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Goyal A, Afzal M, Goyal K, Ganesan S, Kumari M, Sunitha S, Dash A, Saini S, Rana M, Gupta G, Ali H, Wong LS, Kumarasamy V, Subramaniyan V. MSC-derived extracellular vesicles: Precision miRNA delivery for overcoming cancer therapy resistance. Regen Ther 2025; 29:303-318. [PMID: 40237010 PMCID: PMC11999318 DOI: 10.1016/j.reth.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/04/2025] [Accepted: 03/18/2025] [Indexed: 04/17/2025] Open
Abstract
Cancer remains a prominent worldwide health concern, presenting existing therapies with frequent difficulties, including major toxicity, limited effectiveness, and treatment resistance emergence. These issues highlight the necessity for novel and enhanced remedies. Exosomes, tiny extracellular vesicles that facilitate intercellular communication, have attracted interest for their potential medicinal applications. Carrying a variety of molecules, including microRNAs, small interfering RNAs, long non-coding RNAs, proteins, lipids, and DNA, these vesicles are positioned as promising cancer treatment options. Current studies have increasingly investigated the capacity of microRNAs as a strategic approach for combating malignancy. Mesenchymal stem cells (MSC) are recognized for their aptitude to augment blood vessel formation, safeguard against cellular death, and modulate immune responses. Consequently, researchers examine exosomes derived from MSCs as a safer, non-cellular choice over therapies employing MSCs, which risk undesirable differentiation. The focus is shifting towards employing miRNA-encapsulated exosomes sourced from MSCs to target and heal cancerous cells selectively. However, the exact functions of miRNAs within MSC-derived exosomes in the context of cancer are still not fully understood. Additional exploration is necessary to clarify the role of these miRNAs in malignancy progression and to pinpoint viable therapeutic targets. This review offers a comprehensive examination of exosomes derived from mesenchymal stem cells, focusing on the encapsulation of miRNAs, methods for enhancing cellular uptake and stability, and their potential applications in cancer treatment. It also addresses the difficulties linked to this methodology and considers future avenues, including insights from current clinical oncology research.
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Affiliation(s)
- Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah, 21442, Saudi Arabia
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - S. Sunitha
- Department of CHEMISTRY, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Aniruddh Dash
- Department of Orthopaedics IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751030, India
| | - Suman Saini
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia
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Huang D, Huang W, Liu M, Chen J, Xiao D, Peng Z, He H, Shen H, Jin Q, Chen L, Rao D, Zhao M, Huang J. Progress of mesenchymal stem cell-derived exosomes in targeted delivery of antitumor drugs. Cancer Cell Int 2025; 25:169. [PMID: 40301903 PMCID: PMC12042352 DOI: 10.1186/s12935-025-03795-x] [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: 02/10/2025] [Accepted: 04/17/2025] [Indexed: 05/01/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are currently being used in clinical trials for the treatment of a wide range of diseases and have a wide range of applications in the fields of tissue engineering and regeneration. Exosomes are extracellular vesicles containing a variety of components such as proteins, nucleic acids and lipids, which are widely present in biological fluids and have the functions of participating in intercellular information transfer, immune response and tissue repair, and can also be used as carriers to target and deliver tumors to improve therapeutic effects. Mesenchymal stem cell-derived Exosomes (MSC-Exos), which have the advantages of low immunogenicity and high tumor homing ability, have attracted much attention in targeted drug delivery. Here, we review the current knowledge on the involvement of MSC-Exos in tumor progression and their potential as drug delivery systems in targeted therapies. It also discusses the advantages and prospects of MSC-Exos as a drug carrier and the challenges that still need to be overcome.
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Affiliation(s)
- Defa Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Wenlong Huang
- Department of General Medicine, First People's Hospital of Zunyi (Third Affiliated Hospital of Zunyi Medical University), Zunyi, 563000, China
| | - Meijin Liu
- People's Hospital of Ganzhou Economic Development Zone, Ganzhou, 341000, China
| | - Jie Chen
- Department of Laboratory Medicine, the Affiliated Yongchuan Hospital of Chongqing Medical University, Yongchuan, Chongqing, 402177, China
| | - Dewang Xiao
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, 341000, China
| | - Zongbo Peng
- The First School of Clinical Medicine, Gannan Medical University, Ganzhou, 341000, China
| | - Haoquan He
- Department of General Practice, Ditian Community health centre, Jinhua jindong, xiaoshun, 321000, China
| | - Haibin Shen
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Qing Jin
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Linli Chen
- Laboratory Medicine, Guizhou Aerospace Hospital, Zunyi, 563100, China
| | - Dingyu Rao
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
| | - Minghong Zhao
- Laboratory Medicine, Guizhou Aerospace Hospital, Zunyi, 563100, China.
| | - Junyun Huang
- Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China.
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Balaraman AK, Arockia Babu M, Afzal M, Sanghvi G, M M R, Gupta S, Rana M, Ali H, Goyal K, Subramaniyan V, Wong LS, Kumarasamy V. Exosome-based miRNA delivery: Transforming cancer treatment with mesenchymal stem cells. Regen Ther 2025; 28:558-572. [PMID: 40034540 PMCID: PMC11872554 DOI: 10.1016/j.reth.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/14/2025] [Accepted: 01/25/2025] [Indexed: 03/05/2025] Open
Abstract
Recently, increasing interest has been in utilizing mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), especially exosomes, as nanocarriers for miRNA delivery in cancer treatment. Due to such characteristics, nanocarriers are specific: biocompatible, low immunogenicity, and capable of spontaneous tumor accumulation. MSC-EVs were loaded with therapeutic miRNAs and minimized their susceptibility to degradation by protecting the miRNA from accessibility to degrading enzymes and providing targeted delivery of the miRNAs to the tumor cells to modulate oncogenic pathways. In vitro and in vivo experiments suggest that MSC-EVs loaded with miRNAs may inhibit tumor growth, prevent metastasis, and increase the effectiveness of chemotherapy and radiotherapy. However, these improvements present difficulties such as isolation, scalability, and stability of delivered miRNA during storage. Furthermore, the issues related to off-target effects, as well as immunogenicity, can be a focus. The mechanisms of miRNA loading into MSC-EVs, as well as their targeting efficiency and therapeutic potential, can be outlined in this manuscript. For the final part of the manuscript, the current advances in MSC-EV engineering and potential strategies for clinical application have been described. The findings of MSC-EVs imply that they present MSC-EVs as a second-generation tool for precise oncology.
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Affiliation(s)
- Ashok Kumar Balaraman
- Research and Enterprise, University of Cyberjaya, Persiaran Bestari, Cyber 11, Cyberjaya, Selangor, 63000, Malaysia
| | - M. Arockia Babu
- Institute of Pharmaceutical Research, GLA UNIVERSITY, Mathura, UP, 281406, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah, 21442, Saudi Arabia
| | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Rekha M M
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Sofia Gupta
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, 248002, Dehradun, India
| | - Vetriselvan Subramaniyan
- Division of Pharmacology, School of Medical and Life Sciences, Sunway University Jalan Universiti, Bandar Sunway, 47500 Selangor Darul Ehsan, Malaysia
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, 71800, Malaysia
| | - Vinoth Kumarasamy
- Department of Parasitology, Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
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Bogusławska J, Grzanka M, Popławski P, Zarychta-Wiśniewska W, Burdzinska A, Hanusek K, Kossowska H, Iwanicka-Nowicka R, Białas A, Rybicka B, Adamiok-Ostrowska A, Życka-Krzesińska J, Koblowska M, Pączek L, Piekiełko-Witkowska A. Non-coding RNAs secreted by renal cancer include piR_004153 that promotes migration of mesenchymal stromal cells. Cell Commun Signal 2025; 23:3. [PMID: 39754169 PMCID: PMC11697636 DOI: 10.1186/s12964-024-02001-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 12/17/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Renal cell cancer (RCC) is the most common and highly malignant subtype of kidney cancer. Mesenchymal stromal cells (MSCs) are components of tumor microenvironment (TME) that influence RCC progression. The impact of RCC-secreted small non-coding RNAs (sncRNAs) on TME is largely underexplored. Here, we comprehensively analysed the composition of exosomal sncRNAs secreted by RCC cells to identify those that influence MSCs. METHODS Exosomal sncRNAs secreted by RCC cells and normal kidney cells were analyzed using RNAseq, followed by qPCR validation. MSCs were treated by conditioned media (CM) derived from RCC cells and transfected with piRNA, followed by the analysis of proliferation, viability, migration and immunocytochemical detection of piRNA. Expression of MSCs genes was evaluated using microarray and qPCR. TCGA data were analyzed to explore the expression of sncRNAs in RCC tumors. RESULTS RNAseq revealed 40 miRNAs, 71 tRNAs and four piRNAs that were consistently secreted by RCC cells. qPCR validation using five independent RCC cell lines confirmed that expressions of miR-10b-3p and miR-125a-5p were suppressed, while miR-365b-3p was upregulated in exosomes from RCC cells when compared with normal kidney proximal tubules. The expression of miR-10b-3p and miR-125a-5p was decreased, whereas the expression of miR-365b-3p was increased in RCC tumors and correlated with poor survival of patients. Expressions of tRNA-Glu, tRNA-Gly, and tRNA-Val were the most increased, while tRNA-Gln, tRNA-Leu, and tRNA-Lys were top decreased in RCC exosomes when compared with normal kidney cells. Moreover, hsa_piR_004153, hsa_piR_016735, hsa_piR_019521, and hsa_piR_020365 were consistently upregulated in RCC exosomes. piR_004153 (DQ575660.1; aliases: hsa_piRNA_18299, piR-43772, piR-hsa-5938) was the most highly expressed in exosomes from RCC cells when compared with normal kidney cells. Treatment of MSCs with RCC CM resulted in upregulation of piR_004153 expression. Transfection of MSCs with piR_004153 stimulated their migration and viability, and altered expression of 35 genes, including downregulation of FGF2, SLC7A5, and WISP1. Immunocytochemistry confirmed the nuclear localization of piR_004153 transfected in MSCs. CONCLUSION RCC cells secrete multiple sncRNAs, including piR_004153 which targets MSCs, alters expression of FGF2, SLC7A5, and WISP1, and stimulates their motility and viability. To our knowledge, this is the first study showing that cancer-derived piRNA can enhance MSC migration.
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Affiliation(s)
- Joanna Bogusławska
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland.
| | - Małgorzata Grzanka
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland
| | - Piotr Popławski
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland
| | | | - Anna Burdzinska
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Karolina Hanusek
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland
| | - Helena Kossowska
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, Warsaw, 02-106, Poland
| | - Roksana Iwanicka-Nowicka
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, Warsaw, 02-106, Poland
- Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, 02-106, Poland
| | - Alex Białas
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland
| | - Beata Rybicka
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland
| | - Anna Adamiok-Ostrowska
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland
| | - Joanna Życka-Krzesińska
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland
| | - Marta Koblowska
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, Warsaw, 02-106, Poland
- Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, 02-106, Poland
| | - Leszek Pączek
- Department of Clinical Immunology, Medical University of Warsaw, ul. Nowogrodzka 59, Warsaw, Poland
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Agnieszka Piekiełko-Witkowska
- Centre of Postgraduate Medical Education, Centre of Translation Research, Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, Warsaw, 01-813, Poland.
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Afkhami H, Yarahmadi A, Bostani S, Yarian N, Haddad MS, Lesani SS, Aghaei SS, Zolfaghari MR. Converging frontiers in cancer treatment: the role of nanomaterials, mesenchymal stem cells, and microbial agents-challenges and limitations. Discov Oncol 2024; 15:818. [PMID: 39707033 DOI: 10.1007/s12672-024-01590-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/14/2024] [Indexed: 12/23/2024] Open
Abstract
Globally, people widely recognize cancer as one of the most lethal diseases due to its high mortality rates and lack of effective treatment options. Ongoing research into cancer therapies remains a critical area of inquiry, holding significant social relevance. Currently used treatment, such as chemotherapy, radiation, or surgery, often suffers from other problems like damaging side effects, inaccuracy, and the lack of ability to clear tumors. Conventional cancer therapies are usually imprecise and ineffective and usually develop resistance to treatments and cancer recurs. Cancer patients need fresh and innovative treatment that can reduce side effects while maximizing effectiveness. In recent decades several breakthroughs in these, and other areas of medical research, have paved the way for new avenues of fighting cancer including more focused and more effective alternatives. This study reviews exciting possibilities for mesenchymal stem cells (MSCs), nanomaterials, and microbial agents in the modern realm of cancer treatment. Nanoparticles (NPs) have demonstrated surprisingly high potential. They improve drug delivery systems (DDS) significantly, enhance imaging techniques remarkably, and target cancer cells selectively while protecting healthy tissues. MSCs play a double role in tissue repair and are a vehicle for novel cancer treatments such as gene treatments or NPs loaded with therapeutic agents. Additionally, therapies utilizing microbial agents, particularly those involving bacteria, offer an inventive approach to cancer treatment. This review investigates the potential of nanomaterials, MSCs, and microbial agents in addressing the shortcomings of conventional cancer therapies. We will also discuss the challenges and limitations of using these therapeutic approaches.
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Affiliation(s)
- 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
| | - Shoroq Bostani
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
| | - Nahid Yarian
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
| | | | - Shima Sadat Lesani
- Department of Microbiology, Qom Branch, Islamic Azad University, Qom, Iran
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Hong Q, Li O, Zheng W, Xiao WZ, Zhang L, Wu D, Cai GY, He JC, Chen XM. Retraction Note: LncRNA HOTAIR regulates HIF-1α/AXL signaling through inhibition of miR-217 in renal cell carcinoma. Cell Death Dis 2024; 15:716. [PMID: 39353884 PMCID: PMC11445251 DOI: 10.1038/s41419-024-07111-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2024]
Affiliation(s)
- Quan Hong
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Fuxing Road 28, Haidian District, Beijing, 100853, China
| | - Ou Li
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Fuxing Road 28, Haidian District, Beijing, 100853, China
| | - Wei Zheng
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Fuxing Road 28, Haidian District, Beijing, 100853, China
| | - Wen-Zhen Xiao
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Lu Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Di Wu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Fuxing Road 28, Haidian District, Beijing, 100853, China
| | - Guang-Yan Cai
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Fuxing Road 28, Haidian District, Beijing, 100853, China
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Xiang-Mei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Fuxing Road 28, Haidian District, Beijing, 100853, China.
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Švajger U, Kamenšek U. Interleukins and interferons in mesenchymal stromal stem cell-based gene therapy of cancer. Cytokine Growth Factor Rev 2024; 77:76-90. [PMID: 38508954 DOI: 10.1016/j.cytogfr.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
The tumor microenvironment is importantly shaped by various cytokines, where interleukins (ILs) and interferons (IFNs) shape the balance of immune activity within tumor niche and associated lymphoid organs. Their importance in activation and tuning of both innate and adaptive immune responses prompted their use in several clinical trials, albeit with limited therapeutic efficacy and risk of toxicity due to systemic administration. Increasing preclinical evidence suggests that local delivery of ILs and IFNs could significantly increase their effectiveness, while simultaneously attenuate the known side effects and issues related to their biological activity. A prominent way to achieve this is to use cell-based delivery vehicles. For this purpose, mesenchymal stromal stem cells (MSCs) are considered an almost ideal candidate. Namely, MSCs can be obtained in large quantities and from obtainable sources (e.g. umbilical cord or adipose tissue), their ex vivo expansion is relatively straightforward compared to other cell types and they possess very low immunogenicity making them suitable for allogeneic use. Importantly, MSCs have shown an intrinsic capacity to respond to tumor-directed chemotaxis. This review provides a focused and detailed discussion on MSC-based gene therapy using ILs and IFNs, engineering techniques and insights on potential future advancements.
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Affiliation(s)
- Urban Švajger
- Slovenian Institute for Transfusion Medicine, Department for Therapeutic Services, Šlajmerjeva Ulica 6, Ljubljana SI-1000, Slovenia; Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, Ljubljana SI-1000, Slovenia.
| | - Urška Kamenšek
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška Cesta 2, Ljubljana SI-1000, Slovenia; Biotechnical Faculty, University of Ljubljana, Jamnikarjeva Ulica 101, Ljubljana SI-1000, Slovenia
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8
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Wei X, Zhang D, Zhu Y. Exosomes: Toward a potential application in bladder cancer diagnosis and treatment. SMART MEDICINE 2024; 3:e20230027. [PMID: 39188515 PMCID: PMC11235804 DOI: 10.1002/smmd.20230027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 08/27/2023] [Indexed: 08/28/2024]
Abstract
Bladder cancer (BC) is a prevalent malignant tumor of the urinary system, known for its rapid progression and high likelihood of recurrence. Despite ongoing efforts, clinical diagnosis and treatment of BC remain limited. As such, there is an urgent need to investigate potential mechanisms underlying this disease. Exosomes, which contain a variety of bioactive molecules such as nucleic acids, proteins, and lipids, are regarded as extracellular messengers because they are implicated in facilitating intercellular communication in various diseases and are pivotal in tumor advancement, serving as a promising avenue for such researches. Nevertheless, the heterogeneous nature of BC necessitates further exploration of the potential involvement of exosomes in disease progression. This review comprehensively outlines the biological attributes of exosomes and their critical roles in tumorigenesis, while also discussing their potential applications in regulating the progression of BC involving clinical diagnosis, prognostication and treatment.
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Affiliation(s)
- Xiaowei Wei
- Laboratory Medicine Center The Second Affiliated Hospital of Nanjing Medical University Nanjing China
- Department of Rheumatology and Immunology Institute of Translational Medicine Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing China
| | - Dagan Zhang
- Department of Rheumatology and Immunology Institute of Translational Medicine Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing China
| | - Yefei Zhu
- Laboratory Medicine Center The Second Affiliated Hospital of Nanjing Medical University Nanjing China
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9
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Saadh MJ, Alhuthali HM, Gonzales Aníbal O, Asenjo-Alarcón JA, Younus DG, Alhili A, Adhab ZH, Alsalmi O, Gharib AF, Pecho RDC, Akhavan-Sigari R. Mesenchymal stem cells and their extracellular vesicles in urological cancers: Prostate, bladder, and kidney. Cell Biol Int 2024; 48:3-19. [PMID: 37947445 DOI: 10.1002/cbin.12098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/31/2023] [Accepted: 10/12/2023] [Indexed: 11/12/2023]
Abstract
Mesenchymal stem cells (MSCs) are recognized for their remarkable ability to differentiate into multiple cell types. They are also known to possess properties that can fight cancer, leading to attempts to modify MSCs for use in anticancer treatments. However, MSCs have also been found to participate in pathways that promote tumor growth. Many studies have been conducted to explore the potential of MSCs for clinical applications, but the results have been inconclusive, possibly due to the diverse nature of MSC populations. Furthermore, the conflicting roles of MSCs in inhibiting tumors and promoting tumor growth hinder their adaptation to anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in urological cancers such as bladder, prostate, and renal are not as well established, and data comparing them are still limited. MSCs hold significant promise as a vehicle for delivering anticancer agents and suicide genes to tumors. Presently, numerous studies have concentrated on the products derived from MSCs, such as extracellular vesicles (EVs), as a form of cell-free therapy. This work aimed to review and discuss the current knowledge of MSCs and their EVs in urological cancer therapy.
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Affiliation(s)
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | | | | | - Ahmed Alhili
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | | | - Ohud Alsalmi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Amal F Gharib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tuebingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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Jahangiri B, Khalaj-Kondori M, Asadollahi E, Kian Saei A, Sadeghizadeh M. Dual impacts of mesenchymal stem cell-derived exosomes on cancer cells: unravelling complex interactions. J Cell Commun Signal 2023:10.1007/s12079-023-00794-3. [PMID: 37973719 DOI: 10.1007/s12079-023-00794-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 11/06/2023] [Indexed: 11/19/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent, self-renewing stromal cells found in a variety of adult tissues. MSCs possess a remarkable ability to migrate towards tumor sites, known as homing. This homing process is mediated by various factors, including chemokines, growth factors, and extracellular matrix components present in the tumor microenvironment. MSCs release extracellular vesicles known as exosomes (MSC-Exos), which have been suggested to serve a key role in mediating a wide variety of MSC activities. Through cell-cell communication, MSC-Exos have been shown to alter recipient cell phenotype or function and play as a novel cell-free alternative for MSC-based cell therapy. However, MSC recruitment to tumors allows for their interaction with cancer cells and subsequent regulation of tumor behavior. MSC-Exos act as tumor niche modulators via transferring exosomal contents, such as specific proteins or genetic materials, to the nearby cancer cells, leading to either promotion or suppression of tumorigenesis, angiogenesis, and metastasis, depending on the specific microenvironmental cues and recipient cell characteristics. Consequently, there is still a debate about the precise relationship between tumor cells and MSC-Exos, and it is unclear how MSC-Exos impacts tumor cells. Although the dysregulation of miRNAs is caused by the progression of cancer, they also play a direct role in either promoting or inhibiting tumor growth as they act as either oncogenes or tumor suppressors. The utilization of MSC-Exos may prove to be an effective method for restoring miRNA as a means of treating cancer. This review aimed to present the existing understanding of the impact that MSC-Exos could have on cancer. To begin with, we presented a brief explanation of exosomes, MSCs, and MSC-Exos. Following this, we delved into the impact of MSC-Exos on cancer growth, EMT, metastasis, angiogenesis, resistance to chemotherapy and radiotherapy, and modulation of the immune system. Opposing effects of mesenchymal stem cells-derived exosomes on cancer cells.
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Affiliation(s)
- Babak Jahangiri
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Khalaj-Kondori
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Elahe Asadollahi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Kian Saei
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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11
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Szyposzynska A, Bielawska-Pohl A, Murawski M, Sozanski R, Chodaczek G, Klimczak A. Mesenchymal Stem Cell Microvesicles from Adipose Tissue: Unraveling Their Impact on Primary Ovarian Cancer Cells and Their Therapeutic Opportunities. Int J Mol Sci 2023; 24:15862. [PMID: 37958844 PMCID: PMC10647545 DOI: 10.3390/ijms242115862] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 10/29/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) and their derivatives can be promising tools in oncology including ovarian cancer treatment. This study aimed to determine the effect of HATMSC2-MVs (microvesicles derived from human immortalized mesenchymal stem cells of adipose tissue origin) on the fate and behavior of primary ovarian cancer cells. Human primary ovarian cancer (OvCa) cells were isolated from two sources: post-operative tissue of ovarian cancer and ascitic fluid. The phenotype of cells was characterized using flow cytometry, real-time RT-PCR, and immunofluorescence staining. The effect of HATMSC2-MVs on the biological activity of primary cells was analyzed in 2D (proliferation, migration, and cell survival) and 3D (cell survival) models. We demonstrated that HATMSC2-MVs internalized into primary ovarian cancer cells decrease the metabolic activity and induce the cancer cell death and are leading to decreased migratory activity of tumor cells. The results suggests that the anti-cancer effect of HATMSC2-MVs, with high probability, is contributed by the delivery of molecules that induce cell cycle arrest and apoptosis (p21, tumor suppressor p53, executor caspase 3) and proapoptotic regulators (bad, BIM, Fas, FasL, p27, TRAIL-R1, TRAIL-R2), and their presence has been confirmed by apoptotic protein antibody array. In this study, we demonstrate the ability to inhibit primary OvCa cells growth and apoptosis induction after exposure of OvCa cells on HATMSC2-MVs treatment; however, further studies are needed to clarify their anticancer activities.
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Affiliation(s)
- Agnieszka Szyposzynska
- Laboratory of Biology of Stem and Neoplastic Cells, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.S.); (A.B.-P.)
| | - Aleksandra Bielawska-Pohl
- Laboratory of Biology of Stem and Neoplastic Cells, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.S.); (A.B.-P.)
| | - Marek Murawski
- 1st Department of Gynecology and Obstetrics, Wroclaw Medical University, 50-599 Wroclaw, Poland; (M.M.); (R.S.)
| | - Rafal Sozanski
- 1st Department of Gynecology and Obstetrics, Wroclaw Medical University, 50-599 Wroclaw, Poland; (M.M.); (R.S.)
| | - Grzegorz Chodaczek
- Bioimaging Laboratory, Łukasiewicz Research Network-PORT Polish Center for Technology Development, 54-066 Wroclaw, Poland;
| | - Aleksandra Klimczak
- Laboratory of Biology of Stem and Neoplastic Cells, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (A.S.); (A.B.-P.)
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12
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Zhou Y, Dong Y, Zhang A, Wu J, Sun Q. The role of mesenchymal stem cells derived exosomes as a novel nanobiotechnology target in the diagnosis and treatment of cancer. Front Bioeng Biotechnol 2023; 11:1214190. [PMID: 37662434 PMCID: PMC10470003 DOI: 10.3389/fbioe.2023.1214190] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 08/03/2023] [Indexed: 09/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs), one of the most common types of stem cells, are involved in the modulation of the tumor microenvironment (TME). With the advancement of nanotechnology, exosomes, especially exosomes secreted by MSCs, have been found to play an important role in the initiation and development of tumors. In recent years, nanobiotechnology and bioengineering technology have been gradually developed to detect and identify exosomes for diagnosis and modify exosomes for tumor treatment. Several novel therapeutic strategies bioengineer exosomes to carry drugs, proteins, and RNAs, and further deliver their encapsulated cargoes to cancer cells through the properties of exosomes. The unique properties of exosomes in cancer treatment include targeting, low immunogenicity, flexibility in modification, and high biological barrier permeability. Nevertheless, the current comprehensive understanding of the roles of MSCs and their secreted exosomes in cancer development remain inadequate. It is necessary to better understand/update the mechanism of action of MSCs-secreted exosomes in cancer development, providing insights for better modification of exosomes through bioengineering technology and nanobiotechnology. Therefore, this review focuses on the role of MSCs-secreted exosomes and bioengineered exosomes in the development, progression, diagnosis, and treatment of cancer.
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Affiliation(s)
- You Zhou
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yuqing Dong
- China Medical University and Department of Pathology, Shenyang, China
| | - Aixue Zhang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Jibin Wu
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Qiang Sun
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
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13
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Popławski P, Zarychta-Wiśniewska W, Burdzińska A, Bogusławska J, Adamiok-Ostrowska A, Hanusek K, Rybicka B, Białas A, Kossowska H, Iwanicka-Nowicka R, Koblowska M, Pączek L, Piekiełko-Witkowska A. Renal cancer secretome induces migration of mesenchymal stromal cells. Stem Cell Res Ther 2023; 14:200. [PMID: 37563650 PMCID: PMC10413545 DOI: 10.1186/s13287-023-03430-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/25/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND Advanced renal cell carcinoma (RCC) is therapeutically challenging. RCC progression is facilitated by mesenchymal stem/stromal cells (MSCs) that exert remarkable tumor tropism. The specific mechanisms mediating MSCs' migration to RCC remain unknown. Here, we aimed to comprehensively analyze RCC secretome to identify MSCs attractants. METHODS Conditioned media (CM) were collected from five RCC-derived cell lines (Caki-1, 786-O, A498, KIJ265T and KIJ308T) and non-tumorous control cell line (RPTEC/TERT1) and analyzed using cytokine arrays targeting 274 cytokines in addition to global CM proteomics. MSCs were isolated from bone marrow of patients undergoing standard orthopedic surgeries. RCC CM and the selected recombinant cytokines were used to analyze their influence on MSCs migration and microarray-targeted gene expression. The expression of genes encoding cytokines was evaluated in 100 matched-paired control-RCC tumor samples. RESULTS When compared with normal cells, CM from advanced RCC cell lines (Caki-1 and KIJ265T) were the strongest stimulators of MSCs migration. Targeted analysis of 274 cytokines and global proteomics of RCC CM revealed decreased DPP4 and EGF, as well as increased AREG, FN1 and MMP1, with consistently altered gene expression in RCC cell lines and tumors. AREG and FN1 stimulated, while DPP4 attenuated MSCs migration. RCC CM induced MSCs' transcriptional reprogramming, stimulating the expression of CD44, PTX3 and RAB27B. RCC cells secreted hyaluronic acid (HA), a CD44 ligand mediating MSCs' homing to the kidney. AREG emerged as an upregulator of MSCs' transcription. CONCLUSIONS Advanced RCC cells secrete AREG, FN1 and HA to induce MSCs migration, while DPP4 loss prevents its inhibitory effect on MSCs homing. RCC secretome induces MSCs' transcriptional reprograming to facilitate their migration. The identified components of RCC secretome represent potential therapeutic targets.
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Affiliation(s)
- Piotr Popławski
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | | | - Anna Burdzińska
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Joanna Bogusławska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Anna Adamiok-Ostrowska
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Karolina Hanusek
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Beata Rybicka
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Alex Białas
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Helena Kossowska
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106, Warsaw, Poland
| | - Roksana Iwanicka-Nowicka
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106, Warsaw, Poland
- Laboratory of Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Marta Koblowska
- Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106, Warsaw, Poland
- Laboratory of Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Leszek Pączek
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
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14
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Awadalla A, Hamam ET, Mostafa SA, Mahmoud SA, Elazab KM, El Nakib AM, Eldesoqui M, El-Sherbiny M, Ammar OA, Al-Serwi RH, Saleh MA, Sarhan A, Ali M. Hepatoprotective Effects of Hyaluronic Acid-Preconditioned Bone Marrow Mesenchymal Stem Cells against Liver Toxicity via the Inhibition of Apoptosis and the Wnt/β-Catenin Signaling Pathway. Cells 2023; 12:1526. [PMID: 37296647 PMCID: PMC10252276 DOI: 10.3390/cells12111526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/30/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Doxorubicin (DOX) is widely used to treat a variety of malignancies in both adults and children, including those of the bladder, breast, stomach, and ovaries. Despite this, it has been reported to cause hepatotoxicity. The recent discovery of bone marrow-derived mesenchymal stem cells' (BMSCs) therapeutic effects in the context of liver diseases suggests that their administration plays a part in the mitigation and rehabilitation of drug-induced toxicities. OBJECTIVES This study investigated whether bone BMSCs could reduce DOX-induced liver damage by blocking the Wnt/β-catenin pathway that causes fibrotic liver. MATERIALS AND METHODS BMSCs were isolated and treated with hyaluronic acid (HA) for 14 days before injection. Thirty-five mature male SD rats were categorized into four groups; group one (control) rats were supplemented with saline 0.9% for 28 days, group two (DOX) rats were injected with DOX (20 mg/kg), group three (DOX + BMSCs) rats were injected with 2 × 106 BMSCs after 4 days of DOX injection, group four (DOX + BMSCs + HA) rats were injected with 0.1 mL BMSCs pretreated with HA after 4 days of DOX. After 28 days the rats were sacrificed, and blood and liver tissue samples were subjected to biochemical and molecular analysis. Morphological and immunohistochemical observations were also carried out. RESULTS In terms of liver function and antioxidant findings, cells treated with HA showed considerable improvement compared to the DOX group (p < 0.05). Moreover, the expression of inflammatory markers (TGFβ1, iNos), apoptotic markers (Bax, Bcl2), cell tracking markers (SDF1α), fibrotic markers (β-catenin, Wnt7b, FN1, VEGF, and Col-1), and ROS markers (Nrf2, HO-1) was improved in BMSCs conditioned with HA in contrast to BMSCs alone (p < 0.05). CONCLUSION Our findings proved that BMSCs treated with HA exert their paracrine therapeutic effects via their secretome, suggesting that cell-based regenerative therapies conditioned with HA may be a viable alternative to reduce hepatotoxicity.
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Affiliation(s)
- Amira Awadalla
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Eman T. Hamam
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Sally Abdallah Mostafa
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Seham Ahmed Mahmoud
- Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| | - Khalid Mohamed Elazab
- Department of Biology, Faculty of Science, Jazan University, Jazan 82511, Saudi Arabia
| | - Ahmed Mohamed El Nakib
- Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mamdouh Eldesoqui
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia
| | - Omar A. Ammar
- Basic Science Department, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - Rasha Hamed Al-Serwi
- Department of Basic Dental Sciences, College of Dentistry, Princess Nourahbint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Mohamed A. Saleh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates;
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amira Sarhan
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed Ali
- Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
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15
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Ferragu M, Vergori L, Le Corre V, Bellal S, Del Carmen Martinez M, Bigot P. Effects of Large Extracellular Vesicles from Kidney Cancer Patients on the Growth and Environment of Renal Cell Carcinoma Xenografts in a Mouse Model. Curr Issues Mol Biol 2023; 45:2491-2504. [PMID: 36975533 PMCID: PMC10047252 DOI: 10.3390/cimb45030163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/10/2023] [Accepted: 03/14/2023] [Indexed: 03/29/2023] Open
Abstract
Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients' nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression.
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Affiliation(s)
- Matthieu Ferragu
- Urology Department, Angers University Hospital, 49100 Angers, France
| | - Luisa Vergori
- INSERM Unite Mixte de Recherche (UMR) 1063, Stress Oxydant et Pathologies Metaboliques, 49100 Angers, France
| | - Vincent Le Corre
- Urology Department, Angers University Hospital, 49100 Angers, France
| | - Sarah Bellal
- Anatomopathological Department, Angers University Hospital, 49100 Angers, France
| | - Maria Del Carmen Martinez
- INSERM Unite Mixte de Recherche (UMR) 1063, Stress Oxydant et Pathologies Metaboliques, 49100 Angers, France
| | - Pierre Bigot
- Urology Department, Angers University Hospital, 49100 Angers, France
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16
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Zhang YY, Yang W, Zhang Y, Hu Z, Chen Y, Ma Y, Yang A, Shi Z, Zhou H, Ren P, Shi L, Jin J, Rong Y, Tong X, Zhang YL, Zhang S. HucMSC-EVs Facilitate In Vitro Development of Maternally Aged Preantral Follicles and Oocytes. Stem Cell Rev Rep 2023:10.1007/s12015-022-10495-w. [PMID: 36862330 PMCID: PMC10366269 DOI: 10.1007/s12015-022-10495-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2022] [Indexed: 03/03/2023]
Abstract
Follicle developmental capacity and oocyte quality decline with advanced maternal age. Extracellular vesicles from human umbilical cord mesenchymal stem cells (HucMSC-EVs) act as a potential therapeutic product in the treatment of age-related ovarian dysfunction. In vitro culture (IVC) of preantral follicles is a useful method for understanding the mechanism of follicle development and is a promising means for improving female fertility. However, whether HucMSC-EVs have beneficial effects on aged follicle development during IVC has not yet been reported. Our research demonstrated that follicular development with single-addition withdrawal of HucMSC-EVs was better than that with continuous treatment with HucMSC-EVs. HucMSC-EVs facilitated the survival and growth of follicles, promoted the proliferation of granulosa cells (GCs), and improved the steroid hormone secretion of GCs during IVC of aged follicles. Both GCs and oocytes could uptake HucMSC-EVs. Moreover, we observed elevated cellular transcription in GCs and oocytes after treatment with HucMSC-EVs. The RNA sequencing (RNA-seq) results further validated that the differentially expressed genes are related to the promotion of GC proliferation, cell communication, and oocyte spindle organization. Additionally, the aged oocytes displayed a higher maturation rate, presented less aberrant spindle morphology, and expressed a higher level of the antioxidant protein Sirtuin 1 (SIRT1) after treatment with HucMSC-EVs. Our findings suggested that HucMSC-EVs can improve the growth and quality of aged follicles and oocytes in vitro through the regulation of gene transcription, which provides evidence for HucMSC-EVs as potential therapeutic reagents to restore female fertility with advanced age.
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Affiliation(s)
- Ying-Yi Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Weijie Yang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Yi Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Zhanhong Hu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Yingyan Chen
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Yerong Ma
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Anran Yang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Zhan Shi
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Hanjing Zhou
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Peipei Ren
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Libing Shi
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Jiamin Jin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Yan Rong
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Xiaomei Tong
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China
| | - Yin-Li Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. .,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China.
| | - Songying Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. .,Department of Obstetrics and Gynecology, Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, China.
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17
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Liu J, Ma X, Liu C, Cheng Y, Li B, Zhang W, Zeng R, Chen Q, Zhang Y, Hu S. Mesenchymal stem cells elicits Anti-PD1 immunotherapy by targeted delivery of CX3CL1. Front Pharmacol 2023; 14:1136614. [PMID: 36843945 PMCID: PMC9944415 DOI: 10.3389/fphar.2023.1136614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 01/27/2023] [Indexed: 02/11/2023] Open
Abstract
Anti-PD1/PDL1 monotherapy has failed to acquire sufficiently ideal results in most solid tumors. Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on some tumors, but the functions of MSCs in colorectal cancer (CRC) need further research. In this study, we aimed to investigate the therapeutic effect and the improvement of sensitivity of MSCs to anti-PD1 antibodies (αPD1) in CRC and to evaluate the possible mechanism. The relative distribution of immune cells in tumor microenvironment was examined after the mice were treated with MSC and/or αPD1. Our study revealed that MSC recruits CX3CR1high macrophages and promotes M1 polarization to inhibit tumor growth via highly secretion of CX3CL1.The combination of MSC and αPD1 was superior to monotherapy against CRC. MSC inhibits PD1 expression on CD8+ T cells by facilitating M1 macrophage polarization, which promotes the proliferation of CD8+ T cells, thus improving the sensitivity to αPD1 therapy in CRC. Additionally, the above therapeutic effect disappeared after inhibiting the secretion of CX3CL1 in MSC. Our MSC-based immunotherapeutic strategy simultaneously recruited and activated immune effector cells at the tumor site, suggesting that the combination of MSC and αPD1 could be a potential therapy for CRC.
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Affiliation(s)
- Jize Liu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China,Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaomin Ma
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Chuxuan Liu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yang Cheng
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bingjun Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China,Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wenjie Zhang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Runzhi Zeng
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qishuai Chen
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China,Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yun Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China,*Correspondence: Yun Zhang, ; Sanyuan Hu,
| | - Sanyuan Hu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China,*Correspondence: Yun Zhang, ; Sanyuan Hu,
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Silini AR, Ramuta TŽ, Pires AS, Banerjee A, Dubus M, Gindraux F, Kerdjoudj H, Maciulatis J, Weidinger A, Wolbank S, Eissner G, Giebel B, Pozzobon M, Parolini O, Kreft ME. Methods and criteria for validating the multimodal functions of perinatal derivatives when used in oncological and antimicrobial applications. Front Bioeng Biotechnol 2022; 10:958669. [PMID: 36312547 PMCID: PMC9607958 DOI: 10.3389/fbioe.2022.958669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/26/2022] [Indexed: 11/18/2022] Open
Abstract
Perinatal derivatives or PnDs refer to tissues, cells and secretomes from perinatal, or birth-associated tissues. In the past 2 decades PnDs have been highly investigated for their multimodal mechanisms of action that have been exploited in various disease settings, including in different cancers and infections. Indeed, there is growing evidence that PnDs possess anticancer and antimicrobial activities, but an urgent issue that needs to be addressed is the reproducible evaluation of efficacy, both in vitro and in vivo. Herein we present the most commonly used functional assays for the assessment of antitumor and antimicrobial properties of PnDs, and we discuss their advantages and disadvantages in assessing the functionality. This review is part of a quadrinomial series on functional assays for the validation of PnDs spanning biological functions such as immunomodulation, anticancer and antimicrobial, wound healing, and regeneration.
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Affiliation(s)
- Antonietta R. Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Taja Železnik Ramuta
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana, Ljubljana, Slovenia
| | - Ana Salomé Pires
- Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, University of Coimbra, Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
| | - Asmita Banerjee
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Marie Dubus
- Université de Reims Champagne Ardenne, EA 4691 Biomatériaux et Inflammation en Site Osseux (BIOS), Reims, France
| | - Florelle Gindraux
- Service de Chirurgie Orthopédique, Traumatologique et Plastique, CHU Besançon and Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, Université Bourgogne Franche-Comté, Besançon, France
| | - Halima Kerdjoudj
- Université de Reims Champagne Ardenne, EA 4691 Biomatériaux et Inflammation en Site Osseux (BIOS), Reims, France
| | - Justinas Maciulatis
- The Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Adelheid Weidinger
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Günther Eissner
- Systems Biology Ireland, UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Michela Pozzobon
- Stem Cells and Regenerative Medicine Lab, Department of Women’s and Children’s Health, University of Padova, Fondazione Istituto di Ricerca Pediatrica Città Della Speranza, Padoa, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica Del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
| | - Mateja Erdani Kreft
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana, Ljubljana, Slovenia
- *Correspondence: Mateja Erdani Kreft,
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19
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Teixo R, Pires AS, Pereira E, Serambeque B, Marques IA, Laranjo M, Mojsilović S, Gramignoli R, Ponsaerts P, Schoeberlein A, Botelho MF. Application of Perinatal Derivatives on Oncological Preclinical Models: A Review of Animal Studies. Int J Mol Sci 2022; 23:8570. [PMID: 35955703 PMCID: PMC9369310 DOI: 10.3390/ijms23158570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 07/21/2022] [Accepted: 07/28/2022] [Indexed: 11/16/2022] Open
Abstract
The increasing cancer incidence has certified oncological management as one of the most critical challenges for the coming decades. New anticancer strategies are still needed, despite the significant advances brought to the forefront in the last decades. The most recent, promising therapeutic approaches have benefitted from the application of human perinatal derivatives (PnD), biological mediators with proven benefits in several fields beyond oncology. To elucidate preclinical results and clinic outcomes achieved in the oncological field, we present a narrative review of the studies resorting to animal models to assess specific outcomes of PnD products. Recent preclinical evidence points to promising anticancer effects offered by PnD mediators isolated from the placenta, amniotic membrane, amniotic fluid, and umbilical cord. Described effects include tumorigenesis prevention, uncontrolled growth or regrowth inhibition, tumor homing ability, and adequate cell-based delivery capacity. Furthermore, PnD treatments have been described as supportive of chemotherapy and radiological therapies, particularly when resistance has been reported. However, opposite effects of PnD products have also been observed, offering support and trophic effect to malignant cells. Such paradoxical and dichotomous roles need to be intensively investigated. Current hypotheses identify as explanatory some critical factors, such as the type of the PnD biological products used or the manufacturing procedure to prepare the tissue/cellular treatment, the experimental design (including human-relevant animal models), and intrinsic pathophysiological characteristics. The effective and safe translation of PnD treatments to clinical practice relies on the collaborative efforts of all researchers working with human-relevant oncological preclinical models. However, it requires proper guidelines and consensus compiled by experts and health workers who accurately describe the methodology of tissue collection, PnD isolation, manufacturing, preservation, and delivery to the final user.
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Affiliation(s)
- Ricardo Teixo
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (R.T.); (E.P.); (B.S.); (I.A.M.); (M.L.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
| | - Ana Salomé Pires
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (R.T.); (E.P.); (B.S.); (I.A.M.); (M.L.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
| | - Eurico Pereira
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (R.T.); (E.P.); (B.S.); (I.A.M.); (M.L.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
| | - Beatriz Serambeque
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (R.T.); (E.P.); (B.S.); (I.A.M.); (M.L.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
| | - Inês Alexandra Marques
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (R.T.); (E.P.); (B.S.); (I.A.M.); (M.L.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Mafalda Laranjo
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (R.T.); (E.P.); (B.S.); (I.A.M.); (M.L.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
| | - Slavko Mojsilović
- Group for Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, 11129 Belgrade, Serbia;
| | - Roberto Gramignoli
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden;
- Department of Pathology, Medicinsk Cancer Diagnostik, Karolinska University Hospital, 171 64 Huddinge, Sweden
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, 2610 Antwerp, Belgium;
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-Maternal Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland;
- Department for BioMedical Research (DBMR), University of Bern, 3012 Bern, Switzerland
| | - Maria Filomena Botelho
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (R.T.); (E.P.); (B.S.); (I.A.M.); (M.L.); (M.F.B.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3000-548 Coimbra, Portugal
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Awadalla A, Hussein AM, El-Far YM, El-Senduny FF, Barakat N, Hamam ET, Abdeen HM, El-Sherbiny M, Serria MS, Sarhan AA, Sena AM, Shokeir AA. Rapamycin Improves Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Renoprotective Effect against Cisplatin-Induced Acute Nephrotoxicity in Rats by Inhibiting the mTOR/AKT Signaling Pathway. Biomedicines 2022; 10:1295. [PMID: 35740317 PMCID: PMC9220220 DOI: 10.3390/biomedicines10061295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Because the poor survival of transplanted cells in a hostile microenvironment limits stem cell therapy, in the current study, we investigated the effect of rapamycin (Rapa)-preactivated autophagy on the survival and homing of transplanted adipose mesenchymal stem cells (ADMSCs) in a rat model of cisplatin (Cis)-induced nephrotoxicity, as well as the possible role of the mTOR/AKT signaling pathway. MATERIALS AND METHODS In vitro, ADMSCs isolated from rats were treated with 50 nmol/L rapamycin for 2 h, after which the cytoprotective and autophagy-inducing effects of Rapa were investigated. The cis-induced acute nephrotoxicity rat model was constructed in vivo. ADMSCs and Rapa-ADMSCs were administered into the tail vein before Cis therapy. At 3, 7, and 10 days after Cis injection, all animals were euthanized. The renal functions and morphology as well as autophagy response were assessed. RESULTS The pretreatment of cultured ADMSCs with Rapa caused a significant increase in autophagic activities and lysosome production of the cells, with a significant increase in the secretion of SDF-1, IL-10 and autophagy promoter LC3 and Beclin from these cells, while mTOR/AKT pathways were inhibited. In addition, the transplantation of Rapa-pretreated ADMSCs restored the kidney functions and morphology dramatically. Renal expression of SDF-1 and HIF1 was upregulated, while expression of IL-6, NF-kB and TGF-β1 was downregulated. CONCLUSIONS We concluded that the preactivation of autophagy with Rapa improves the survival and differentiation of the transplanted ADMSCs by inhibiting the mTOR/AKT signaling pathway, which in turn could significantly attenuate the Cis-induced acute renal injury.
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Affiliation(s)
- Amira Awadalla
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Abdelaziz M. Hussein
- Medical Physiology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Yousra M. El-Far
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
| | - Fardous F. El-Senduny
- Biochemistry Division, Chemistry Department, Faculty of Sciences, Mansoura University, Mansoura 35516, Egypt;
| | - Nashwa Barakat
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Eman T. Hamam
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Hanaa M. Abdeen
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; (H.M.A.); (M.S.S.)
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh 13713, Saudi Arabia;
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed S. Serria
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; (H.M.A.); (M.S.S.)
| | - Amira A. Sarhan
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Asmaa M. Sena
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Ahmed A. Shokeir
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
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21
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Gilazieva Z, Ponomarev A, Rizvanov A, Solovyeva V. The Dual Role of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Carcinogenesis. BIOLOGY 2022; 11:biology11060813. [PMID: 35741334 PMCID: PMC9220333 DOI: 10.3390/biology11060813] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/07/2023]
Abstract
Simple Summary Extracellular vesicles (EVs) are membrane structures that play the role of intermediaries between tumor cells and the tumor microenvironment (TME) because they have the ability to transport lipids, transcription factors, mRNA, and proteins. Mesenchymal stem cells (MSCs) are a major component of the TME and may have different effects on tumor progression using EVs. This review includes information about various studies which have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. It provides an overview of the published data on EV MSCs and their effect on tumor cells. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described. Abstract Mesenchymal stem cells (MSCs) are a major component of the tumor microenvironment (TME) and play an important role in tumor progression. MSCs remodel the extracellular matrix, participate in the epithelial–mesenchymal transition, promote the spread of metastases, and inhibit antitumor immune responses in the TME; however, there are also data pertaining to the antitumor effects of MSCs. MSCs activate the cell death mechanism by modulating the expression of proteins involved in the regulation of the cell cycle, angiogenesis receptors, and proapoptotic proteins. One of the main ways in which MSCs and TME interact is through the production of extracellular vesicles (EVs) by cells. Currently, data on the effects of both MSCs and their EVs on tumor cells are rather contradictory. Various studies have reported that EVs from MSCs can have either antitumor or pro-tumor effects, depending on both the tumor type and developmental stage. In this review, we discuss published data on EV MSCs and their effect on tumor cells. The molecular composition of vesicles obtained from MSCs is also presented in the review. In addition, the use of EV MSCs for the development of new methods for treating oncological diseases is described.
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22
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Chen L, Wang L, Zhu L, Xu Z, Liu Y, Li Z, Zhou J, Luo F. Exosomes as Drug Carriers in Anti-Cancer Therapy. Front Cell Dev Biol 2022; 10:728616. [PMID: 35155421 PMCID: PMC8826094 DOI: 10.3389/fcell.2022.728616] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 01/04/2022] [Indexed: 12/18/2022] Open
Abstract
Over the years, there has been a high demand for developing new safe and effective drug carriers for cancer therapy. Emerging studies have indicated that exosomes can serve as potent therapeutic carriers since they offer low immunogenicity, high stability, innate and acquired targetability, and the stimulation of anti-cancer immune responses. Yet, the development of exosome-based drug delivery systems remains challenging due to their heterogeneity, low yield, and limited drug loading efficiency. Herein, we summarized the current application of exosomes derived from different cells as drug carriers in anti-cancer therapy in vitro and in vivo. We also discussed the challenges and prospects of exosome-based drug delivery systems in cancer therapy.
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Affiliation(s)
- Lan Chen
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Li Wang
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
- *Correspondence: Li Wang, ; Jin Zhou, ; Feng Luo,
| | - Lingling Zhu
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Zihan Xu
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Yanyang Liu
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Zhixi Li
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
| | - Jin Zhou
- School of Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
- *Correspondence: Li Wang, ; Jin Zhou, ; Feng Luo,
| | - Feng Luo
- Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China
- *Correspondence: Li Wang, ; Jin Zhou, ; Feng Luo,
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23
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Najar M, Melki R, Khalife F, Lagneaux L, Bouhtit F, Moussa Agha D, Fahmi H, Lewalle P, Fayyad-Kazan M, Merimi M. Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization. Front Cell Dev Biol 2022; 9:716853. [PMID: 35096805 PMCID: PMC8795900 DOI: 10.3389/fcell.2021.716853] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022] Open
Abstract
Cellular therapy aims to replace damaged resident cells by restoring cellular and molecular environments suitable for tissue repair and regeneration. Among several candidates, mesenchymal stem/stromal cells (MSCs) represent a critical component of stromal niches known to be involved in tissue homeostasis. In vitro, MSCs appear as fibroblast-like plastic adherent cells regardless of the tissue source. The therapeutic value of MSCs is being explored in several conditions, including immunological, inflammatory and degenerative diseases, as well as cancer. An improved understanding of their origin and function would facilitate their clinical use. The stemness of MSCs is still debated and requires further study. Several terms have been used to designate MSCs, although consensual nomenclature has yet to be determined. The presence of distinct markers may facilitate the identification and isolation of specific subpopulations of MSCs. Regarding their therapeutic properties, the mechanisms underlying their immune and trophic effects imply the secretion of various mediators rather than direct cellular contact. These mediators can be packaged in extracellular vesicles, thus paving the way to exploit therapeutic cell-free products derived from MSCs. Of importance, the function of MSCs and their secretome are significantly sensitive to their environment. Several features, such as culture conditions, delivery method, therapeutic dose and the immunobiology of MSCs, may influence their clinical outcomes. In this review, we will summarize recent findings related to MSC properties. We will also discuss the main preclinical and clinical challenges that may influence the therapeutic value of MSCs and discuss some optimization strategies.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Rahma Melki
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Ferial Khalife
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Fatima Bouhtit
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Douaa Moussa Agha
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Mohammad Fayyad-Kazan
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Hadath, Lebanon
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Lebanon
| | - Makram Merimi
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
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24
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Wang N, Pei B, Yuan X, Yi C, Wiredu Ocansey DK, Qian H, Mao F. Emerging roles of mesenchymal stem cell-derived exosomes in gastrointestinal cancers. Front Bioeng Biotechnol 2022; 10:1019459. [PMID: 36338118 PMCID: PMC9631450 DOI: 10.3389/fbioe.2022.1019459] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 10/10/2022] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal tumours are the most common solid tumours, with a poor prognosis and remain a major challenge in cancer treatment. Mesenchymal stem cells (MSC) are multipotent stromal cells with the potential to differentiate into multiple cell types. Several studies have shown that MSC-derived exosomes have become essential regulators of intercellular communication in a variety of physiological and pathological processes. Notably, MSC-derived exosomes support or inhibit tumour progression in different cancers through the delivery of proteins, RNA, DNA, and bioactive lipids. Herein, we summarise current advances in MSC-derived exosomes in cancer research, with particular reference to their role in gastrointestinal tumour development. MSC-derived exosomes are expected to be a novel potential strategy for the treatment of gastrointestinal cancers.
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Affiliation(s)
- Naijian Wang
- Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People’s Hospital of Nanjing Medical University, Suqian, Jiangsu, China
| | - Xinyi Yuan
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chengxue Yi
- School of Medical Technology, Zhenjiang College, Zhenjiang, Jiangsu, China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Hua Qian
- Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
- *Correspondence: Hua Qian,
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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Extracellular Vesicles in Musculoskeletal Regeneration: Modulating the Therapy of the Future. Cells 2021; 11:cells11010043. [PMID: 35011605 PMCID: PMC8750529 DOI: 10.3390/cells11010043] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022] Open
Abstract
Tissue regeneration is a hot topic in health sciences, particularly because effective therapies promoting the healing of several cell types are lacking, specifically those of the musculoskeletal system. Mesenchymal Stem/Stromal Cells (MSCs) have been identified as crucial players in bone homeostasis, and are considered a promising therapy for diseases such as osteoarthritis (OA) and Rheumatoid Arthritis (RA). However, some known drawbacks limit their use, particularly ethical issues and immunological rejections. Thus, MSCs byproducts, namely Extracellular Vesicles (EVs), are emerging as potential solutions to overcome some of the issues of the original cells. EVs can be modulated by either cellular preconditioning or vesicle engineering, and thus represent a plastic tool to be implemented in regenerative medicine. Further, the use of biomaterials is important to improve EV delivery and indirectly to modulate their content and secretion. This review aims to connect the dots among MSCs, EVs, and biomaterials, in the context of musculoskeletal diseases.
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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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Exosomes Derived from miR-146a-5p-Enriched Mesenchymal Stem Cells Protect the Cardiomyocytes and Myocardial Tissues in the Polymicrobial Sepsis through Regulating MYBL1. Stem Cells Int 2021; 2021:1530445. [PMID: 34691188 PMCID: PMC8536448 DOI: 10.1155/2021/1530445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 09/13/2021] [Indexed: 12/20/2022] Open
Abstract
Background At present, the study has confirmed that the mesenchymal stem cell-derived exosomes (MCSs-Exo) possess cardio-protection in sepsis. Nevertheless, the molecular mechanism of the protection of MSCs-Exo in sepsis remains unknown. Therefore, this research is aimed at studying the molecular mechanism. Methods The effects of MSCs-Exo and miR-146a-5p in LPS-induced cardiomyocytes (H9C2 cells) in vitro were verified by CCK-8, EdU assay, flow cytometry, Western blot assay, and RT-qPCR. The effect of MSCs-Exo in vivo was evaluated by CLP-induced sepsis model. The potential gene in MSCs-Exo was verified by bioinformatics analysis, and the potential target of miR-146a-5p was identified by bioinformatics analysis and luciferase reporter assay. At last, the function of miR-146a-5p and its target genes on LPS-induced cardiomyocytes (H9C2 cells) in vitro was validated by recuse experiment. Results Our findings revealed that MSCs-Exo could effectively protect cardiomyocytes of inflammation model in vitro and myocardial tissues of sepsis model in vivo. Meanwhile, we found that miR-146a-5p was a potential gene in MSCs-Exo, and MYBL1 was the target gene of miR-146a-5p and negatively regulated by miR-146a-5p. In addition, miR-146a-5p overexpression promoted proliferation and inhibited apoptosis of LPS-induced cardiomyocytes. The rescue experiment demonstrated that miR-146a-5p could effectively repress the inflammatory response of cardiomyocytes via decreasing MYBL1 expression. Conclusion This study suggests that miR-146a-5p-bearing MSC-derived exosomes may become an effective treatment for sepsis.
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Weng Z, Zhang B, Wu C, Yu F, Han B, Li B, Li L. Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer. J Hematol Oncol 2021; 14:136. [PMID: 34479611 PMCID: PMC8414028 DOI: 10.1186/s13045-021-01141-y] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/16/2021] [Indexed: 02/08/2023] Open
Abstract
Extracellular vesicles (EVs) are cell-derived membrane structures enclosing proteins, lipids, RNAs, metabolites, growth factors, and cytokines. EVs have emerged as essential intercellular communication regulators in multiple physiological and pathological processes. Previous studies revealed that mesenchymal stem cells (MSCs) could either support or suppress tumor progression in different cancers by paracrine signaling via MSC-derived EVs. Evidence suggested that MSC-derived EVs could mimic their parental cells, possessing pro-tumor and anti-tumor effects, and inherent tumor tropism. Therefore, MSC-derived EVs can be a cell-free cancer treatment alternative. This review discusses different insights regarding MSC-derived EVs' roles in cancer treatment and summarizes bioengineered MSC-derived EVs’ applications as safe and versatile anti-tumor agent delivery platforms. Meanwhile, current hurdles of moving MSC-derived EVs from bench to bedside are also discussed.
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Affiliation(s)
- Zhijie Weng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bowen Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Comfort Care Dental Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fanyuan Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Han
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Comfort Care Dental Center, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Longjiang Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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Panda B, Sharma Y, Gupta S, Mohanty S. Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine: A Comprehensive Review. Life (Basel) 2021; 11:life11080784. [PMID: 34440528 PMCID: PMC8399916 DOI: 10.3390/life11080784] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 01/08/2023] Open
Abstract
Mesenchymal Stem Cells are potent therapeutic candidates in the field of regenerative medicine, owing to their immunomodulatory and differentiation potential. However, several complications come with their translational application like viability, duration, and degree of expansion, long-term storage, and high maintenance cost. Therefore, drawbacks of cell-based therapy can be overcome by a novel therapeutic modality emerging in translational research and application, i.e., exosomes. These small vesicles derived from mesenchymal stem cells are emerging as new avenues in the field of nano-medicine. These nano-vesicles have caught the attention of researchers with their potency as regenerative medicine both in nanotherapeutics and drug delivery systems. In this review, we discuss the current knowledge in the biology and handling of exosomes, with their limitations and future applications. Additionally, we highlight current perspectives that primarily focus on their effect on various diseases and their potential as a drug delivery vehicle.
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Spelling Out CICs: A Multi-Organ Examination of the Contributions of Cancer Initiating Cells' Role in Tumor Progression. Stem Cell Rev Rep 2021; 18:228-240. [PMID: 34244971 DOI: 10.1007/s12015-021-10195-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2021] [Indexed: 12/15/2022]
Abstract
Tumor invasion and metastasis remain the leading causes of mortality for patients with cancer despite current treatment strategies. In some cancer types, recurrence is considered inevitable due to the lack of effective anti-metastatic therapies. Recent studies across many cancer types demonstrate a close relationship between cancer-initiating cells (CICs) and metastasis, as well as general cancer progression. First, this review describes CICs' contribution to cancer progression. Then we discuss our recent understanding of mechanisms through which CICs promote tumor invasion and metastasis by examining the role of CICs in each stage. Finally, we examine the current understanding of CICs' contribution to therapeutic resistance and recent developments in CIC-targeting drugs. We believe this understanding is key to advancing anti-CIC clinical therapeutics.
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Mesenchymal Stromal Cell-derived Extracellular Vesicles in Preclinical Animal Models of Tumor Growth: Systematic Review and Meta-analysis. Stem Cell Rev Rep 2021; 18:993-1006. [PMID: 33860455 DOI: 10.1007/s12015-021-10163-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) have been implicated in the regulation of tumor growth. Studies remain preclinical with effects ranging from inhibition of tumor growth to cancer progression. A systematic review and meta-analysis is needed to clarify the effect of MSC-EVs on tumor growth to facilitate potential translation to clinical trials. METHODS A systematic search of the literature (MEDLINE, Embase, and BIOSIS databases to June 1, 2019) identified all pre-clinical controlled studies investigating the effect of MSC-EVs on tumor growth. Study selection and data extraction were performed in duplicate. Potential risk of bias was assessed using the SYRCLE tool. A random effects meta-analysis of reduction in tumor weight/volume (primary outcome) was performed. RESULTS We identified 29 articles and 22 reported data on tumor responses that were included for meta-analysis. Studies were associated with unclear risk of bias in a large proportion of domains in accordance with the SYRCLE tool for determining risk of bias in preclinical studies. A high risk of bias was not identified in any study. MSC-EVs had a mixed response on tumor progression with some studies reporting inhibition of tumor growth and others reporting tumor progression. Overall, MSC-EVs exerted a non-significant reduction in tumor growth compared to controls (standardized mean difference (SMD) -0.80, 95 % CI -1.64 to 0.03, p = 0.06, I2 = 87 %). Some studies reported increased tumor growth which aligned with their stated hypothesis and some interrogated mechanisms in cancer biology. EVs isolated from MSCs that overexpressed anti-tumor RNAs were associated with significant tumor reduction in meta-analysis (SMD - 2.40, 95 % CI -3.36 to -1.44, p < 0.001). Heterogeneity between studies was observed and included aspects of study design such as enrichment of MSC-EVs with specific anti-tumor molecules, tissue source of MSCs, method of EV isolation, characterization of MSCs and EVs, dosage and administration schedules, and tissue type and source of tumor cells studied. CONCLUSIONS MSC-EVs are associated with mixed effects on tumor growth in animal models of cancer. In studies where anti-tumor RNAs are packaged in EVs, a significant reduction in tumor growth was observed. Reducing heterogeneity in study design may accelerate our understanding of the potential effects of MSC-EVs on cancer. [274 words] Forest plot of MSC-EV effect on tumor growth accordinggenetic modification of EVs in animal studies identified from a systematicreview of the literature. All cohorts from studies with multiple interventiongroups are presented separately with control groups divided equally among thegroups. M, modified; H, hypoxia.
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Zhuang WZ, Lin YH, Su LJ, Wu MS, Jeng HY, Chang HC, Huang YH, Ling TY. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci 2021; 28:28. [PMID: 33849537 PMCID: PMC8043779 DOI: 10.1186/s12929-021-00725-7] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.
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Affiliation(s)
- Wei-Zhan Zhuang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Yi-Heng Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 10041, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University Hospital Yunlin Branch, Yunlin, 64041, Taiwan
| | - Long-Jyun Su
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan
| | - Meng-Shiue Wu
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan
| | - Han-Yin Jeng
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Huan-Cheng Chang
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan.,Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106, Taiwan
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. .,Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. .,Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031, Taiwan. .,The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan. .,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan.
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González-González A, García-Sánchez D, Dotta M, Rodríguez-Rey JC, Pérez-Campo FM. Mesenchymal stem cells secretome: The cornerstone of cell-free regenerative medicine. World J Stem Cells 2020; 12:1529-1552. [PMID: 33505599 PMCID: PMC7789121 DOI: 10.4252/wjsc.v12.i12.1529] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/07/2020] [Accepted: 11/11/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues, their ability of homing to injury sites and their potential to differentiate into multiple cell types. However, the realization that the beneficial effect of MSCs relies mainly on their paracrine action, rather than on their engraftment in the recipient tissue and subsequent differentiation, has opened the way to cell-free therapeutic strategies in regenerative medicine. All the soluble factors and vesicles secreted by MSCs are commonly known as secretome. MSCs secretome has a key role in cell-to-cell communication and has been proven to be an active mediator of immune-modulation and regeneration both in vitro and in vivo. Moreover, the use of secretome has key advantages over cell-based therapies, such as a lower immunogenicity and easy production, handling and storage. Importantly, MSCs can be modulated to alter their secretome composition to better suit specific therapeutic goals, thus, opening a large number of possibilities. Altogether these advantages now place MSCs secretome at the center of an important number of investigations in different clinical contexts, enabling rapid scientific progress in this field.
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Affiliation(s)
- Alberto González-González
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Daniel García-Sánchez
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Monica Dotta
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - José C Rodríguez-Rey
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain.
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Szyposzynska A, Bielawska-Pohl A, Krawczenko A, Doszyn O, Paprocka M, Klimczak A. Suppression of Ovarian Cancer Cell Growth by AT-MSC Microvesicles. Int J Mol Sci 2020; 21:ijms21239143. [PMID: 33266317 PMCID: PMC7730946 DOI: 10.3390/ijms21239143] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 11/27/2020] [Indexed: 12/17/2022] Open
Abstract
Transport of bioactive cargo of microvesicles (MVs) into target cells can affect their fate and behavior and change their microenvironment. We assessed the effect of MVs derived from human immortalized mesenchymal stem cells of adipose tissue-origin (HATMSC2-MVs) on the biological activity of the ovarian cancer cell lines ES-2 (clear cell carcinoma) and OAW-42 (cystadenocarcinoma). The HATMSC2-MVs were characterized using dynamic light scattering (DLS), transmission electron microscopy, and flow cytometry. The anti-tumor properties of HATMSC2-MVs were assessed using MTT for metabolic activity and flow cytometry for cell survival, cell cycle progression, and phenotype. The secretion profile of ovarian cancer cells was evaluated with a protein antibody array. Both cell lines internalized HATMSC2-MVs, which was associated with a decreased metabolic activity of cancer cells. HATMSC2-MVs exerted a pro-apoptotic and/or necrotic effect on ES-2 and OAW-42 cells and increased the expression of anti-tumor factors in both cell lines compared to control. In conclusion, we confirmed an effective transfer of HATMSC2-MVs into ovarian cancer cells that resulted in the inhibition of cell proliferation via different pathways, apoptosis and/or necrosis, which, with high likelihood, is related to the presence of different anti-tumor factors secreted by the ES-2 and OAW-42 cells.
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Zinger A, Brozovich A, Pasto A, Sushnitha M, Martinez JO, Evangelopoulos M, Boada C, Tasciotti E, Taraballi F. Bioinspired Extracellular Vesicles: Lessons Learned From Nature for Biomedicine and Bioengineering. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E2172. [PMID: 33143238 PMCID: PMC7693812 DOI: 10.3390/nano10112172] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/23/2020] [Accepted: 10/23/2020] [Indexed: 12/14/2022]
Abstract
Efficient communication is essential in all layers of the biological chain. Cells exchange information using a variety of signaling moieties, such as small molecules, proteins, and nucleic acids. Cells carefully package these messages into lipid complexes, collectively named extracellular vesicles (EVs). In this work, we discuss the nature of these cell carriers, categorize them by their origin, explore their role in the homeostasis of healthy tissues, and examine how they regulate the pathophysiology of several diseases. This review will also address the limitations of using EVs for clinical applications and discuss novel methods to engineer nanoparticles to mimic the structure, function, and features of EVs. Using lessons learned from nature and understanding how cells use EVs to communicate across distant sites, we can develop a better understanding of how to tailor the fundamental features of drug delivery carriers to encapsulate various cargos and target specific sites for biomedicine and bioengineering.
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Affiliation(s)
- Assaf Zinger
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ava Brozovich
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
- Texas A&M College of Medicine, Bryan, TX 77807, USA
| | - Anna Pasto
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, 20089 Rozzano, Italy
| | - Manuela Sushnitha
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Jonathan O. Martinez
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Michael Evangelopoulos
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Christian Boada
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ennio Tasciotti
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
- Biotechnology Program, San Raffaele University, Via di Val Cannuta, 247, 00166 Roma RM, Italy
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA; (A.B.); (A.P.); (M.S.); (J.O.M.); (M.E.); (C.B.); (E.T.)
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
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Tieu A, Lalu MM, Slobodian M, Gnyra C, Fergusson DA, Montroy J, Burger D, Stewart DJ, Allan DS. An Analysis of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Preclinical Use. ACS NANO 2020; 14:9728-9743. [PMID: 32697573 DOI: 10.1021/acsnano.0c01363] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can reduce inflammation, promote healing, and improve organ function, thereby providing a potential "cell-free" therapy. Prior to clinical translation, it is critical to synthesize existing evidence on preclinical methods and efficacy. To address these issues, we used gold standard systematic review methodology to consolidate information from all published animal studies investigating MSC-EVs as an intervention. A systematic search of MEDLINE and Embase identified 206 studies. Data were extracted in duplicate for methodology, experimental design, interventional traits, modifications, and outcomes. MSC-EVs were used to treat a variety of diseases and demonstrated benefits in 97% of studies. Adverse effects were reported in only three studies, two demonstrating tumor growth. A quarter of articles modified EVs to enhance efficacy, with 72% leading to markedly improved outcomes as compared to unmodified EVs. However, several key methodological concerns were evident. Only 60% of studies used nomenclature consistent with the size definitions of EVs. Ultracentrifugation (70%) and isolation kits (23%) were the most common isolation techniques with noted differences in yield and purity. EVs were inconsistently dosed by protein (68%) or particle concentration (16%). Two-thirds of studies administered xenogeneic EVs, suggesting immunocompatibility. Less than 25% of studies assessed EV biodistribution. Approaches for determining size, protein markers, and morphology were highly heterogeneous, with only 12 and 4 studies meeting the MISEV 2014 and 2018 recommendations, respectively. Knowledge gaps identified from this systematic review highlight important opportunities to improve preclinical design and methodology in the rapidly growing field of EV therapeutics.
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Affiliation(s)
- Alvin Tieu
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1
| | - Manoj M Lalu
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1
- Departments of Anesthesiology and Pain Medicine, University of Ottawa, The Ottawa Hospital, Ottawa, Canada, K1H 8L6
| | | | | | | | | | - Dylan Burger
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1
| | - Duncan J Stewart
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada, K1H 8L1
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Cheng YQ, Wang SB, Liu JH, Jin L, Liu Y, Li CY, Su YR, Liu YR, Sang X, Wan Q, Liu C, Yang L, Wang ZC. Modifying the tumour microenvironment and reverting tumour cells: New strategies for treating malignant tumours. Cell Prolif 2020; 53:e12865. [PMID: 32588948 PMCID: PMC7445401 DOI: 10.1111/cpr.12865] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/02/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023] Open
Abstract
The tumour microenvironment (TME) plays a pivotal role in tumour fate determination. The TME acts together with the genetic material of tumour cells to determine their initiation, metastasis and drug resistance. Stromal cells in the TME promote the growth and metastasis of tumour cells by secreting soluble molecules or exosomes. The abnormal microenvironment reduces immune surveillance and tumour killing. The TME causes low anti‐tumour drug penetration and reactivity and high drug resistance. Tumour angiogenesis and microenvironmental hypoxia limit the drug concentration within the TME and enhance the stemness of tumour cells. Therefore, modifying the TME to effectively attack tumour cells could represent a comprehensive and effective anti‐tumour strategy. Normal cells, such as stem cells and immune cells, can penetrate and disrupt the abnormal TME. Reconstruction of the TME with healthy cells is an exciting new direction for tumour treatment. We will elaborate on the mechanism of the TME to support tumours and the current cell therapies for targeting tumours and the TME—such as immune cell therapies, haematopoietic stem cell (HSC) transplantation therapies, mesenchymal stem cell (MSC) transfer and embryonic stem cell‐based microenvironment therapies—to provide novel ideas for producing breakthroughs in tumour therapy strategies.
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Affiliation(s)
- Ya Qi Cheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Shou Bi Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jia Hui Liu
- Affiliated Dongguan People's Hospital, Southern Medical University, Dongguan, China
| | - Lin Jin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ying Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chao Yang Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Ya Ru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yu Run Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xuan Sang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Qi Wan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chang Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Liu Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Zhi Chong Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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38
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Papait A, Stefani FR, Cargnoni A, Magatti M, Parolini O, Silini AR. The Multifaceted Roles of MSCs in the Tumor Microenvironment: Interactions With Immune Cells and Exploitation for Therapy. Front Cell Dev Biol 2020; 8:447. [PMID: 32637408 PMCID: PMC7317293 DOI: 10.3389/fcell.2020.00447] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/13/2020] [Indexed: 12/18/2022] Open
Abstract
The tumor microenvironment (TME) plays a critical role in tumorigenesis and is composed of different cellular components, including immune cells and mesenchymal stromal cells (MSCs). In this review, we will discuss MSCs in the TME setting and more specifically their interactions with immune cells and how they can both inhibit (immunosurveillance) and favor (immunoediting) tumor growth. We will also discuss how MSCs are used as a therapeutic strategy in cancer. Due to their unique immunomodulatory properties, MSCs isolated from perinatal tissues are intensely explored as therapeutic interventions in various inflammatory-based disorders with promising results. However, their therapeutic applications in cancer remain for the most part controversial and, importantly, the interactions between administered perinatal MSC and immune cells in the TME remain to be clearly defined.
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Affiliation(s)
- Andrea Papait
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | | | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Marta Magatti
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Largo A. Gemelli, Rome, Italy
| | - Antonietta Rosa Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
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39
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Branscome H, Paul S, Yin D, El-Hage N, Agbottah ET, Zadeh MA, Liotta LA, Kashanchi F. Use of Stem Cell Extracellular Vesicles as a "Holistic" Approach to CNS Repair. Front Cell Dev Biol 2020; 8:455. [PMID: 32587858 PMCID: PMC7298153 DOI: 10.3389/fcell.2020.00455] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 05/15/2020] [Indexed: 12/20/2022] Open
Abstract
Neurodegeneration is a hallmark of many diseases and disorders of the central nervous system (CNS). High levels of neuroinflammation are often associated with irreparable damage to CNS cells due to the dysregulation of signaling cascades that are unable to restore a homeostatic balance. Due to the inherent complexity of the CNS, development of CNS-related therapeutics has met limited success. While stem cell therapy has been evaluated in the context of CNS repair, the mechanisms responsible for their functional properties have not been clearly defined. In recent years, there has been growing interest in the use of stem cell extracellular vesicles (EVs) for the treatment of various CNS pathologies as these vesicles are believed to mediate many of the functional effects associated with their donor stem cells. The potency of stem cell EVs is believed to be largely driven by their biological cargo which includes various types of RNAs, proteins, and cytokines. In this review, we describe the characteristic properties of stem cell EVs and summarize their reported neuroprotective and immunomodulatory functions. A special emphasis is placed on the identification of specific biological cargo, including proteins and non-coding RNA molecules, that have been found to be associated with stem cell EVs. Collectively, this review highlights the potential of stem cell EVs as an alternative to traditional stem cell therapy for the repair of cellular damage associated with diverse CNS pathologies.
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Affiliation(s)
- Heather Branscome
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
- American Type Culture Collection (ATCC), Manassas, VA, United States
| | - Siddhartha Paul
- American Type Culture Collection (ATCC) Cell Systems, Gaithersburg, MD, United States
| | - Dezhong Yin
- American Type Culture Collection (ATCC) Cell Systems, Gaithersburg, MD, United States
| | - Nazira El-Hage
- Department of Immunology and Nano-Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, United States
| | - Emmanuel T. Agbottah
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| | - Mohammad Asad Zadeh
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
| | - Lance A. Liotta
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, United States
| | - Fatah Kashanchi
- Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA, United States
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40
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Parfejevs V, Sagini K, Buss A, Sobolevska K, Llorente A, Riekstina U, Abols A. Adult Stem Cell-Derived Extracellular Vesicles in Cancer Treatment: Opportunities and Challenges. Cells 2020; 9:cells9051171. [PMID: 32397238 PMCID: PMC7290929 DOI: 10.3390/cells9051171] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 12/16/2022] Open
Abstract
Adult stem cells (SCs) participate in tissue repair and homeostasis regulation. The relative ease of SC handling and their therapeutic effect has made of these cell popular candidates for cellular therapy. However, several problems interfere with their clinical application in cancer treatment, like safety issues, unpredictable pro-tumour effects, and tissue entrapment. Therefore cell-free therapies that exhibit SC properties are being investigated. It is now well known that adult SCs exhibit their therapeutic effect via paracrine mechanisms. In addition to secretory proteins, SCs also release extracellular vesicles (EV) that deliver their contents to the target cells. Cancer treatment is one of the most promising applications of SC-EVs. Moreover, SC-EVs could be modified to improve targeted drug delivery. The aim of the review is to summarise current knowledge of adult SC-EV application in cancer treatment and to emphasise future opportunities and challenges in cancer treatment.
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Affiliation(s)
- Vadims Parfejevs
- Faculty of Medicine, University of Latvia, House of Science, Jelgavas Str 3, LV-1004 Riga, Latvia; (V.P.); (U.R.)
| | - Krizia Sagini
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; (K.S.); (A.L.)
| | - Arturs Buss
- Latvian Biomedical Research and Study Centre, Ratsupites Str 1, k-1, LV-1067 Riga, Latvia; (A.B.); (K.S.)
| | - Kristine Sobolevska
- Latvian Biomedical Research and Study Centre, Ratsupites Str 1, k-1, LV-1067 Riga, Latvia; (A.B.); (K.S.)
| | - Alicia Llorente
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway; (K.S.); (A.L.)
| | - Una Riekstina
- Faculty of Medicine, University of Latvia, House of Science, Jelgavas Str 3, LV-1004 Riga, Latvia; (V.P.); (U.R.)
| | - Arturs Abols
- Latvian Biomedical Research and Study Centre, Ratsupites Str 1, k-1, LV-1067 Riga, Latvia; (A.B.); (K.S.)
- Correspondence:
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41
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Qin Z, Xu Q, Hu H, Yu L, Zeng S. Extracellular Vesicles in Renal Cell Carcinoma: Multifaceted Roles and Potential Applications Identified by Experimental and Computational Methods. Front Oncol 2020; 10:724. [PMID: 32457844 PMCID: PMC7221139 DOI: 10.3389/fonc.2020.00724] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/16/2020] [Indexed: 12/24/2022] Open
Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer. Increasingly evidences indicate that extracellular vesicles (EVs) orchestrate multiple processes in tumorigenesis, metastasis, immune evasion, and drug response of RCC. EVs are lipid membrane-bound vesicles in nanometer size and secreted by almost all cell types into the extracellular milieu. A myriad of bioactive molecules such as RNA, DNA, protein, and lipid are able to be delivered via EVs for the intercellular communication. Hence, the abundant content of EVs is appealing reservoir for biomarker identification through computational analysis and experimental validation. EVs with excellent biocompatibility and biodistribution are natural platforms that can be engineered to offer achievable drug delivery strategies for RCC therapies. Moreover, the multifaceted roles of EVs in RCC progression also provide substantial targets and facilitate EVs-based drug discovery, which will be accelerated by using artificial intelligence approaches. In this review, we summarized the vital roles of EVs in occurrence, metastasis, immune evasion, and drug resistance of RCC. Furthermore, we also recapitulated and prospected the EVs-based potential applications in RCC, including biomarker identification, drug vehicle development as well as drug target discovery.
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Affiliation(s)
| | | | | | | | - Su Zeng
- College of Pharmaceutical Sciences, Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang University, Hangzhou, China
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42
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Brossa A, Fonsato V, Grange C, Tritta S, Tapparo M, Calvetti R, Cedrino M, Fallo S, Gontero P, Camussi G, Bussolati B. Extracellular vesicles from human liver stem cells inhibit renal cancer stem cell-derived tumor growth in vitro and in vivo. Int J Cancer 2020; 147:1694-1706. [PMID: 32064610 PMCID: PMC7496472 DOI: 10.1002/ijc.32925] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 01/28/2020] [Accepted: 02/04/2020] [Indexed: 12/16/2022]
Abstract
Cancer stem cells (CSCs) are considered as responsible for initiation, maintenance and recurrence of solid tumors, thus representing the key for tumor eradication. The antitumor activity of extracellular vesicles (EVs) derived from different stem cell sources has been investigated with conflicting results. In our study, we evaluated, both in vitro and in vivo, the effect of EVs derived from human bone marrow mesenchymal stromal cells (MSCs) and from a population of human liver stem cells (HLSCs) of mesenchymal origin on renal CSCs. In vitro, both EV sources displayed pro‐apoptotic, anti‐proliferative and anti‐invasive effects on renal CSCs, but not on differentiated tumor cells. Pre‐treatment of renal CSCs with EVs, before subcutaneous injection in SCID mice, delayed tumor onset. We subsequently investigated the in vivo effect of MSC‐ and HLSC‐EVs systemic administration on progression of CSC‐generated renal tumors. Tumor bio‐distribution analysis identified intravenous treatment as best route of administration. HLSC‐EVs, but not MSC‐EVs, significantly impaired subcutaneous tumor growth by reducing tumor vascularization and inducing tumor cell apoptosis. Moreover, intravenous treatment with HLSC‐EVs improved metastasis‐free survival. In EV treated tumor explants, we observed both the transfer and the induction of miR‐145 and of miR‐200 family members. In transfected CSCs, the same miRNAs affected cell growth, invasion and survival. In conclusion, our results showed a specific antitumor effect of HLSC‐EVs on CSC‐derived renal tumors in vivo, possibly ascribed to the transfer and induction of specific antitumor miRNAs. Our study provides further evidence for a possible clinical application of stem cell‐EVs in tumor treatment. What's new? Stem cell‐derived extracellular vesicles (EVs) can reprogram target cells and promote tissue repair by transferring their cargo. However, the anti‐tumor activity of EVs derived from different stem cell sources has been investigated with conflicting results. Here, the authors demonstrate for the first time the anti‐tumor effect of EVs from human liver stem cells (HLSC‐EVs) in a systemic intravenous administration model. HLSC‐EVs had a selective effect on cancer stem cells that could be ascribed to the transfer and induction of anti‐tumor miRNAs. This study highlights the potential clinical use of stem cell‐derived EVs, alone or in combination with other cancer therapies.
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Affiliation(s)
- Alessia Brossa
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.,Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Valentina Fonsato
- Molecular Biotechnology Center, University of Torino, Torino, Italy.,2i3T, Società per la Gestione dell'incubatore di Imprese e per il Trasferimento Tecnologico, University of Torino, Torino, Italy
| | - Cristina Grange
- Department of Medical Science, University of Torino, Torino, Italy
| | - Stefania Tritta
- Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Marta Tapparo
- Department of Medical Science, University of Torino, Torino, Italy
| | - Ruggero Calvetti
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Massimo Cedrino
- Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Sofia Fallo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Paolo Gontero
- Department of Surgical Sciences, University of Torino, Torino, Italy
| | - Giovanni Camussi
- Department of Medical Science, University of Torino, Torino, Italy
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.,Molecular Biotechnology Center, University of Torino, Torino, Italy
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43
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Zhang ZY, Hou YP, Zou XY, Xing XY, Ju GQ, Zhong L, Sun J. Oct-4 Enhanced the Therapeutic Effects of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Acute Kidney Injury. Kidney Blood Press Res 2020; 45:95-108. [PMID: 31927554 DOI: 10.1159/000504368] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 10/24/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Acute kidney injury (AKI) is a common clinical condition that can lead to chronic kidney failure. Although mesenchymal stem cell-derived extracellular vesicles (MSC EVs) are regarded as a potent AKI treatment, the mechanisms underlying their beneficial effects remain unclear. Oct-4 may play an important role in tissue injury repair. We thus hypothesized that oct-4 overexpression might enhance the therapeutic effects of MSC EVs in AKI treatment. METHODS Renal tubular epithelial cells were cultured in a low oxygen environment, then cocultured with MSC EVs or control medium for 48 h. BrdU and transferase-mediated dUTP nick-end labeling (TUNEL) staining were used to assess cell proliferation and apoptosis. Mice subjected to ischemia reperfusion were randomly divided into 4 groups, then injected with either phosphate-buffered saline (vehicle), EVs, EVs overexpressing oct-4 (EVs+Oct-4), and EVs not expressing Oct-4 (EVs-Oct-4). Blood creatinine (CREA) and urine nitrone levels were assessed 48 h and 2 weeks after injection. After ischemia reperfusion, renal tissues from each group were stained with TUNEL and proliferating cell nuclear antigen (PCNA) to determine the degree of apoptosis and proliferation. Masson trichrome staining was used to evaluate renal fibrosis progression. Snail gene expression was assessed using polymerase chain reaction (PCR). RESULTS At 48 h after hypoxic treatment, TUNEL and BrdU staining indicated that the EVs+Oct-4 group had the least apoptosis and the most proliferation, respectively. Treatment with EVs overexpressing Oct-4 significantly decreased serum Crea and blood urea nitrogen levels and rescued kidney fibrosis, as indicated by the low proportion of Masson staining, high number of PCNA-positive cells, and low number of TUNEL-positive cells. PCR analysis indicated that Snail was most upregulated in the vehicle group and least upregulated in the EVs+Oct-4 group. CONCLUSIONS MSC EVs had a pronounced therapeutic effect on ischemic reperfusion injury-related AKI, and Oct-4 overexpression enhanced these therapeutic effects. Our results may inspire a new direction for AKI treatment with MSC EVs.
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Affiliation(s)
- Zhi-Yuan Zhang
- Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan-Ping Hou
- Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiang-Yu Zou
- Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Yu Xing
- Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guan-Qun Ju
- Shanghai Changzheng Hospital, Shanghai, China
| | - Liang Zhong
- Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Sun
- Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China,
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44
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Abstract
Extracellular vesicles (EVs) have an essential functional role in local tumour progression, metastatic spread and the emergence of drug resistance in bladder, kidney and prostate cancer. Thus, EVs could be diagnostic, prognostic and predictive biomarkers for these malignancies. Virtually all biomolecules (including DNA, mRNA, microRNA, long non-coding RNA, proteins and lipids) packaged into EVs have been tested as biomarkers in blood and urine samples. The results are very heterogeneous, but promising biomarker candidates have been identified. Differing methods of EV isolation, characterization and analysis of their content have been used owing to a lack of international consensus; hence, comparing study results is challenging. Furthermore, validation of potential biomarkers in independent cohorts or prospective trials has rarely been performed. Future efforts to establish EV-derived biomarkers need to adequately address these points. In addition, emerging technologies such as mass spectroscopy and chip-based approaches can identify surface markers specific for cancer-associated EVs and will enable specific separation from blood and urine EVs, which probably will improve their performance as biomarkers. Moreover, EVs could be harnessed as therapeutic drug delivery vehicles for precise and effective anticancer therapy.
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45
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Wu Z, Zhang Z, Xia W, Cai J, Li Y, Wu S. Extracellular vesicles in urologic malignancies-Implementations for future cancer care. Cell Prolif 2019; 52:e12659. [PMID: 31469460 PMCID: PMC6869217 DOI: 10.1111/cpr.12659] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/20/2019] [Accepted: 05/23/2019] [Indexed: 12/20/2022] Open
Abstract
Extracellular vesicles (EVs), a heterogeneous group of vesicles differing in size and shape, cargo content and function, are membrane-bound and nano-sized vesicles that could be released by nearly all variations of cells. EVs have gained considerable attention in the past decades for their functions in modulating intercellular signalling and roles as potential pools for the novel diagnostic and prognostic biomarkers, as well as therapeutic targets in several cancers including urological neoplasms. In general, human and animal cells both can release distinct types of EVs, including exosomes, microvesicles, oncosomes and large oncosomes, and apoptotic bodies, while the content of EVs can be divided into proteins, lipids and nucleic acids. However, the lack of standard methods for isolation and detection platforms rein the widespread usage in clinical applications warranted furthermore investigations in the development of reliable, specific and sensitive isolation techniques. Whether and how the EVs work has become pertinent issues. With the aid of high-throughput proteomics or genomics methods, a fully understanding of contents contained in EVs from urogenital tumours, beyond all doubt, will improve our ability to identify the complex genomic alterations in the process of cancer and, in turn, contribute to detect potential therapeutic target and then provide personalization strategy for patient.
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Affiliation(s)
- Zhangsong Wu
- Medical CollegeShenzhen UniversityShenzhenChina
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
- Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
| | - Zhiqiang Zhang
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
- Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
| | - Wuchao Xia
- Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
- Medical CollegeAnhui University of Science and TechnologyHuainanChina
| | - Jiajia Cai
- Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
- Medical CollegeAnhui University of Science and TechnologyHuainanChina
| | - Yuqing Li
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
- Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
| | - Song Wu
- Medical CollegeShenzhen UniversityShenzhenChina
- Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
- Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen UniversityShenzhen UniversityShenzhenChina
- Medical CollegeAnhui University of Science and TechnologyHuainanChina
- Department of Urological Surgery, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouChina
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46
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Karaoz E, Sun E, Demir CS. Mesenchymal stem cell-derived exosomes do not promote the proliferation of cancer cells in vitro. INTERNATIONAL JOURNAL OF PHYSIOLOGY, PATHOPHYSIOLOGY AND PHARMACOLOGY 2019; 11:177-189. [PMID: 31523364 PMCID: PMC6737426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 08/09/2019] [Indexed: 06/10/2023]
Abstract
Nowadays, the use of Mesenchymal stem cells (MSCs) in clinical therapies have an increased acceleration, while it constitutes two sides of yin-yang with its ameliorating effects in regenerative medicine and promoting effects in carcinogenesis. It has been shown that the treatment activities of MSCs are mediated by paracrine factors secreted. These paracrine factors are transmitting via exosomes secreted from MSCs. With the understanding of this mechanism, cell-free therapies have begun to create a new path in MSC based therapies. At this point, two sides of the yin-yang have once again become controversial. In addition, there are conflicting study results in the literature. Due to this contradiction, we have designed this study to demonstrate the role of MSCs in the carcinogenesis process and we investigated the proliferation effect of MSC-derived exosomes on cancer cell lines. Two parallel experimental setups were established, as an experimental group, the four-different epithelial cancer cell lines and Wharton's Jelly (WJ)-MSC derived exosomes were directly co-cultured with in 6 different concentrations and simultaneously in the control group cells were cultured respectively. PKH-26 labelling was performed for detection of exosome locations in co-cultures. Each group were evaluated by WST-1 and xCelligence assays for proliferation and confirmed with PCNA staining. The results were analysed with paired t-test and Newman-Keuls comparison. The relative comparison demonstrated a significant increase in the rate of proliferation only in exosome co-cultures with WJ-MSCs and it was supported by PCNA staining. Cancer cell lines in co-cultures have not shown any significant increase neither in proliferation assays nor in PCNA staining. MSCs regulate their secretions according to the microenvironment, they have more dominant regenerative feature rather than triggering cancer proliferation.
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Affiliation(s)
- Erdal Karaoz
- Histology and Embriology Department, Faculty of Medicine, İstinye Universityİstanbul, Turkey
- Center for Stem Cell and Tissue Engineering Research & Pracitce, İstinye Universityİstanbul, Turkey
- Center for Regenerative Medicine and Stem Cell Research and Manufacturing, Liv Hospitalİstanbul, Turkey
| | - Eda Sun
- Histology and Embriology Department, Faculty of Medicine, İstinye Universityİstanbul, Turkey
- Center for Stem Cell and Tissue Engineering Research & Pracitce, İstinye Universityİstanbul, Turkey
| | - Cansu Subası Demir
- Center for Regenerative Medicine and Stem Cell Research and Manufacturing, Liv Hospitalİstanbul, Turkey
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47
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Allan D, Tieu A, Lalu M, Burger D. Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application. Stem Cells Transl Med 2019; 9:39-46. [PMID: 31411820 PMCID: PMC6954691 DOI: 10.1002/sctm.19-0114] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have emerged as a promising form of regenerative therapy and immune modulation. Fundamental advances in our understanding of MSCs and EVs have allowed these fields to merge and create potential cell-free therapy options that are cell-based. EVs contain active cargo including proteins, microRNA, and mRNA species that can impact signaling responses in target cells to modify inflammatory and repair responses. Increasing numbers of preclinical studies in animals with various types of injury models have been published that demonstrate the potential impact of MSC-EV therapy. Although the emergence of registered clinical protocols suggests translation to clinical application has already begun, several barriers to more widespread clinical adoption remain. In this review, we highlight the progress made in MSC-derived small EV-based therapy by summarizing aspects pertaining to the starting material for MSC expansion, EV production, and isolation methods, studies from preclinical models that have established a foundation of knowledge to support translation into the patient setting, and potential barriers to overcome on the path to clinical application.
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Affiliation(s)
- David Allan
- Hematology and Blood and Marrow Transplantation, The Ottawa Hospital, Ottawa, Ontario, Canada.,Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Alvin Tieu
- Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Manoj Lalu
- Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Dylan Burger
- Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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48
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Wang B, Wang Y, Yan Z, Sun Y, Su C. Colorectal cancer cell-derived exosomes promote proliferation and decrease apoptosis by activating the ERK pathway. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:2485-2495. [PMID: 31934075 PMCID: PMC6949542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Accepted: 05/23/2019] [Indexed: 06/10/2023]
Abstract
Exosomes are small microvesicles released by various cells that play important roles in cell-cell communication. Numerous studies show that colorectal cancer (CRC) cell-derived exosomes are involved in the progression of CRC. However, the specific ways and mechanisms of action have not yet been fully clarified. In the present study, we found that, compared to normal colon epithelial cell (NCM460) derived exosomes, CRC cell-Lovo derived exosomes (Lovo-exo) could be more easily taken up by Lovo cells, most likely because of their cell tropism. In addition, Lovo-exo promoted Lovo cell proliferation and inhibited apoptosis, which is associated with an increased activation of the extracellular signal-regulated protein kinase (ERK). Lovo-exo also dramatically increased Lovo tumor cell growth in vivo. Moreover, the intratumoral injection of GW4869 (an exosomes inhibitor) suppressed tumor growth. These results indicate that CRC cell Lovo-derived exosomes may be a messenger for the proliferation requirements of the originating cancer cells, and targeting tumor-derived exosomes may be very promising for tumor treatment.
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Affiliation(s)
- Baochen Wang
- Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical UniversityNanjing 211166, Jiangsu, P. R. China
- Department of General Surgery, Nanjing Tongren HospitalNanjing 211166, Jiangsu, P. R. China
| | - Yong Wang
- Department of General Surgery, First Affiliated Hospital of Nanjing Medical UniversityNanjing 211166, Jiangsu, P. R. China
| | - Zhanfu Yan
- Department of General Surgery, Nanjing Tongren HospitalNanjing 211166, Jiangsu, P. R. China
| | - Yueming Sun
- Department of General Surgery, First Affiliated Hospital of Nanjing Medical UniversityNanjing 211166, Jiangsu, P. R. China
| | - Chuan Su
- Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical UniversityNanjing 211166, Jiangsu, P. R. China
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Xie X, Wu H, Li M, Chen X, Xu X, Ni W, Lu C, Ni R, Bao B, Xiao M. Progress in the application of exosomes as therapeutic vectors in tumor-targeted therapy. Cytotherapy 2019; 21:509-524. [DOI: 10.1016/j.jcyt.2019.01.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 01/05/2019] [Accepted: 01/08/2019] [Indexed: 12/13/2022]
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50
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Regmi S, Pathak S, Kim JO, Yong CS, Jeong JH. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur J Cell Biol 2019; 98:151041. [PMID: 31023504 DOI: 10.1016/j.ejcb.2019.04.002] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/01/2019] [Accepted: 04/09/2019] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are promising alternative agents for the treatment of inflammatory disorders due to their immunomodulatory functions, and several clinical trials on MSC-based products are currently being conducted. In this review, we discuss recent progress made on the use of MSCs as immunomodulatory agents, developmental challenges posed by MSC-based therapy, and the strategies being used to overcome these challenges. In this context, current understanding of the mechanisms responsible for MSC interactions with the immune system and the molecular responses of MSCs to inflammatory signals are discussed. The immunosuppressive activities of MSCs are initiated by cell-to-cell contact and the release of immuno-regulatory molecules. By doing so, MSCs can inhibit the proliferation and function of T cells, natural killer cells, B cells, and dendritic cells, and can also increase the proliferation of regulatory T cells. However, various problems, such as low transplanted cell viability, poor homing and engraftment into injured tissues, MSC heterogeneity, and lack of adequate information on optimum MSC doses impede clinical applications. On the other hand, it has been shown that the immunomodulatory activities and viabilities of MSCs might be enhanced by 3D-cultured systems, genetic modifications, preconditioning, and targeted-delivery.
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Affiliation(s)
- Shobha Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Shiva Pathak
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
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