhad
- Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariba Alizadeh Eghtedar
- Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Saeid Kargozar
- Tissue Engineering Research Group (TERG), Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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35
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Lyu T, Zhang B, Li M, Jiao X, Song Y. Research progress on exosomes derived from mesenchymal stem cells in hematological malignancies. Hematol Oncol 2021; 39:162-169. [PMID: 32869900 PMCID: PMC8246925 DOI: 10.1002/hon.2793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/13/2020] [Accepted: 08/15/2020] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) are a subset of multifunctional stem cells with self-renewal and multidirectional differentiation properties that play a pivotal role in tumor progression. MSCs are reported to exert biological functions by secreting specialized vesicles, known as exosomes, with tumor cells. Exosomes participate in material and information exchange between cells and are crucial in multiple physiological and pathological processes. This study provides a comprehensive overview of the roles, mechanisms of action and sources of MSC exosomes in hematological malignancies, and different tumor types.
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Affiliation(s)
- Tianxin Lyu
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Binglei Zhang
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Mengjia Li
- School of Life Sciences, Zhengzhou University, Zhengzhou, China
| | - Xueli Jiao
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Yongping Song
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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36
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Hu J, Chen X, Li P, Lu X, Yan J, Tan H, Zhang C. Exosomes derived from human amniotic fluid mesenchymal stem cells alleviate cardiac fibrosis via enhancing angiogenesis in vivo and in vitro. Cardiovasc Diagn Ther 2021; 11:348-361. [PMID: 33968614 DOI: 10.21037/cdt-20-1032] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Background Cardiac fibrosis is a pathological process characterized by excess extracellular matrix (ECM) deposition and plays a critical role in nearly all types of heart disease. The mechanism of cardiac fibrosis is still unclear and no effective medication treatment of cardiac fibrosis. Research showed that mesenchymal stem cell (MSC) derived exosomes may play a critical role in cardiac fibrosis. The effect of human amniotic fluid MSC (hAFMSC)-derived exosomes (hAFMSCExos) on cardiac fibrosis has remained unclear. Methods The hAFMSCExos were extracted using a sequential centrifugation approach. The effects of hAFMSCExos on angiogenesis were analyzed both in human umbilical vein endothelial cells (HUVECs) after oxygen and glucose deprivation (OGD) in vitro, and in isoproterenol (ISO) induced-cardiac fibrosis in vivo. Results The hAFMSCExos remarkably up-regulate the motility and migration of HUVECs after OGD compared with phosphate-buffered saline (PBS). Meanwhile, total tube length, total branching points and total loops were significantly raised in HUVECs after OGD treated with hAFMSCExos. The hAFMSCExos alleviated the cardiac fibrosis degree tested by hematoxylin-eosin (H&E) and Masson staining. The protein levels of Collagen I and α-smooth muscle actin (α-SMA) were lower in exosomes group rats than PBS group. Immunofluorescence suggested that hAFMSCExos can promote the expression of CD31 in the rats. Meanwhile, the number of regenerated microvessels was significantly enhanced in rats administrated with exosomes by quantitative analysis of microvessel density. Furthermore, the micro-CT scanning evidenced that hAFMSCExos promote angiogenesis after cardiac fibrosis. The levels of hypoxia-inducible factor 1 α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in the left ventricle accepted HUVECs were higher than PBS treatment at 7 days post-treatment by Western blot analysis. Conclusions The hAFMSCExos have proangiogenic effects on endothelial cells and enhanced angiogenesis in cardiac fibrosis. The hAFMSCExos may be a promising potential treatment strategy for cardiac fibrosis.
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Affiliation(s)
- Jiajia Hu
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Xuliang Chen
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ping Li
- Department of Obstetrics, Xiangya Hospital, Central South University, Changsha, China.,Hunan Engineering Research Center of Early Life Development and Disease Prevention, Changsha, China
| | - Xiaoxu Lu
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Jianqin Yan
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Huiling Tan
- Department of Anesthesiology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Chengliang Zhang
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, China
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37
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Gómez-Serrano M, Ponath V, Preußer C, Pogge von Strandmann E. Beyond the Extracellular Vesicles: Technical Hurdles, Achieved Goals and Current Challenges When Working on Adipose Cells. Int J Mol Sci 2021; 22:ijms22073362. [PMID: 33805982 PMCID: PMC8036456 DOI: 10.3390/ijms22073362] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/18/2021] [Accepted: 03/22/2021] [Indexed: 12/17/2022] Open
Abstract
Adipose tissue and its crosstalk with other organs plays an essential role in the metabolic homeostasis of the entire body. Alteration of this communication (i.e., due to obesity) is related to the development of several comorbidities including type 2 diabetes, cardiovascular diseases, or cancer. Within the adipose depot, adipocytes are the main cell type and thus the main source of secreted molecules, which exert modulating effects not only at a local but also at a systemic level. Extracellular vesicles (EVs) have recently emerged as important mediators in cell–cell communication and account for part of the cellular secretome. In recent years, there has been a growing body of research on adipocyte-derived extracellular vesicles (Ad-EVs). However, there is still a lack of standardized methodological approaches, especially regarding primary adipocytes. In this review, we will provide an outline of crucial aspects when working on adipose-derived material, with a special focus on primary adipocytes. In parallel, we will point out current methodological challenges in the EV field and how they impact the transcriptomic, proteomic and functional evaluations of Ad-EVs.
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38
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Dong X, Shen LH, Yi Z, He LH, Yi Z. Exosomes from Adipose-Derived Stem Cells Can Prevent Medication-Related Osteonecrosis of the Jaw. Med Sci Monit 2021; 27:e929684. [PMID: 33690263 PMCID: PMC7958499 DOI: 10.12659/msm.929684] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The treatment measures of medication-related osteonecrosis of the jaw (MRONJ) is a worldwide challenge in oral and maxillofacial surgery because of its unclear pathogenesis. Previous studies suggested that mesenchymal stem cells played important roles in promoting MRONJ lesion healing, but the detailed mechanisms were unknown. Increasing numbers of studies have demonstrated that exosomes derived from mesenchymal stem cells, especially adipose-derived stem cells, have key roles in stem cell-based therapies by accelerating bone remodeling, facilitating angiogenesis, and promoting wound healing. We hypothesized that exosomes derived from adipose-derived stem cells can prevent MRONJ by accelerating gingival healing and enhancing bone remodeling processes. Our results may provide a promising therapeutic option for MRONJ clinical therapy.
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Affiliation(s)
- Xian Dong
- Laboratory of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China (mainland)
| | - Li-Hang Shen
- Laboratory of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China (mainland)
| | - Zheng Yi
- Laboratory of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China (mainland)
| | - Lin-Hai He
- First Clinical Division, Peking University School Hospital of Stomatology, Beijing, China (mainland)
| | - Zhang Yi
- Laboratory of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China (mainland)
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Al-Ghadban S, Bunnell BA. Adipose Tissue-Derived Stem Cells: Immunomodulatory Effects and Therapeutic Potential. Physiology (Bethesda) 2021; 35:125-133. [PMID: 32027561 DOI: 10.1152/physiol.00021.2019] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Adipose-derived stem cells (ASCs) can self-renew and differentiate along multiple cell lineages. ASCs are also potently anti-inflammatory due to their inherent ability to regulate the immune system by secreting anti-inflammatory cytokines and growth factors that play a crucial role in the pathology of many diseases, including multiple sclerosis, diabetes mellitus, Crohn's, SLE, and graft-versus-host disease. The immunomodulatory effects and mechanisms of action of ASCs on pathological conditions are reviewed here.
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Affiliation(s)
- Sara Al-Ghadban
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Bruce A Bunnell
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana.,Department of Pharmacology, School of Medicine, Tulane University, New Orleans, Louisiana
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40
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Zhang C, Zhang C, Xu Y, Li C, Cao Y, Li P. Exosomes derived from human placenta-derived mesenchymal stem cells improve neurologic function by promoting angiogenesis after spinal cord injury. Neurosci Lett 2020; 739:135399. [PMID: 32979457 DOI: 10.1016/j.neulet.2020.135399] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/16/2020] [Accepted: 09/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Spinal cord injury (SCI) is a serious central nervous system condition with no effective clinal treatment. Recently, transplantation of bone marrow mesenchymal stem cells (MSCs) derived exosomes has been proposed as a potential treatment for SCI. However, whether exosomes have similar functions as transplanted human placenta-derived MSCs(hPMSCs) has remained unclear. METHODS The hPMSCs-derived exosomes (hPMSCs-Exos) were extracted using a sequential centrifugation approach. Then, the effects of hPMSCs-Exos on angiogenesis were analysis both in vitro and in vivo. In addition, the sensory and locomotor functions of mice after SCI were also analyzed. RESULTS The administration of hPMSCs-Exos promote the tube formation and migration of human umbilical vein endothelial cell (HUVECs). Furthermore, vessel numbers, vessel volume fraction and vessel connectivity in spinal cords significantly increased after exosomes were intrathecally injected in the SCI model. In addition, the locomotor and sensory function, also significantly improved in the exosome treatment group. CONCLUSIONS The results of the present study demonstrated that hPMSCs-Exos have proangiogenic effects on endothelial cells and enhanced angiogenesis in SCI model. Thus, this treatment strategy demonstrates great potential for the treatment of SCI.
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Affiliation(s)
- Ciliu Zhang
- Department of Pediatrics, Xiangya Hospital, Central South University Changsha, 410008, China
| | - ChengLiang Zhang
- Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 410008 Changsha, China
| | - Yan Xu
- Department of Sports Medicine, Xiangya Hospital, Central South University, 410008 Changsha, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, 410008 Changsha, China
| | - Chengjun Li
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, 410008 Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008 Changsha, China.
| | - Yong Cao
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, 410008 Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008 Changsha, China.
| | - Ping Li
- Department of Obstetrics, Xiangya Hospital, Central South University Changsha, 410008, China; Hunan Engineering Research Center of Early Life Development and Disease Prevention, Changsha, 410008, China.
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Prautsch KM, Schmidt A, Paradiso V, Schaefer DJ, Guzman R, Kalbermatten DF, Madduri S. Modulation of Human Adipose Stem Cells' Neurotrophic Capacity Using a Variety of Growth Factors for Neural Tissue Engineering Applications: Axonal Growth, Transcriptional, and Phosphoproteomic Analyses In Vitro. Cells 2020; 9:E1939. [PMID: 32839392 PMCID: PMC7565501 DOI: 10.3390/cells9091939] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/11/2020] [Accepted: 08/19/2020] [Indexed: 12/16/2022] Open
Abstract
We report on a potential strategy involving the exogenous neurotrophic factors (NTF) for enhancing the neurotrophic capacity of human adipose stem cells (ASC) in vitro. For this, ASC were stimulated for three days using NTF, i.e., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), NT4, glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF). The resulting conditioned medium (CM) as well as individual NTF exhibited distinct effects on axonal outgrowth from dorsal root ganglion (DRG) explants. In particular, CM derived from NT3-stimulated ASC (CM-NT3-ASC) promoted robust axonal outgrowth. Subsequent transcriptional analysis of DRG cultures in response to CM-NT3-ASC displayed significant upregulation of STAT-3 and GAP-43. In addition, phosphoproteomic analysis of NT3-stimulated ASC revealed significant changes in the phosphorylation state of different proteins that are involved in cytokine release, growth factors signaling, stem cell maintenance, and differentiation. Furthermore, DRG cultures treated with CM-NT3-ASC exhibited significant changes in the phosphorylation levels of proteins involved in tubulin and actin cytoskeletal pathways, which are crucial for axonal growth and elongation. Thus, the results obtained at the transcriptional, proteomic, and cellular level reveal significant changes in the neurotrophic capacity of ASC following NT3 stimulation and provide new options for improving the axonal growth-promoting potential of ASC in vitro.
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Affiliation(s)
- Katharina M. Prautsch
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland; (K.M.P.); (D.J.S.); (D.F.K.)
- Department of Pathology, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
- Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, 4123 Allschwil, Switzerland
| | - Alexander Schmidt
- Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland;
| | - Viola Paradiso
- Department of Pathology, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
| | - Dirk J. Schaefer
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland; (K.M.P.); (D.J.S.); (D.F.K.)
- Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
| | - Raphael Guzman
- Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
- Department of Neurosurgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland
| | - Daniel F. Kalbermatten
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland; (K.M.P.); (D.J.S.); (D.F.K.)
- Department of Pathology, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
- Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, 4123 Allschwil, Switzerland
| | - Srinivas Madduri
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Spitalstrasse 21, 4021 Basel, Switzerland; (K.M.P.); (D.J.S.); (D.F.K.)
- Department of Pathology, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
- Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, 4123 Allschwil, Switzerland
- Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4021 Basel, Switzerland;
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Maqsood M, Kang M, Wu X, Chen J, Teng L, Qiu L. Adult mesenchymal stem cells and their exosomes: Sources, characteristics, and application in regenerative medicine. Life Sci 2020; 256:118002. [PMID: 32585248 DOI: 10.1016/j.lfs.2020.118002] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/11/2020] [Accepted: 06/20/2020] [Indexed: 02/08/2023]
Abstract
Human mesenchymal stem cells (MSCs) have become a hot topic in the development of cell therapies and bioengineering. All kinds of MSCs are genomic stable and have the self-renewal ability. Main sources of MSCs are bone marrow, adipose tissues, umbilical cord and placental tissues. MSCs can be cultured in many undifferentiated passages to grow into more specialized cells, produce secretory factors and also support trophic functions in the body. Exosomes, derived from MSCs also have great potential in regenerative medicine and tissue engineering. Exosomes are secreted by MSCs and have the same therapeutic potential as their parent cells. MSCs and their exosomes combined with biomaterials can also be more effective in promoting the regeneration of tissues and organs. However, for use of MSCs-exosomes as a clinical agent different MSCs-exosomes have been manufactured and their therapeutics effects demonstrated in clinical studies. But there are still many characteristics which are unknown and many barriers still need to be conquered. In this review, we not only highlighted the characteristics of human MSCs and their exosomes, but also provided their latest therapeutic strategies in regenerative medicine.
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Affiliation(s)
- Maria Maqsood
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Mingzhu Kang
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Xiaotao Wu
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Jinghua Chen
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China
| | - Liping Teng
- Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China.
| | - Lipeng Qiu
- School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China.
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Lepeltier E, Rijo P, Rizzolio F, Popovtzer R, Petrikaite V, Assaraf YG, Passirani C. Nanomedicine to target multidrug resistant tumors. Drug Resist Updat 2020; 52:100704. [PMID: 32512316 DOI: 10.1016/j.drup.2020.100704] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 12/21/2019] [Accepted: 05/13/2020] [Indexed: 12/12/2022]
Abstract
Nanomedicine employs nanotechnologies to develop innovative applications, and more specifically nano-objects in the field of human health, through exploitation of the physical, chemical and biological properties of materials at the nanoscale. The use of nanovehicles capable of transporting and releasing the active therapeutic payload into target cells, particularly in the case of cancer or inflammatory diseases, can also enhance diagnosis. Therefore, nanomedicines improve the benefit/risk ratio of drugs by increasing their bioavailability, selectivity, and efficacy in the target tissue, while reducing the necessary doses and hence diminishing untoward toxicity to healthy tissues. Overcoming multidrug resistance (MDR) to antitumor agents is a central goal of cancer research and therapeutics, making it possible to treat these diseases more accurately and effectively. The adaptability of nanomedicines e.g. modulation of their components, surface functionalization, encapsulation of various active therapeutics as well as the possibility of combining several treatments using a single nanoparticle platform, are characteristics which are perfectly poised to address classical chemoresistance, a major obstacle towards curative cancer therapy. In this review, we discuss an assortment of nanomedicines along with those that should be developed in order to surmount cancer MDR; these include exosomes, natural compounds, lipid nanocapsules, prodrug self-assemblies, and gold nanoparticles.
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Affiliation(s)
- Elise Lepeltier
- Micro et Nanomédecines Translationnelles, MINT, UNIV Angers, UMR INSERM 1066, UMR CNRS 6021, Angers, France
| | - Patricia Rijo
- Research Center for Biosciences & Health Technologies (CBIOS), Lisboa, Portugal; iMed.ULisboa - Research Institute for Medicines, Lisboa, Portugal
| | - Flavio Rizzolio
- Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, 30123 Venezia, Italy; Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Rachela Popovtzer
- Faculty of Engineering and the Institute of Nanotechnology & Advanced Materials Bar-Ilan University, Ramat Gan, 5290002, Israel
| | - Vilma Petrikaite
- Laboratory of Drug Targets Histopathology, Institute of Cardiology, Lithuanian University of Health Sciences, Sukilėlių Av. 13, LT-50161 Kaunas, Lithuania; Institute of Physiology and Pharmacology, Faculty of Medicine, Lithuanian University of Health Sciences, A. Mickevičiaus 9, LT-44307 Kaunas, Lithuania
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Catherine Passirani
- Micro et Nanomédecines Translationnelles, MINT, UNIV Angers, UMR INSERM 1066, UMR CNRS 6021, Angers, France.
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Ex-Vivo Stimulation of Adipose Stem Cells by Growth Factors and Fibrin-Hydrogel Assisted Delivery Strategies for Treating Nerve Gap-Injuries. Bioengineering (Basel) 2020; 7:bioengineering7020042. [PMID: 32380789 PMCID: PMC7357460 DOI: 10.3390/bioengineering7020042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/01/2020] [Accepted: 05/03/2020] [Indexed: 12/22/2022] Open
Abstract
Peripheral nerve injuries often result in lifelong disabilities despite advanced surgical interventions, indicating the urgent clinical need for effective therapies. In order to improve the potency of adipose-derived stem cells (ASC) for nerve regeneration, the present study focused primarily on ex-vivo stimulation of ASC by using growth factors, i.e., nerve growth factor (NGF) or vascular endothelial growth factor (VEGF) and secondly on fibrin-hydrogel nerve conduits (FNC) assisted ASC delivery strategies, i.e., intramural vs. intraluminal loading. ASC were stimulated by NGF or VEGF for 3 days and the resulting secretome was subsequently evaluated in an in vitro axonal outgrowth assay. For the animal study, a 10 mm sciatic nerve gap-injury was created in rats and reconstructed using FNC loaded with ASC. Secretome derived from NGF-stimulated ASC promoted significant axonal outgrowth from the DRG-explants in comparison to all other conditions. Thus, NGF-stimulated ASC were further investigated in animals and found to enhance early nerve regeneration as evidenced by the increased number of β-Tubulin III+ axons. Notably, FNC assisted intramural delivery enabled the improvement of ASC’s therapeutic efficacy in comparison to the intraluminal delivery system. Thus, ex-vivo stimulation of ASC by NGF and FNC assisted intramural delivery may offer new options for developing effective therapies.
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Proteomic Analysis of Exosomes from Adipose-Derived Mesenchymal Stem Cells: A Novel Therapeutic Strategy for Tissue Injury. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6094562. [PMID: 32190672 PMCID: PMC7073480 DOI: 10.1155/2020/6094562] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 02/04/2020] [Accepted: 02/18/2020] [Indexed: 12/27/2022]
Abstract
Exosomes are extracellular membranous nanovesicles that mediate local and systemic cell-to-cell communication by transporting functional molecules, such as proteins, into target cells, thereby affecting the behavior of receptor cells. Exosomes originating from adipose-derived mesenchymal stem cells (ADSCs) are considered a multipotent and abundant therapeutic tool for tissue injury. To investigate ADSC-secreted exosomes and their potential function in tissue repair, we isolated exosomes from the supernatants of ADSCs via ultracentrifugation, characterized them via transmission electron microscopy, nanoparticle tracking analysis, and Western blot analysis. Then, we determined their protein profile via proteomic analysis. Results showed that extracellular vesicles, which have an average diameter of 116 nm, exhibit a cup-shaped morphology and express exosomal markers. A total of 1,185 protein groups were identified in the exosomes. Gene Ontology analysis indicated that exosomal proteins are mostly derived from cells mainly involved in protein binding. Protein annotation via the Cluster of Orthologous Groups system indicated that most proteins were involved in general function prediction, posttranslational modification, protein turnover, and chaperoning. Further, pathway analysis revealed that most of the proteins obtained participated in metabolic pathways, focal adhesion, regulation of the actin cytoskeleton, and microbial metabolism. Some tissue repair-related signaling pathways were also discovered. The identified molecules might serve as potential therapeutic targets for future studies.
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Shen T, Zheng Q, Luo H, Li X, Chen Z, Song Z, Zhou G, Hong C. Exosomal miR-19a from adipose-derived stem cells suppresses differentiation of corneal keratocytes into myofibroblasts. Aging (Albany NY) 2020; 12:4093-4110. [PMID: 32112551 PMCID: PMC7093196 DOI: 10.18632/aging.102802] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 01/19/2020] [Indexed: 04/11/2023]
Abstract
In this study, we investigated the effects of exosomal microRNAs (miRNAs) from adipose-derived stem cells (ADSCs) on the differentiation of rabbit corneal keratocytes. Keratocytes grown in 10% FBS differentiated into myofibroblasts by increasing HIPK2 kinase levels and activity. HIPK2 enhanced p53 and Smad3 pathways in FBS-induced keratocytes. Keratocytes grown in 10% FBS also showed increased levels of pro-fibrotic proteins, including collagen III, MMP9, fibronectin, and α-SMA. These effects were reversed by knocking down HIPK2. Moreover, ADSCs and exosomes derived from ADSCs (ADSCs-Exo) suppressed FBS-induced differentiation of keratocytes into myofibroblasts by inhibiting HIPK2. Quantitative RT-PCR analysis showed that ADSCs-Exos were significantly enriched in miRNA-19a as compared to ADSCs. Targetscan and dual luciferase reporter assays confirmed that the HIPK2 3'UTR is a direct binding target of miR-19a. Keratocytes treated with 10% FBS and ADSCs-Exo-miR-19a-agomir or ADSCs-Exo-NC-antagomir showed significantly lower levels of HIPK2, phospho-Smad3, phospho-p53, collagen III, MMP9, fibronectin and α-SMA than those treated with 10% FBS plus ADSCs-Exo-NC-agomir or ADSCs-Exo-miR-19a-antagomir. Thus, exosomal miR-19a derived from the ADSCs suppresses FBS-induced differentiation of rabbit corneal keratocytes into myofibroblasts by inhibiting HIPK2 expression. This suggests their potential use in the treatment of corneal fibrosis.
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Affiliation(s)
- Ting Shen
- Department of Ophthalmology, Zhejiang Provincial People’s Hospital and People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, P. R. China
| | - Qingqing Zheng
- Department of Ophthalmology, Zhejiang Provincial People’s Hospital and People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, P. R. China
| | - Hongbo Luo
- Department of Ophthalmology, Zhejiang Provincial People’s Hospital and People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang, P. R. China
| | - Xin Li
- Wenzhou School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P. R. China
| | - Zhuo Chen
- Bengbu Medical College, Bengbu 233030, Anhui, P. R. China
| | - Zeyu Song
- Wenzhou School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P. R. China
| | - Guanfang Zhou
- Bengbu Medical College, Bengbu 233030, Anhui, P. R. China
| | - Chaoyang Hong
- Wenzhou School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325035, Zhejiang, P. R. China
- Department of Ophthalmology, Zhejiang Hospital, Hangzhou 310007, Zhejiang, P. R. China
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Ren J, Liu N, Sun N, Zhang K, Yu L. Mesenchymal Stem Cells and their Exosomes: Promising Therapeutics for Chronic Pain. Curr Stem Cell Res Ther 2019; 14:644-653. [PMID: 31512998 DOI: 10.2174/1574888x14666190912162504] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/27/2019] [Accepted: 06/17/2019] [Indexed: 12/13/2022]
Abstract
Chronic pain is a common condition that seriously affects the quality of human life with
variable etiology and complicated symptoms; people who suffer from chronic pain may experience
anxiety, depression, insomnia, and other harmful emotions. Currently, chronic pain treatments are nonsteroidal
anti-inflammatory drugs and opioids; these drugs are demonstrated to be insufficient and
cause severe side effects. Therefore, research into new therapeutic strategies for chronic pain is a top
priority. In recent years, stem cell transplantation has been demonstrated to be a potent alternative for
the treatment of chronic pain. Mesenchymal stem cells (MSCs), a type of pluripotent stem cell, exhibit
multi-directional differentiation, promotion of stem cell implantation, and immune regulation; they
have also been shown to exert analgesic effects in several chronic pain models. Exosomes produced by
MSCs have been demonstrated to relieve painful symptoms with fewer side effects. In this review, we
summarize the therapeutic use of MSCs in various chronic pain studies. We also discuss ways to enhance
the treatment effect of MSCs. We predict in the future, cell-free therapies for chronic pain will
develop from exosomes secreted by MSCs.
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Affiliation(s)
- Jinxuan Ren
- Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Na Liu
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Na Sun
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, China
| | - Kehan Zhang
- Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lina Yu
- Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Bai L, Li J, Li H, Song J, Zhou Y, Lu R, Liu B, Pang Y, Zhang P, Chen J, Liu X, Wu J, Liang C, Zhou J. Renoprotective effects of artemisinin and hydroxychloroquine combination therapy on IgA nephropathy via suppressing NF-κB signaling and NLRP3 inflammasome activation by exosomes in rats. Biochem Pharmacol 2019; 169:113619. [DOI: 10.1016/j.bcp.2019.08.021] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/22/2019] [Indexed: 12/19/2022]
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Lin Y, Lu Y, Li X. Biological characteristics of exosomes and genetically engineered exosomes for the targeted delivery of therapeutic agents. J Drug Target 2019; 28:129-141. [PMID: 31280623 DOI: 10.1080/1061186x.2019.1641508] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
A primary focus of pharmacology is the accurate transport of drugs from the peripheral veins and their delivery to specific tissues and organs. Exosomes are nanoscale extracellular vesicles with comparatively enhanced circulation stability, biocompatibility, physicochemical stability and bio-barrier permeation ability, as well as reduced toxicity. Therefore, they are considered a superior drug delivery platform. Core ligands and homing peptides fuse with transmembrane proteins on the exosome surface. Genetically engineered exosomes target specific tissues or organs and agents such as siRNA, miRNA and chemotherapeutics can be loaded into exosomes to improve the regulation of target tissues and organs. Here, we review exosome biogenesis, release, uptake and isolation. We also summarise the current applications of genetically engineered exosomes for tumours, and neurological, cardiovascular and liver diseases.
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Affiliation(s)
- Yan Lin
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China
| | - Yaqiong Lu
- Gansu Provincial Cancer Hospital, Gansu Provincial Academic Institute for Medical Research, Lanzhou, People's Republic of China
| | - Xun Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, People's Republic of China.,The Fifth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, People's Republic of China.,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, People's Republic of China.,Hepatopancreatobiliary Surgery Institute of Gansu Province, Medical College Cancer Center of Lanzhou, Lanzhou, People's Republic of China
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