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Huang WC, Li YC, Chen PX, Ma KSK, Wang LT. Mesenchymal stem cell therapy as a game-changer in liver diseases: review of current clinical trials. Stem Cell Res Ther 2025; 16:3. [PMID: 39762946 PMCID: PMC11705688 DOI: 10.1186/s13287-024-04127-y] [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: 10/28/2024] [Accepted: 12/21/2024] [Indexed: 01/11/2025] Open
Abstract
Chronic liver diseases, including cirrhosis and liver failure, remain formidable challenges due to their complex progression and limited therapeutic options. Mesenchymal stem cell (MSC) therapy has emerged as a game-changing approach, leveraging its potent immunomodulatory, anti-fibrotic, and regenerative capabilities, along with the ability to transdifferentiate into hepatocytes. This review delves into the latest advances in MSC-based treatments for chronic and end-stage liver diseases, as highlighted in current clinical trials. MSCs derived from bone marrow and umbilical cord have shown remarkable promise in reversing liver damage, improving liver function, and providing hope for patients who do not respond to conventional therapies. When administered through hepatic, portal, or peripheral veins, MSCs have significantly improved liver histology, reduced fibrosis, and restored functional capacity. Furthermore, MSC-derived materials, such as extracellular vesicles and exosomes, are emerging as cutting-edge tools for treating liver failure and mitigating post-transplant complications. While autologous MSC-derived hepatocytes hold promise for non-fatal cirrhosis, allogeneic MSCs are being applied in more severe conditions, including liver failure and transplantation cases. Despite these promising early outcomes, larger trials and long-term studies are essential to fully harness MSCs as a transformative, off-the-shelf alternative to liver transplantation, heralding a new era in regenerative liver therapies.
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Affiliation(s)
- Wei-Chen Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Laboratory of Clinical Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Yuan-Chi Li
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Pin-Xuan Chen
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Kevin Sheng-Kai Ma
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Li-Tzu Wang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan.
- Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
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Ding JY, Meng TT, Du RL, Song XB, Li YX, Gao J, Ji R, He QY. Bibliometrics of trends in global research on the roles of stem cells in myocardial fibrosis therapy. World J Stem Cells 2024; 16:1086-1105. [PMID: 39734477 PMCID: PMC11669986 DOI: 10.4252/wjsc.v16.i12.1086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/05/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted. AIM To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy. METHODS We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends. RESULTS Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress. CONCLUSION This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.
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Affiliation(s)
- Jing-Yi Ding
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Tian-Tian Meng
- Department of Rehabilitation, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100071, China
| | - Ruo-Lin Du
- Department of Emergency Medicine, South Branch of Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xin-Bin Song
- Department of Intensive Care Unit, Zhumadian Hospital of Traditional Chinese Medicine, Zhumadian 463000, Henan Province, China
| | - Yi-Xiang Li
- Department of Chinese Medicine, The Third People's Hospital of Henan Province, Zhengzhou 450000 Henan Province, China
| | - Jing Gao
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ran Ji
- Department of Intensive Care Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Qing-Yong He
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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Yamada S, Yamada K, Sugawara-Narutaki A, Baba Y, Yukawa H. Near-infrared-II fluorescence/magnetic resonance double modal imaging of transplanted stem cells using lanthanide co-doped gadolinium oxide nanoparticles. ANAL SCI 2024; 40:1043-1050. [PMID: 38430367 DOI: 10.1007/s44211-024-00507-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 01/04/2024] [Indexed: 03/03/2024]
Abstract
To ensure maximum therapeutic safety and efficacy of stem cell transplantation, it is essential to observe the kinetics of behavior, accumulation, and engraftment of transplanted stem cells in vivo. However, it is difficult to detect transplanted stem cells with high sensitivity by conventional in vivo imaging technologies. To diagnose the kinetics of transplanted stem cells, we prepared multifunctional nanoparticles, Gd2O3 co-doped with Er3+ and Yb3+ (Gd2O3: Er, Yb-NPs), and developed an in vivo double modal imaging technique with near-infrared-II (NIR-II) fluorescence imaging and magnetic resonance imaging (MRI) of stem cells using Gd2O3: Er, Yb-NPs. Gd2O3: Er, Yb-NPs were transduced into adipose tissue-derived stem cells (ASCs) through a simple incubation process without cytotoxicity under certain concentrations of Gd2O3: Er, Yb-NPs and were found not to affect the morphology of ASCs. ASCs labeled with Gd2O3: Er, Yb-NPs were transplanted subcutaneously onto the backs of mice, and successfully imaged with good contrast using an in vivo NIR-II fluorescence imaging and MRI system. These data suggest that Gd2O3: Er, Yb-NPs may be useful for in vivo double modal imaging with NIR-II fluorescence imaging and MRI of transplanted stem cells.
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Affiliation(s)
- Shota Yamada
- Department of Energy Engineering, Graduate School of Engineering, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan.
| | - Kaori Yamada
- Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan
| | - Ayae Sugawara-Narutaki
- Department of Energy Engineering, Graduate School of Engineering, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan
| | - Yoshinobu Baba
- Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan
- Institute for Quantum Life Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, Anagawa 4-9-1, Inage-Ku, Chiba, 263-8555, Japan
- Department of Medical-Engineering Collaboration Supported by SEI Group CSR Foundation, Nagoya University, Tsurumai 65, Showa-Ku, Nagoya, 466-8550, Japan
| | - Hiroshi Yukawa
- Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan.
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan.
- Institute for Quantum Life Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, Anagawa 4-9-1, Inage-Ku, Chiba, 263-8555, Japan.
- Department of Medical-Engineering Collaboration Supported by SEI Group CSR Foundation, Nagoya University, Tsurumai 65, Showa-Ku, Nagoya, 466-8550, Japan.
- B-3Frontier, Advanced Analytical and Diagnostic Imaging Center (AADIC)/Medical Engineering Unit (MEU), Institute for Advanced Research, Nagoya University, Tsurumai 65, Showa-Ku, Nagoya, 466-8550, Japan.
- Department of Quantum Life Science, Graduate School of Science, Chiba University, Chiba, Japan.
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Che Shaffi S, Hairuddin ON, Mansor SF, Syafiq TMF, Yahaya BH. Unlocking the Potential of Extracellular Vesicles as the Next Generation Therapy: Challenges and Opportunities. Tissue Eng Regen Med 2024; 21:513-527. [PMID: 38598059 PMCID: PMC11087396 DOI: 10.1007/s13770-024-00634-4] [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: 11/14/2022] [Revised: 08/25/2023] [Accepted: 08/25/2023] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have undergone extensive investigation for their potential therapeutic applications, primarily attributed to their paracrine activity. Recently, researchers have been exploring the therapeutic potential of extracellular vesicles (EVs) released by MSCs. METHODS MEDLINE/PubMed and Google scholar databases were used for the selection of literature. The keywords used were mesenchymal stem cells, extracellular vesicles, clinical application of EVs and challenges EVs production. RESULTS These EVs have demonstrated robust capabilities in transporting intracellular cargo, playing a critical role in facilitating cell-to-cell communication by carrying functional molecules, including proteins, RNA species, DNAs, and lipids. Utilizing EVs as an alternative to stem cells offers several benefits, such as improved safety, reduced immunogenicity, and the ability to traverse biological barriers. Consequently, EVs have emerged as an increasingly attractive option for clinical use. CONCLUSION From this perspective, this review delves into the advantages and challenges associated with employing MSC-EVs in clinical settings, with a specific focus on their potential in treating conditions like lung diseases, cancer, and autoimmune disorders.
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Affiliation(s)
- Syahidatulamali Che Shaffi
- Lung Stem Cell and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
| | - Omar Nafiis Hairuddin
- Lung Stem Cell and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
| | - Siti Farizan Mansor
- Lung Stem Cell and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia
- Faculty of Health Sciences, Universiti Teknologi MARA, Cawangan Pulau Pinang, Kampus Bertam, 13200, Kepala Batas, Penang, Malaysia
| | - Tengku Muhamad Faris Syafiq
- IIUM Molecular and Cellular Biology Research, Department of Basic Medical Sciences, Kulliyyah of Nursing, International Islamic University Malaysia, 25100, Kuantan, Pahang, Malaysia
| | - Badrul Hisham Yahaya
- Lung Stem Cell and Gene Therapy Group, Department of Biomedical Sciences, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200, Kepala Batas, Penang, Malaysia.
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Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: Part 2-Emerging leaders in regenerative medicine. Periodontol 2000 2024; 94:257-414. [PMID: 38591622 DOI: 10.1111/prd.12561] [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: 02/04/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.
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Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Nathan E Estrin
- Advanced PRF Education, Venice, Florida, USA
- School of Dental Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
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Mahmoodi M, Cheraghi E, Riahi A. The Effect of Wharton's Jelly-Derived Conditioned Medium on the In Vitro Maturation of Immature Oocytes, Embryo Development, and Genes Expression Involved in Apoptosis. Reprod Sci 2024; 31:190-198. [PMID: 37697205 DOI: 10.1007/s43032-023-01345-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/30/2023] [Indexed: 09/13/2023]
Abstract
Oocyte cytoplasmic maturation is a crucial process during in vitro maturation (IVM), and finding an appropriate IVM medium that promotes oocyte competence is very critical in assisted reproductive technology (ART). The aim of this study was to investigate the effects of umbilical cord Wharton's jelly (WJ-MSCs)-derived conditioned media on the maturation of immature oocytes and their developmental potential in humans after IVM, as well as apoptotic gene expression. A total of 392 germinal vesicle (GV) oocytes were collected from 207 women aged 25-35 years and divided into two IVM groups: (1) control group, which was cultured in CleavTM medium, and (2) experimental group, which was cultured in supernatants of umbilical cord Wharton's jelly as a conditioned medium (CM). First, WJ-MSCs were isolated, and their purity was analyzed. The immunophenotypes of WJ-MSCs were analyzed by flow cytometry. The quantitative expression of BCL2, BAX, and BAG1 in matured oocytes and embryos was evaluated through quantitative real-time polymerase chain reaction (qRT-PCR). Our findings showed that WJ-MSCs have a high proliferating capacity. The purity of the isolated cells was further validated by immunophenotyping, which revealed that their surface antigen expression had phenotypical properties similar to WJ-MSCs. When compared to CD34 and CD45 surface markers, the enlarged cells were positive for CD90, CD105, and CD44. There were significant differences in cytoplasmic maturation of oocytes and embryo quality between the two groups. The mRNA expression levels of BCL-2, BAG1, and BAX in matured oocytes and embryos were also significantly different between the two groups. Therefore, WJ-MSCs medium indicated potential efficacy in terms of ameliorating oocyte maturation and in promoting the development and genes expression of BAX, BCL-2, and BAG1.
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Affiliation(s)
- Monireh Mahmoodi
- Department of Biology, Faculty of Sciences, Arak University, Arak, Iran.
| | - Ebrahim Cheraghi
- Department of Biology, Faculty of Sciences, University of Qom, Qom, Iran
| | - Alireza Riahi
- Department of Biology, Faculty of Sciences, Arak University, Arak, Iran
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Hazrati A, Malekpour K, Mirsanei Z, Khosrojerdi A, Rahmani-Kukia N, Heidari N, Abbasi A, Soudi S. Cancer-associated mesenchymal stem/stromal cells: role in progression and potential targets for therapeutic approaches. Front Immunol 2023; 14:1280601. [PMID: 38022534 PMCID: PMC10655012 DOI: 10.3389/fimmu.2023.1280601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Mirsanei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Nasim Rahmani-Kukia
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Saltzman RG, G Campbell K, J Ripps S, Golan R, Cabreja-Castillo MA, Garzon AM, Rahman F, Caceres LV, Tovar JA, Khan A, Hare JM, Ramasamy R. The impact of cell-based therapy on female sexual dysfunction: a systematic review and meta-analysis. Sex Med Rev 2023; 11:333-341. [PMID: 37279578 PMCID: PMC12017765 DOI: 10.1093/sxmrev/qead023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/04/2023] [Accepted: 05/07/2023] [Indexed: 06/08/2023]
Abstract
INTRODUCTION Female sexual dysfunction (FSD) is a complex issue affecting women of all ages; it involves several overlapping body systems and profoundly affects quality of life. The use of cell-based therapy, such as mesenchymal stem cells, has recently been investigated as a potential treatment for FSD. OBJECTIVES This systematic review and meta-analysis aim to assess FSD outcomes following cell-based therapy. METHODS We evaluated peer-reviewed articles from multiple online databases through November 2022 to identify studies that used cell-based therapy and reported sexual function outcomes in women. We performed a meta-analysis using data pooled from 3 clinical trials at our institution: CRATUS (NCT02065245), ACESO (NCT02886884), and CERES (NCT03059355). All 3 trials collected data from the Sexual Quality of Life-Female (SQOL-F) questionnaire as an exploratory outcome. RESULTS Existing literature on this topic is scarce. Five clinical studies and 1 animal study were included in the systematic review, and only 2 clinical studies were considered good quality: 1 reported significant SQOL-F improvement in women 6 months after cell therapy, and 1 reported posttherapy sexual satisfaction in all women. When individual patient data were pooled in a meta-analysis from 29 women across 3 trials at our institution, the SQOL-F was not significantly improved. CONCLUSION Despite growing interest in cell-based therapy for women's sexual health, this important issue is understudied in the literature. The optimal route, source, and dose of cell therapy to produce clinically meaningful change have yet to be determined, and further research is needed in larger randomized placebo-controlled clinical trials.
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Affiliation(s)
- Russell G Saltzman
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Katherine G Campbell
- Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Sarah J Ripps
- College of Medicine, Florida State University, Tallahassee, FL 32304, United States
| | - Roei Golan
- College of Medicine, Florida State University, Tallahassee, FL 32304, United States
| | - Maria A Cabreja-Castillo
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Ana Maria Garzon
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Farah Rahman
- Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Lina V Caceres
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Jairo A Tovar
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Aisha Khan
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
- Division of Cardiovascular Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, 33136. United States
| | - Ranjith Ramasamy
- Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
- Desai Sethi Urology Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
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Wang YH, Chen EQ. Mesenchymal Stem Cell Therapy in Acute Liver Failure. Gut Liver 2023; 17:674-683. [PMID: 36843422 PMCID: PMC10502502 DOI: 10.5009/gnl220417] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 02/28/2023] Open
Abstract
Acute liver failure (ALF) is a severe liver disease syndrome with rapid deterioration and high mortality. Liver transplantation is the most effective treatment, but the lack of donor livers and the high cost of transplantation limit its broad application. In recent years, there has been no breakthrough in the treatment of ALF, and the application of stem cells in the treatment of ALF is a crucial research field. Mesenchymal stem cells (MSCs) are widely used in disease treatment research due to their abundant sources, low immunogenicity, and no ethical restrictions. Although MSCs are effective for treating ALF, the application of MSCs to ALF needs to be further studied and optimized. In this review, we discuss the potential mechanisms of MSCs therapy for ALF, summarize some methods to enhance the efficacy of MSCs, and explore optimal approaches for MSC transplantation.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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10
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Khan S, Mahgoub S, Fallatah N, Lalor PF, Newsome PN. Liver Disease and Cell Therapy: Advances Made and Remaining Challenges. Stem Cells 2023; 41:739-761. [PMID: 37052348 PMCID: PMC10809282 DOI: 10.1093/stmcls/sxad029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 02/27/2023] [Indexed: 04/14/2023]
Abstract
The limited availability of organs for liver transplantation, the ultimate curative treatment for end stage liver disease, has resulted in a growing and unmet need for alternative therapies. Mesenchymal stromal cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties have therefore emerged as a promising therapeutic agent in treating inflammatory liver disease. Significant strides have been made in exploring their biological activity. Clinical application of MSC has shifted the paradigm from using their regenerative potential to one which harnesses their immunomodulatory properties. Reassuringly, MSCs have been extensively investigated for over 30 years with encouraging efficacy and safety data from translational and early phase clinical studies, but questions remain about their utility. Therefore, in this review, we examine the translational and clinical studies using MSCs in various liver diseases and their impact on dampening immune-mediated liver damage. Our key observations include progress made thus far with use of MSCs for clinical use, inconsistency in the literature to allow meaningful comparison between different studies and need for standardized protocols for MSC manufacture and administration. In addition, the emerging role of MSC-derived extracellular vesicles as an alternative to MSC has been reviewed. We have also highlighted some of the remaining clinical challenges that should be addressed before MSC can progress to be considered as therapy for patients with liver disease.
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Affiliation(s)
- Sheeba Khan
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Sara Mahgoub
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Nada Fallatah
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Patricia F Lalor
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
| | - Philip N Newsome
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
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11
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Sitbon A, Delmotte PR, Goumard C, Turco C, Gautheron J, Conti F, Aoudjehane L, Scatton O, Monsel A. Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review. Minerva Anestesiol 2023; 89:690-706. [PMID: 37079286 DOI: 10.23736/s0375-9393.23.17265-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Liver failure includes distinct subgroups of diseases: Acute liver failure (ALF) without preexisting cirrhosis, acute-on-chronic liver failure (ACLF) (severe form of cirrhosis associated with organ failures and excess mortality), and liver fibrosis (LF). Inflammation plays a key role in ALF, LF, and more specifically in ACLF for which we have currently no treatment other than liver transplantation (LT). The increasing incidence of marginal liver grafts and the shortage of liver grafts require us to consider strategies to increase the quantity and quality of available liver grafts. Mesenchymal stromal cells (MSCs) have shown beneficial pleiotropic properties with limited translational potential due to the pitfalls associated with their cellular nature. MSC-derived extracellular vesicles (MSC-EVs) are innovative cell-free therapeutics for immunomodulation and regenerative purposes. MSC-EVs encompass further advantages: pleiotropic effects, low immunogenicity, storage stability, good safety profile, and possibility of bioengineering. Currently, no human studies explored the impact of MSC-EVs on liver disease, but several preclinical studies highlighted their beneficial effects. In ALF and ACLF, data showed that MSC-EVs attenuate hepatic stellate cells activation, exert antioxidant, anti-inflammatory, anti-apoptosis, anti-ferroptosis properties, and promote regeneration of the liver, autophagy, and improve metabolism through mitochondrial function recovery. In LF, MSC-EVs demonstrated anti-fibrotic properties associated with liver tissue regeneration. Normothermic-machine perfusion (NMP) combined with MSC-EVs represents an attractive therapy to improve liver regeneration before LT. Our review suggests a growing interest in MSC-EVs in liver failure and gives an appealing insight into their development to rehabilitate marginal liver grafts through NMP.
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Affiliation(s)
- Alexandre Sitbon
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France -
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France -
| | - Pierre-Romain Delmotte
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Claire Goumard
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Célia Turco
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Liver Transplantation Unit, Department of Digestive and Oncologic Surgery, University Hospital of Besançon, Besançon, France
| | - Jérémie Gautheron
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
| | - Filomena Conti
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Lynda Aoudjehane
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Olivier Scatton
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- INSERM UMRS-959 Immunology-Immunopathology-Immunotherapy (I3), Sorbonne University, Paris, France
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12
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Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol 2023; 20:583-599. [PMID: 36823236 PMCID: PMC10229624 DOI: 10.1038/s41423-023-00983-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/29/2023] [Indexed: 02/25/2023] Open
Abstract
Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.
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Affiliation(s)
- Xue Yang
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Qing Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China.
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Zhipeng Han
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China.
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13
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Doshi A, Erickson P, Teryek M, Parekkadan B. Dynamics of Ex Vivo Mesenchymal Stromal Cell Potency under Continuous Perfusion. Int J Mol Sci 2023; 24:ijms24119602. [PMID: 37298556 DOI: 10.3390/ijms24119602] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a candidate for cell immunotherapy due to potent immunomodulatory activity found in their secretome. Though studies on their secreted substances have been reported, the time dynamics of MSC potency remain unclear. Herein, we report on the dynamics of MSC secretome potency in an ex vivo hollow fiber bioreactor using a continuous perfusion cell culture system that fractionated MSC-secreted factors over time. Time-resolved fractions of MSC-conditioned media were evaluated for potency by incubation with activated immune cells. Three studies were designed to characterize MSC potency under: (1) basal conditions, (2) in situ activation, and (3) pre-licensing. Results indicate that the MSC secretome is most potent in suppressing lymphocyte proliferation during the first 24 h and is further stabilized when MSCs are prelicensed with a cocktail of pro-inflammatory cytokines, IFNγ, TNFα, and IL-1β. The evaluation of temporal cell potency using this integrated bioreactor system can be useful in informing strategies to maximize MSC potency, minimize side effects, and allow greater control for the duration of ex vivo administration approaches.
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Affiliation(s)
- Aneesha Doshi
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA
| | - Patrick Erickson
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA
| | - Matthew Teryek
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA
| | - Biju Parekkadan
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA
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14
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Miceli V, Zito G, Bulati M, Gallo A, Busà R, Iannolo G, Conaldi PG. Different priming strategies improve distinct therapeutic capabilities of mesenchymal stromal/stem cells: Potential implications for their clinical use. World J Stem Cells 2023; 15:400-420. [PMID: 37342218 PMCID: PMC10277962 DOI: 10.4252/wjsc.v15.i5.400] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/07/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) have shown significant therapeutic potential, and have therefore been extensively investigated in preclinical studies of regenerative medicine. However, while MSCs have been shown to be safe as a cellular treatment, they have usually been therapeutically ineffective in human diseases. In fact, in many clinical trials it has been shown that MSCs have moderate or poor efficacy. This inefficacy appears to be ascribable primarily to the heterogeneity of MSCs. Recently, specific priming strategies have been used to improve the therapeutic properties of MSCs. In this review, we explore the literature on the principal priming approaches used to enhance the preclinical inefficacy of MSCs. We found that different priming strategies have been used to direct the therapeutic effects of MSCs toward specific pathological processes. Particularly, while hypoxic priming can be used primarily for the treatment of acute diseases, inflammatory cytokines can be used mainly to prime MSCs in order to treat chronic immune-related disorders. The shift in approach from regeneration to inflammation implies, in MSCs, a shift in the production of functional factors that stimulate regenerative or anti-inflammatory pathways. The opportunity to fine-tune the therapeutic properties of MSCs through different priming strategies could conceivably pave the way for optimizing their therapeutic potential.
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Affiliation(s)
- Vitale Miceli
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy.
| | - Giovanni Zito
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Matteo Bulati
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
| | - Pier Giulio Conaldi
- Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta Specializzazione), Palermo 90127, Italy
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15
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Ahn SY, Chang YS, Park WS. Stem cells for neonatal brain injury - Lessons from the bench. Semin Perinatol 2023; 47:151726. [PMID: 37003920 DOI: 10.1016/j.semperi.2023.151726] [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] [Indexed: 04/03/2023]
Abstract
Neonatal brain injury resulting from various intractable disorders including intraventricular hemorrhage and hypoxic ischemic encephalopathy still remains a major cause of mortality and morbidities with few effective treatments. Recent preclinical research results showing the pleiotropic neuroprotective effects of stem cell therapy, specifically mesenchymal stem cells (MSCs), suggest that MSCs transplantation might be a promising new therapeutic modality for neuroprotection against the currently intractable and devastating neonatal brain injury with complex multifactorial etiology. This review summarizes recent advances in preclinical stem cell research for treating neonatal brain injury with a focus on the important issues including the mechanism of neuroprotection, and determining the ideal cell source, route, timing and dose of MSCs transplantation.
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Affiliation(s)
- So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea
| | - Yun Sil Chang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAHIST), Samsung Medical Center, Seoul 06351, South Korea
| | - Won Soon Park
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAHIST), Samsung Medical Center, Seoul 06351, South Korea.
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16
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Garg A, Khan S, Luu N, Nicholas DJ, Day V, King AL, Fear J, Lalor PF, Newsome PN. TGFβ 1 priming enhances CXCR3-mediated mesenchymal stromal cell engraftment to the liver and enhances anti-inflammatory efficacy. J Cell Mol Med 2023; 27:864-878. [PMID: 36824012 PMCID: PMC10002976 DOI: 10.1111/jcmm.17698] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/07/2023] [Accepted: 02/11/2023] [Indexed: 02/25/2023] Open
Abstract
The immunomodulatory characteristics of mesenchymal stromal cells (MSC) confers them with potential therapeutic value in the treatment of inflammatory/immune-mediated conditions. Previous studies have reported only modest beneficial effects in murine models of liver injury. In our study we explored the role of MSC priming to enhance their effectiveness. Herein we demonstrate that stimulation of human MSC with cytokine TGβ1 enhances their homing and engraftment to human and murine hepatic sinusoidal endothelium in vivo and in vitro, which was mediated by increased expression of CXCR3. Alongside improved hepatic homing there was also greater reduction in liver inflammation and necrosis, with no adverse effects, in the CCL4 murine model of liver injury treated with primed MSC. Priming of MSCs with TGFβ1 is a novel strategy to improve the anti-inflammatory efficacy of MSCs.
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Affiliation(s)
- Abhilok Garg
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Sheeba Khan
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - N Luu
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Davies J Nicholas
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Victoria Day
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Andrew L King
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Janine Fear
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Patricia F Lalor
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Philip N Newsome
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK.,Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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17
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Xu Y, Wang J, Ren H, Dai H, Zhou Y, Ren X, Wang Y, Feng S, Deng X, Wu J, Fu T, Nie T, He H, Wei T, Zhu B, Hui L, Li B, Wang J, Wang H, Chen L, Shi X, Cheng X. Human endoderm stem cells reverse inflammation-related acute liver failure through cystatin SN-mediated inhibition of interferon signaling. Cell Res 2023; 33:147-164. [PMID: 36670290 PMCID: PMC9892047 DOI: 10.1038/s41422-022-00760-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 11/25/2022] [Indexed: 01/22/2023] Open
Abstract
Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.
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Affiliation(s)
- Yilin Xu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Jinglin Wang
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Hepatobiliary Institute Nanjing University, Nanjing, Jiangsu, China
| | - Haozhen Ren
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
- Hepatobiliary Institute Nanjing University, Nanjing, Jiangsu, China
| | - Hao Dai
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Institute of Brain-Intelligence Technology, Zhangjiang Laboratory, Shanghai, China
| | - Ying Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiongzhao Ren
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yang Wang
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Sisi Feng
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiaogang Deng
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Jiaying Wu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Tianlong Fu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Tengfei Nie
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Haifeng He
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Tongkun Wei
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Bing Zhu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Lijian Hui
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Bin Li
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Wang
- Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hongyan Wang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
| | - Luonan Chen
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
- Hepatobiliary Institute Nanjing University, Nanjing, Jiangsu, China.
| | - Xin Cheng
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
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18
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Anwar I, Ashfaq UA. Impact of Nanotechnology on Differentiation and Augmentation of Stem Cells for Liver Therapy. Crit Rev Ther Drug Carrier Syst 2023; 40:89-116. [PMID: 37585310 DOI: 10.1615/critrevtherdrugcarriersyst.2023042400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
The liver is one of the crucial organs of the body that performs hundreds of chemical reactions needed by the body to survive. It is also the largest gland of the body. The liver has multiple functions, including the synthesis of chemicals, metabolism of nutrients, and removal of toxins. It also acts as a storage unit. The liver has a unique ability to regenerate itself, but it can lead to permanent damage if the injury is beyond recovery. The only possible treatment of severe liver damage is liver transplant which is a costly procedure and has several other drawbacks. Therefore, attention has been shifted towards the use of stem cells that have shown the ability to differentiate into hepatocytes. Among the numerous kinds of stem cells (SCs), the mesenchymal stem cells (MSCs) are the most famous. Various studies suggest that an MSC transplant can repair liver function, improve the signs and symptoms, and increase the chances of survival. This review discusses the impact of combining stem cell therapy with nanotechnology. By integrating stem cell science and nanotechnology, the information about stem cell differentiation and regulation will increase, resulting in a better comprehension of stem cell-based treatment strategies. The augmentation of SCs with nanoparticles has been shown to boost the effect of stem cell-based therapy. Also, the function of green nanoparticles in liver therapies is discussed.
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Affiliation(s)
- Ifrah Anwar
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
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19
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Ma X, Liu B, Fan L, Liu Y, Zhao Y, Ren T, Li Y, Li Y. Native and engineered exosomes for inflammatory disease. NANO RESEARCH 2022; 16:6991-7006. [PMID: 36591564 PMCID: PMC9793369 DOI: 10.1007/s12274-022-5275-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 05/24/2023]
Abstract
Exosomes are extracellular vesicles which carry specific molecular information from donor cells and act as an intercellular communication vehicle, which have emerged as a novel cell-free strategy for the treatment of many diseases including inflammatory disease. Recently, rising studies have developed exosome-based strategies for novel inflammation therapy due to their biocompatibility and bioactivity. Researchers not only use native exosomes as therapeutic agents for inflammation, but also strive to make up for the natural defects of exosomes through engineering methods to improve and update the property of exosomes for enhanced therapeutic effects. The engineered exosomes can improve cargo-loading efficiency, targeting ability, stability, etc., to achieve combined and diverse treatment strategies in inflammation diseases. Herein, a comprehensive overview of the recent advances in application studies of native and engineered exosomes as well as the engineered methods is provided. Meanwhile, potential application prospects, possible challenges, and the development of clinical researches of exosome treatment strategy are concluded from plentiful examples, which may be able to provide guidance and suggestions for the future research and application of exosomes.
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Affiliation(s)
- Xiaoyi Ma
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Bingbing Liu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Limin Fan
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yiqiong Liu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yuge Zhao
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Tianbin Ren
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yan Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
| | - Yongyong Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092 China
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20
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Effect of ovarian growth factors on ultra-structural maturation in frozen human immature oocytes after in vitro maturation: a comparative study. Reprod Health 2022; 19:215. [PMID: 36457030 PMCID: PMC9714011 DOI: 10.1186/s12978-022-01521-8] [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: 12/05/2021] [Accepted: 11/04/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND In artificial reproductive technique (ART), nearly 20% of human oocytes are immature in the germinal vesicle (GV) phase. Consequently, the best method for reserving them is cryopreserving GV oocytes, and in vitro maturation (IVM) is recommended. The aim of this study was to determine the ultrastructure characteristics of fresh and vitrified immature human oocytes after in vitro maturation in conditioned mediums. METHODS This study was a comparative laboratory study carried out in 2018 at Afzalipur Infertility Center in Kerman. 170 fresh and 198 vitrified GV oocytes were cultured within three IVM mediums; α-mem as control medium, α-mem supplemented with human bone marrow mesenchymal stem cells (BM-MSCs) and α-mem supplemented with ovarian growth factors (O.F). After 48 h, the maturation rate and morphological feature of IVM oocytes [132 fresh IVM (fIVM) and 134 vitrified IVM (vIVM)] were evaluated. For the ultrastructure study, 10 IVM oocytes from each medium were compared with 10 fresh in vivo oocytes cancelled from ART. RESULTS The survival rate of vitrified GV oocyte after thawing was 88.88%. The oocyte maturation rate was reduced in vIVM compared to the fIVM group (76.33% vs. 77.95%); the highest oocyte maturation rate in the O.F fIVM and lowest in α-mem vIVM (82.35% vs. 71.42%). The lowest number of cortical granules was observed in α-mem vIVM, but the greatest presence of M-SER aggregates was in O.F fIVM. In vIVM oocytes, the oolemma contained irregular little microvillus organization. CONCLUSIONS The O.F mediums have shown the highest maturation which defends the oocyte ultra-structural conservation.
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21
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Molaei S, Amiri F, Salimi R, Ferdowsi S, Bahadori M. Therapeutic effects of mesenchymal stem cells-conditioned medium derived from suspension cultivation or silymarin on liver failure mice. Mol Biol Rep 2022; 49:10315-10325. [PMID: 36097106 DOI: 10.1007/s11033-022-07785-4] [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] [Received: 01/24/2022] [Accepted: 07/08/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Common treatments of liver disease failed to meet all the needs in this important medical field. It results in an urgent need for proper some new adjuvant therapies. Mesenchymal stem cells (MSCs) and their derivatives are promising tools in this regard. We aimed to compare the Silymarin, as traditional treatment with mesenchymal stem cell conditioned medium (MSC-CM), as a novel strategy, both with therapeutic potentialities in term of liver failure (LF) treatment. METHODS AND RESULTS Mice models with liver failure were induced with CCl4 and were treated in the groups as follows: normal mice receiving DMEM-LG medium as control, LF-mice receiving DMEM-LG medium as sham, LF-mice receiving Silymarin as LF-SM, and LF-mice receiving MSC sphere CM as LF-MSC-CM. Biochemical, histopathological, molecular and protein level parameters were evaluated using blood and liver samples. Liver enzymes, MicroRNA-122 values as well as necrotic score were significantly lower in the LF-SM and LF-MSC-CM groups compared to sham. LF-SM showed significantly higher level of total antioxidant capacity and malondialdehyde than that of LF-MSC-CM groups. Sph-MSC-CM not only induced more down-regulated expression of fibrinogen-like protein 1 and receptor interacting protein kinases1 but also led to higher expression level of keratinocyte growth factor. LF-MSC-CM showed less mortality rate compared to other groups. CONCLUSIONS Hepato-protective potentialities of Sph-MSC-CM are comparable to those of Silymarin. More inhibition of necroptosis/ necrosis and inflammation might result in rapid liver repair in case of MSC-CM administration.
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Affiliation(s)
- Sedigheh Molaei
- Social Determinants of Health Research Center, Saveh University of Medical Sciences, Saveh, Iran
| | - Fatemeh Amiri
- Department of Medical Laboratory Sciences, School of Para Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Rasoul Salimi
- Department of Emergency Medicine, Besat Hospital, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Shirin Ferdowsi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Marzie Bahadori
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
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22
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Ibrahim MA, Khalifa AM, Mohamed AA, Galhom RA, Korayem HE, Abd El-Fadeal NM, Abd-Eltawab Tammam A, Khalifa MM, Elserafy OS, Abdel-Karim RI. Bone-Marrow-Derived Mesenchymal Stem Cells, Their Conditioned Media, and Olive Leaf Extract Protect against Cisplatin-Induced Toxicity by Alleviating Oxidative Stress, Inflammation, and Apoptosis in Rats. TOXICS 2022; 10:toxics10090526. [PMID: 36136492 PMCID: PMC9504158 DOI: 10.3390/toxics10090526] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/26/2022] [Accepted: 09/01/2022] [Indexed: 06/01/2023]
Abstract
BACKGROUND Hepatic and renal damage is a cisplatin (Cis)-induced deleterious effect that is a major limiting factor in clinical chemotherapy. OBJECTIVES The current study was designed to investigate the influence of pretreatment with olive leaf extract (OLE), bone-marrow-derived mesenchymal stem cells (BM-MSC), and their conditioned media (CM-MSC) against genotoxicity, nephrotoxicity, hepatotoxicity, and immunotoxicity induced by cisplatin in rats. METHODS The rats were randomly divided into six groups (six rats each) as follows: Control; OLE group, treated with OLE; Cis group, treated with a single intraperitoneal dose of Cis (7 mg/kg bw); Cis + OLE group, treated with OLE and cisplatin; Cis + CM-MSC group, treated with BM-MSC conditioned media and Cis; and Cis + MSC group, treated with BM-MSC in addition to Cis. RESULTS Cis resulted in a significant deterioration in hepatic and renal functions and histological structures. Furthermore, it increased inflammatory markers (TNF-α, IL-6, and IL-1β) and malondialdehyde (MDA) levels and decreased glutathione (GSH) content, total antioxidant capacity (TAC), catalase (CAT), and superoxide dismutase (SOD) activity in hepatic and renal tissues. Furthermore, apoptosis was evident in rat tissues. A significant increase in serum 8-hydroxy-2-deoxyguanosine (8-OH-dG), nitric oxide (NO) and lactate dehydrogenase (LDH), and a decrease in lysozyme activity were detected in Cis-treated rats. OLE, CM-MSC, and BM-MSC have significantly ameliorated Cis-induced deterioration in hepatic and renal structure and function and improved oxidative stress and inflammatory markers, with preference to BM-MSC. Moreover, apoptosis was significantly inhibited, evident from the decreased expression of Bax and caspase-3 genes and upregulation of Bcl-2 proteins in protective groups as compared to Cis group. CONCLUSIONS These findings indicate that BM-MSC, CM-MSC, and OLE have beneficial effects in ameliorating cisplatin-induced oxidative stress, inflammation, and apoptosis in the hepatotoxicity, nephrotoxicity, immunotoxicity, and genotoxicity in a rat model.
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Affiliation(s)
- Mahrous A. Ibrahim
- Forensic Medicine and Clinical Toxicology, College of Medicine, Jouf University, Sakaka 41412, Saudi Arabia
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt or
| | - Athar M. Khalifa
- Pathology Department, College of Medicine, Jouf University, Sakaka 41412, Saudi Arabia
| | - Alaa A. Mohamed
- Medical Biochemistry Division, Pathology Department, College of Medicine, Jouf University, Sakaka 41412, Saudi Arabia
- Medical Biochemistry Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Rania A. Galhom
- Human Anatomy and Embryology Department, Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt
- Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt
- Human Anatomy and Embryology Department, Faculty of Medicine, Badr University in Cairo (BUC), Cairo 11829, Egypt
| | - Horeya E. Korayem
- Histology and Cell Biology Department, Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt
| | - Noha M. Abd El-Fadeal
- Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt
- Oncology Diagnostic Unit, Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt
| | - Ahmed Abd-Eltawab Tammam
- Physiology Department, College of Medicine, Jouf University, Sakaka 41412, Saudi Arabia
- Physiology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Mohamed Mansour Khalifa
- Human Physiology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
- Human Physiology Department, College of Medicine, King Saud University, Riyadh 11472, Saudi Arabia
| | - Osama S. Elserafy
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
- Criminal Justice and Forensic Sciences Department, King Fahd Security College, Riyadh 11451, Saudi Arabia
| | - Rehab I. Abdel-Karim
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt or
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23
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Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs). Int J Mol Sci 2022; 23:ijms23169274. [PMID: 36012544 PMCID: PMC9409099 DOI: 10.3390/ijms23169274] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis.
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Ting AE, Baker EK, Champagne J, Desai TJ, Dos Santos CC, Heijink IH, Itescu S, Le Blanc K, Matthay MA, McAuley DF, McIntyre L, Mei SHJ, Parekkadan B, Rocco PRM, Sheridan J, Thébaud B, Weiss DJ. Proceedings of the ISCT scientific signature series symposium, "Advances in cell and gene therapies for lung diseases and critical illnesses": International Society for Cell & Gene Therapy, Burlington VT, US, July 16, 2021. Cytotherapy 2022; 24:774-788. [PMID: 35613962 DOI: 10.1016/j.jcyt.2021.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/05/2021] [Indexed: 11/20/2022]
Abstract
The ISCT Scientific Signature Series Symposium "Advances in Cell and Gene Therapies for Lung Diseases and Critical Illnesses" was held as an independent symposium in conjunction with the biennial meeting, "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases," which took place July 12-15, 2021, at the University of Vermont. This is the third Respiratory System-based Signature Series event; the first 2, "Tracheal Bioengineering, the Next Steps" and "Cellular Therapies for Pulmonary Diseases and Critical Illnesses: State of the Art of European Science," took place in 2014 and 2015, respectively. Cell- and gene-based therapies for respiratory diseases and critical illnesses continue to be a source of great promise and opportunity. This reflects ongoing advancements in understanding of the mechanisms by which cell-based therapies, particularly those using mesenchymal stromal cells (MSCs), can mitigate different lung injuries and the increasing sophistication with which preclinical data is translated into clinical investigations. This also reflects continuing evolution in gene transfer vectors, including those designed for in situ gene editing in parallel with those targeting gene or cell replacement. Therefore, this symposium convened global thought leaders in a forum designed to catalyze communication and collaboration to bring the greatest possible innovation and value of cell- and gene-based therapies for patients with respiratory diseases and critical illnesses.
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Affiliation(s)
| | - Elizabeth K Baker
- Newborn Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia
| | | | - Tushar J Desai
- Stanford University School of Medicine, Stanford, California, USA
| | - Claudia C Dos Santos
- Interdepartmental Division of Critical Care, Department of Medicine and the Keenan Center for Biomedical Research, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Irene H Heijink
- Medical Center Groningen, Department of Pathology and Medical Biology, University of Groningen, Groningen, the Netherlands
| | | | - Katarina Le Blanc
- Department of Laboratory Medicine, Karolinska Institutet, Sweden; Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - Michael A Matthay
- University of San Francisco, San Francisco, California, United States
| | - Daniel F McAuley
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, NI, UK
| | | | - Shirley H J Mei
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Biju Parekkadan
- Sentien Biotechnologies, Lexington, Massachusetts, USA; Rutgers University, Piscataway, New Jersey, USA
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | - Daniel J Weiss
- University of Vermont College of Medicine, Burlington, Vermont, USA.
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25
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Yao L, Hu X, Dai K, Yuan M, Liu P, Zhang Q, Jiang Y. Mesenchymal stromal cells: promising treatment for liver cirrhosis. Stem Cell Res Ther 2022; 13:308. [PMID: 35841079 PMCID: PMC9284869 DOI: 10.1186/s13287-022-03001-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/13/2022] [Indexed: 11/11/2022] Open
Abstract
Liver fibrosis is a wound-healing process that occurs in response to severe injuries and is hallmarked by the excessive accumulation of extracellular matrix or scar tissues within the liver. Liver fibrosis can be either acute or chronic and is induced by a variety of hepatotoxic causes, including lipid deposition, drugs, viruses, and autoimmune reactions. In advanced fibrosis, liver cirrhosis develops, a condition for which there is no successful therapy other than liver transplantation. Although liver transplantation is still a viable option, numerous limitations limit its application, including a lack of donor organs, immune rejection, and postoperative complications. As a result, there is an immediate need for a different kind of therapeutic approach. Recent research has shown that the administration of mesenchymal stromal cells (MSCs) is an attractive treatment modality for repairing liver injury and enhancing liver regeneration. This is accomplished through the cell migration into liver sites, immunoregulation, hepatogenic differentiation, as well as paracrine mechanisms. MSCs can also release a huge variety of molecules into the extracellular environment. These molecules, which include extracellular vesicles, lipids, free nucleic acids, and soluble proteins, exert crucial roles in repairing damaged tissue. In this review, we summarize the characteristics of MSCs, representative clinical study data, and the potential mechanisms of MSCs-based strategies for attenuating liver cirrhosis. Additionally, we examine the processes that are involved in the MSCs-dependent modulation of the immune milieu in liver cirrhosis. As a result, our findings lend credence to the concept of developing a cell therapy treatment for liver cirrhosis that is premised on MSCs. MSCs can be used as a candidate therapeutic agent to lengthen the survival duration of patients with liver cirrhosis or possibly reverse the condition in the near future.
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Affiliation(s)
- Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
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26
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Shao B, Qin YF, Ren SH, Peng QF, Qin H, Wang ZB, Wang HD, Li GM, Zhu YL, Sun CL, Zhang JY, Li X, Wang H. Structural and Temporal Dynamics of Mesenchymal Stem Cells in Liver Diseases From 2001 to 2021: A Bibliometric Analysis. Front Immunol 2022; 13:859972. [PMID: 35663940 PMCID: PMC9160197 DOI: 10.3389/fimmu.2022.859972] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/20/2022] [Indexed: 12/14/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have important research value and broad application prospects in liver diseases. This study aims to comprehensively review the cooperation and influence of countries, institutions, authors, and journals in the field of MSCs in liver diseases from the perspective of bibliometrics, evaluate the clustering evolution of knowledge structure, and discover hot trends and emerging topics. Methods The articles and reviews related to MSCs in liver diseases were retrieved from the Web of Science Core Collection using Topic Search. A bibliometric study was performed using CiteSpace and VOSviewer. Results A total of 3404 articles and reviews were included over the period 2001-2021. The number of articles regarding MSCs in liver diseases showed an increasing trend. These publications mainly come from 3251 institutions in 113 countries led by China and the USA. Li L published the most papers among the publications, while Pittenger MF had the most co-citations. Analysis of the most productive journals shows that most are specialized in medical research, experimental medicine and cell biology, and cell & tissue engineering. The macroscopical sketch and micro-representation of the whole knowledge field are realized through co-citation analysis. Liver scaffold, MSC therapy, extracellular vesicle, and others are current and developing areas of the study. The keywords "machine perfusion", "liver transplantation", and "microRNAs" also may be the focus of new trends and future research. Conclusions In this study, bibliometrics and visual methods were used to review the research of MSCs in liver diseases comprehensively. This paper will help scholars better understand the dynamic evolution of the application of MSCs in liver diseases and point out the direction for future research.
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Affiliation(s)
- Bo Shao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Ya-Fei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Shao-Hua Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Qiu-Feng Peng
- Department of Respiratory and Critical Care Medicine, Tianjin Fourth Central Hospital, Tianjin, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhao-Bo Wang
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Hong-da Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Guang-Ming Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yang-Lin Zhu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Cheng-Lu Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing-Yi Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
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27
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Romano V, Belviso I, Sacco AM, Cozzolino D, Nurzynska D, Amarelli C, Maiello C, Sirico F, Di Meglio F, Castaldo C. Human Cardiac Progenitor Cell-Derived Extracellular Vesicles Exhibit Promising Potential for Supporting Cardiac Repair in Vitro. Front Physiol 2022; 13:879046. [PMID: 35669580 PMCID: PMC9163838 DOI: 10.3389/fphys.2022.879046] [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: 02/18/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Although human Cardiac Progenitor Cells (hCPCs) are not retained by host myocardium they still improve cardiac function when injected into ischemic heart. Emerging evidence supports the hypothesis that hCPC beneficial effects are induced by paracrine action on resident cells. Extracellular vesicles (EVs) are an intriguing mechanism of cell communication based on the transport and transfer of peptides, lipids, and nucleic acids that have the potential to modulate signaling pathways, cell growth, migration, and proliferation of recipient cells. We hypothesize that EVs are involved in the paracrine effects elicited by hCPCs and held accountable for the response of the infarcted myocardium to hCPC-based cell therapy. To test this theory, we collected EVs released by hCPCs isolated from healthy myocardium and evaluated the effects they elicited when administered to resident hCPC and cardiac fibroblasts (CFs) isolated from patients with post-ischemic end-stage heart failure. Evidence emerging from our study indicated that hCPC-derived EVs impacted upon proliferation and survival of hCPCs residing in the ischemic heart and regulated the synthesis and deposition of extracellular-matrix by CFs. These findings suggest that beneficial effects exerted by hCPC injection are, at least to some extent, ascribable to the delivery of signals conveyed by EVs.
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Affiliation(s)
- Veronica Romano
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Immacolata Belviso
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Anna Maria Sacco
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Domenico Cozzolino
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Daria Nurzynska
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”/DIPMED, University of Salerno, Baronissi, Italy
| | - Cristiano Amarelli
- Department of Cardiovascular Surgery and Transplant, Monaldi Hospital, Naples, Italy
| | - Ciro Maiello
- Department of Cardiovascular Surgery and Transplant, Monaldi Hospital, Naples, Italy
| | - Felice Sirico
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Franca Di Meglio
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Clotilde Castaldo
- Department of Public Health, University of Naples Federico II, Naples, Italy
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28
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Shokravi S, Borisov V, Zaman BA, Niazvand F, Hazrati R, Khah MM, Thangavelu L, Marzban S, Sohrabi A, Zamani A. Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review. Stem Cell Res Ther 2022; 13:192. [PMID: 35527304 PMCID: PMC9080215 DOI: 10.1186/s13287-022-02825-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/28/2022] [Indexed: 12/13/2022] Open
Abstract
Recently, mesenchymal stromal cells (MSCs) and their derivative exosome have become a promising approach in the context of liver diseases therapy, in particular, acute liver failure (ALF). In addition to their differentiation into hepatocytes in vivo, which is partially involved in liver regeneration, MSCs support liver regeneration as a result of their appreciated competencies, such as antiapoptotic, immunomodulatory, antifibrotic, and also antioxidant attributes. Further, MSCs-secreted molecules inspire hepatocyte proliferation in vivo, facilitating damaged tissue recovery in ALF. Given these properties, various MSCs-based approaches have evolved and resulted in encouraging outcomes in ALF animal models and also displayed safety and also modest efficacy in human studies, providing a new avenue for ALF therapy. Irrespective of MSCs-derived exosome, MSCs-based strategies in ALF include administration of native MSCs, genetically modified MSCs, pretreated MSCs, MSCs delivery using biomaterials, and also MSCs in combination with and other therapeutic molecules or modalities. Herein, we will deliver an overview regarding the therapeutic effects of the MSCs and their exosomes in ALF. As well, we will discuss recent progress in preclinical and clinical studies and current challenges in MSCs-based therapies in ALF, with a special focus on in vivo reports.
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Affiliation(s)
- Samin Shokravi
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Vitaliy Borisov
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Burhan Abdullah Zaman
- Basic Sciences Department, College of Pharmacy, University of Duhok, Duhok, Kurdistan Region Iraq
| | - Firoozeh Niazvand
- School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Raheleh Hazrati
- Department of Medicinal Chemistry, Pharmacy Faculty, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Meysam Mohammadi Khah
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Sima Marzban
- Department of Research and Academic Affairs, Larkin Community Hospital, Miami, FL USA
| | - Armin Sohrabi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Dai TY, Pan ZY, Yin F. In Vivo Studies of Mesenchymal Stem Cells in the Treatment of Meniscus Injury. Orthop Surg 2021; 13:2185-2195. [PMID: 34747566 PMCID: PMC8654668 DOI: 10.1111/os.13002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/27/2021] [Accepted: 03/04/2021] [Indexed: 12/27/2022] Open
Abstract
This review summarizes the literature of preclinical studies and clinical trials on the use of mesenchymal stem cells (MSCs) to treat meniscus injury and promote its repair and regeneration and provide guidance for future clinical research. Due to the special anatomical features of the meniscus, conservative or surgical treatment can hardly achieve complete physiological and histological repair. As a new method, stem cells promote meniscus regeneration in preclinical research and human preliminary research. We expect that, in the near future, in vivo injection of stem cells to promote meniscus repair can be used as a new treatment model in clinical treatment. The treatment of animal meniscus injury, and the clinical trial of human meniscus injury has begun preliminary exploration. As for the animal experiments, most models of meniscus injury are too simple, which can hardly simulate the complexity of actual meniscal tears, and since the follow-up often lasts for only 4-12 weeks, long-term results could not be observed. Lastly, animal models failed to simulate the actual stress environment faced by the meniscus, so it needs to be further studied if regenerated meniscus has similar anti-stress or anti-twist features. Despite these limitations, repair of the meniscus by MSCs has great potential in clinics. MSCs can differentiate into fibrous chondrocytes, which can possibly repair the meniscus and provide a new strategy for repairing meniscus injury.
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Affiliation(s)
- Tian-Yu Dai
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhang-Yi Pan
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Feng Yin
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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30
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Foroutan T, Kassaee MZ, Salari M, Ahmady F, Molavi F, Moayer F. Magnetic Fe 3 O 4 @graphene oxide improves the therapeutic effects of embryonic stem cells on acute liver damage. Cell Prolif 2021; 54:e13126. [PMID: 34569673 PMCID: PMC8560617 DOI: 10.1111/cpr.13126] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/12/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE Acute liver failure is usually associated with inflammation and oxidation of hepatocytes and has high mortality and resource costs. Mesenchymal stem cell (MSCs) has occasionally been reported to have no beneficial effect due to poor transplantation and the survival of implanted cells. Recent studies showed that embryonic stem cell (ESC)-derived MSCs are an alternative for regenerative medicine. On the other hand, graphene-based nanostructures have proven useful in biomedicine. In this study, we investigated whether magnetic graphene oxide (MGO) improved the effects of ESC-MSC conditioned medium (CM) on protecting hepatocytes and stimulating the regeneration of damaged liver cells. MATERIALS AND METHODS To provide a rat model of acute liver failure, male rats were injected intraperitoneally with carbon tetrachloride (CCl4 ). The rats were randomly divided into six groups, namely control, sham, CCl4 , ESC-MSC-CM, MGO and ESC-MSC-CM + MGO. In the experimental groups, the rats received, depending on the group, 2 ml/kg body weight CCl4 and either ESC-MSC-CM with 5 × 106 MSCs or 300 μg/kg body weight MGO or both. Symptoms of acute liver failure appeared 4 days after the injection. All groups were compared and analysed both histologically and biochemically 4 days after the injection. Finally, the results of ESC-MSC-CM and MSC-CM were compared. RESULTS The results indicated that the use of MGO enhanced the effect of ESC-MSC-CM on reducing necrosis, inflammation, aspartate transaminase, alanine aminotransferase and alkaline phosphatase in the CCl4 -induced liver failure of the rat model. Also, the expression of vascular endothelial growth factor and matrix metalloproteinase-9 (MMP-9) was significantly upregulated after treatment with MGO. Also, the results showed that the ESC-MSC-CM has more efficient effective compared to MSC-CM. CONCLUSION Magnetic graphene oxide improved the hepatoprotective effects of ESC-MSC-CM on acute liver damage, probably by suppressing necrosis, apoptosis and inflammation of hepatocytes.
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Affiliation(s)
- Tahereh Foroutan
- Department of Animal BiologyFaculty of Biological SciencesKharazmi UniversityTehranIran
| | | | - Mahdi Salari
- Department of Environmental Health EngineeringSchool of Public HealthHamadan University of Medical SciencesHamadanIran
| | - Fatemeh Ahmady
- Department of Animal BiologyFaculty of Biological SciencesKharazmi UniversityTehranIran
| | - Fatemeh Molavi
- Department of Animal BiologyFaculty of Biological SciencesKharazmi UniversityTehranIran
| | - Fariborz Moayer
- Faculty of Veterinary MedicineIslamic Azad UniversityKarajIran
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31
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Rathi S, Hussaini T, Yoshida EM. Granulocyte colony stimulating factor: A potential therapeutic rescue in severe alcoholic hepatitis and decompensated cirrhosis. Ann Hepatol 2021; 20:100211. [PMID: 32533952 DOI: 10.1016/j.aohep.2020.04.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/29/2020] [Accepted: 04/29/2020] [Indexed: 02/06/2023]
Abstract
Liver cirrhosis accounts for over 2 million deaths annually worldwide. A subset of these patients - those with alcoholic hepatitis and decompensated cirrhosis, have abysmal short-term survival. Liver transplant is the only intervention of proven survival benefit; however organ availability is a major limitation. It is thus imperative to assess potential benefit of experimental therapies as a bridge to transplant. Stem cell therapies have shown some promise in patients with end-stage liver disease. Of these, bone-marrow derived hematopoietic stem cells have generated the most interest. Animal as well as human data suggest biological plausibility of stem cell translocation from bone marrow to liver, giving credence to cytokine therapies based on bone marrow stimulation. Granulocyte colony stimulating factor has been the most frequently used cytokine for this purpose. This intervention has shown encouraging results in terms of safety as well as survival benefits in small clinical trials. The evidence, however, is sparse and heterogeneous. In this review we describe the biological plausibility, mechanisms of action, and clinical evidence of the use of cytokine based stem cell therapy in patients with end-stage liver disease.
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Affiliation(s)
- Sahaj Rathi
- Division of Gastroenterology, University of British Columbia and Vancouver General Hospital, Canada
| | - Trana Hussaini
- Division of Gastroenterology, University of British Columbia and Vancouver General Hospital, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia and Vancouver General Hospital, Canada.
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32
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Swaminathan M, Kopyt N, Atta MG, Radhakrishnan J, Umanath K, Nguyen S, O'Rourke B, Allen A, Vaninov N, Tilles A, LaPointe E, Blair A, Gemmiti C, Miller B, Parekkadan B, Barcia RN. Pharmacological effects of ex vivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation. Stem Cells Transl Med 2021; 10:1588-1601. [PMID: 34581517 PMCID: PMC8641088 DOI: 10.1002/sctm.21-0043] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 06/07/2021] [Accepted: 06/30/2021] [Indexed: 01/20/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase Ib study was conducted to evaluate the safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI-101) to preserve cell activity in patients with severe acute kidney injury. Pharmacological data demonstrated MSC-secreted factor activity that was associated with anti-inflammatory signatures in the molecular and cellular profiling of patient blood. Systems biology analysis captured multicompartment effects consistent with immune reprogramming and kidney tissue repair. Although the study was not powered for clinical efficacy, these results are supportive of the therapeutic hypothesis, namely, that treatment with SBI-101 elicits an immunotherapeutic response that triggers an accelerated phenotypic switch from tissue injury to tissue repair. Ex vivo administration of MSCs, with increased power of testing, is a potential new biological delivery paradigm that assures sustained MSC activity and immunomodulation.
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Affiliation(s)
- Madhav Swaminathan
- Department of Anesthesiology, Duke University School of Medicine, Duke University, Durham, North Carolina, USA
| | - Nelson Kopyt
- Nephrology Section, Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, USA
| | - Mohamed G Atta
- Department of Medicine, Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Jai Radhakrishnan
- Columbia University Medical Center, Division of Nephrology, NY Presbyterian Hospital/Columbia, New York, New York, USA
| | - Kausik Umanath
- Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan, USA.,Division of Nephrology and Hypertension, Wayne State University, Detroit, Michigan, USA
| | - Sunny Nguyen
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Ashley Allen
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Arno Tilles
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Andrew Blair
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Chris Gemmiti
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Brian Miller
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Biju Parekkadan
- Sentien Biotechnologies, Lexington, Massachusetts, USA.,Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.,Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA
| | - Rita N Barcia
- Sentien Biotechnologies, Lexington, Massachusetts, USA
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33
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Lo Nigro A, Gallo A, Bulati M, Vitale G, Paini DS, Pampalone M, Galvagno D, Conaldi PG, Miceli V. Amnion-Derived Mesenchymal Stromal/Stem Cell Paracrine Signals Potentiate Human Liver Organoid Differentiation: Translational Implications for Liver Regeneration. Front Med (Lausanne) 2021; 8:746298. [PMID: 34631757 PMCID: PMC8494784 DOI: 10.3389/fmed.2021.746298] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/30/2021] [Indexed: 02/05/2023] Open
Abstract
The prevalence of end-stage liver diseases has reached very high levels globally. The election treatment for affected patients is orthotopic liver transplantation, which is a very complex procedure, and due to the limited number of suitable organ donors, considerable research is being done on alternative therapeutic options. For instance, the use of cell therapy, such as the transplantation of hepatocytes to promote liver repair/regeneration, has been explored, but standardized protocols to produce suitable human hepatocytes are still limited. On the other hand, liver progenitor and multipotent stem cells offer potential cell sources that could be used clinically. Different studies have reported regarding the therapeutic effects of transplanted mesenchymal stromal/stem cells (MSCs) on end-stage liver diseases. Moreover, it has been shown that delivery of MSC-derived conditioned medium (MSC-CM) can reduce cell death and enhance liver proliferation in fulminant hepatic failure. Therefore, it is believed that MSC-CM contains many factors that probably support liver regeneration. In our work, we used an in vitro model of human liver organoids to study if the paracrine components secreted by human amnion-derived MSCs (hAMSCs) affected liver stem/progenitor cell differentiation. In particular, we differentiated liver organoids derived from bipotent EpCAM+ human liver cells and tested the effects of hAMSC secretome, derived from both two-dimensional (2D) and three-dimensional (3D) hAMSC cultures, on that model. Our analysis showed that conditioned medium (CM) produced by 3D hAMSCs was able to induce an over-expression of mature hepatocyte markers, such as ALB, NTCP, and CYP3A4, compared with both 2D hAMSC cultures and the conventional differentiation medium (DM). These data were confirmed by the over-production of ALB protein and over-activity of CYP3A4 observed in organoids grown in 3D hAMSC-CM. Liver repair dysfunction plays a role in the development of liver diseases, and effective repair likely requires the normal functioning of liver stem/progenitor cells. Herein, we showed that hAMSC-CM produced mainly by 3D cultures had the potential to increase hepatic stem/progenitor cell differentiation, demonstrating that soluble factors secreted by those cells are potentially responsible for the reaction. This work shows a potential approach to improve liver repair/regeneration also in a transplantation setting.
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Affiliation(s)
| | - Alessia Gallo
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Matteo Bulati
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | | | | | - Mariangela Pampalone
- Ri.MED Foundation, Palermo, Italy
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | | | - Pier Giulio Conaldi
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Vitale Miceli
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
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34
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Lee J, Kim SR, Lee C, Jun YI, Bae S, Yoon YJ, Kim OY, Gho YS. Extracellular vesicles from in vivo liver tissue accelerate recovery of liver necrosis induced by carbon tetrachloride. J Extracell Vesicles 2021; 10:e12133. [PMID: 34401049 PMCID: PMC8357636 DOI: 10.1002/jev2.12133] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 07/19/2021] [Accepted: 07/27/2021] [Indexed: 01/07/2023] Open
Abstract
Extracellular vesicles (EVs) are nano-sized vesicles composed of proteolipid bilayers carrying various molecular signatures of the cells. As mediators of intercellular communications, EVs have gained great attention as new therapeutic agents in the field of nanomedicine. Therefore, many studies have explored the roles of cell-derived EVs isolated from cultured hepatocytes or stem cells as inducer of liver proliferation and regeneration under various pathological circumstances. However, study investigating the role of EVs directly isolated from liver tissue has not been performed. Herein, to understand the pathophysiological role and to investigate the therapeutic potential of in vivo liver EVs, we isolated EVs from both normal and carbon tetrachloride (CCl4)-induced damaged in vivo liver tissues. The in vivo EVs purified from liver tissues display typical features of EVs including spherical morphology, nano-size, and enrichment of tetraspanins. Interestingly, administration of both normal and damaged liver EVs significantly accelerated the recovery of liver tissue from CCl4-induced hepatic necrosis. This restorative action was through the induction of hepatocyte growth factor at the site of the injury. These results suggest that not only normal liver EVs but also damaged liver EVs play important pathophysiological roles of maintaining homeostasis after tissue damage. Our study, therefore, provides new insight into potentially developing in vivo EV-based therapeutics for preventing and treating liver diseases.
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Affiliation(s)
- Jaemin Lee
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Sae Rom Kim
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Changjin Lee
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Ye In Jun
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Seoyoon Bae
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Yae Jin Yoon
- Genome Editing Research CentreKorea Research Institute of Bioscience and BiotechnologyDaejeonRepublic of Korea
| | - Oh Youn Kim
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
- Department of MedicineYonsei University College of MedicineSeoulRepublic of Korea
| | - Yong Song Gho
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
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35
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LIU L, YANG F. Application of Modified Mesenchymal Stem Cells Transplantation in the Treatment of Liver Injury. Physiol Res 2021. [DOI: 10.33549/physiolres.934623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Acute and chronic hepatitis, cirrhosis, and other liver diseases pose a serious threat to human health; however, liver transplantation is the only reliable treatment for the terminal stage of liver diseases. Previous researchers have shown that mesenchymal stem cells (MSCs) are characterized by differentiation and paracrine effects, as well as anti-oxidative stress and immune regulation functions. When MSCs are transplanted into animals, they migrate to the injured liver tissue along with the circulation, to protect the liver and alleviate the injury through the paracrine, immune regulation and other characteristics, making mesenchymal stem cell transplantation a promising alternative therapy for liver diseases. Although the efficacy of MSCs transplantation has been confirmed in various animal models of liver injury, many researchers have also proposed various pretreatment methods to improve the efficacy of mesenchymal stem cell transplantation, but there is still lack a set of scientific methods system aimed at improving the efficacy of transplantation therapy in scientific research and clinical practice. In this review, we summarize the possible mechanisms of MSCs therapy and compare the existing methods of MSCs modification corresponding to the treatment mechanism, hoping to provide as a reference to help future researchers explore a safe and simple transplantation strategy.
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Affiliation(s)
- L LIU
- School of Basic Medicine, Yangtze University Health Science Center, Jingzhou, China
| | - F YANG
- School of Basic Medicine, Yangtze University Health Science Center, Jingzhou, China
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36
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Nguyen Thanh L, Dam PTM, Nguyen HP, Nguyen TST, To HM, Nguyen HB, Luu NA, Hoang DM. Can Autologous Adipose-Derived Mesenchymal Stem Cell Transplantation Improve Sexual Function in People with Sexual Functional Deficiency? Stem Cell Rev Rep 2021; 17:2153-2163. [PMID: 34129158 DOI: 10.1007/s12015-021-10196-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Sexual functional deficiency occurs at some point in life and becomes a problematic issue in middle-aged adulthood. Regenerative medicine, especially mesenchymal stem cell (MSC) transplantation, has developed extensively, with preclinical and clinical trials emphasizing the benefits of stem cell therapy for restoration of sexual deficiency. This study was designed to develop a new therapeutic stem cell treatment for people with sexual functional deficiency. METHODS Thirty-one patients, including 15 males and 16 females with a medical history of reduced sexual activity, met the inclusion criteria and were enrolled in the study, phase I/IIa clinical trial with a 12-month follow-up. Adipose tissue-derived mesenchymal stem/stromal cells (ADSC) were isolated by type I collagenase digestion and cultured at the Stem Cell Core Facility under ISO 14644-1. Each participant received 1 million cells/kg of body weight via the intravenous route. Safety was evaluated by assessing the occurrence of adverse events or severe adverse events. Efficacy was assessed in males by monitoring testosterone levels and administering the International Index of Erectile Function (IIEF) questionnaire and in females by monitoring anti-Mullerian hormone (AMH), estradiol (E2), and follicle-stimulating hormone (FSH) levels and administering the Female Sexual Functioning Index (FSFI) questionnaire at baseline and 3-, 6-, and 12-months post-transplantation. RESULTS There was no occurrence of severe adverse events after ADSC administration in our study. Post-transplantation sexual satisfaction was observed in all patients enrolled in this study. Testosterone levels in males increased soon after transplantation and were maintained at high levels for up to 6 months before decreasing again at the 12-month follow-up. No significant changes in AMH, FSH or E2 levels were recorded in female patients. CONCLUSIONS Autologous ADSC infusion is a potential therapeutic option for patients with reduced sexual activity, especially for male patients. TRIAL REGISTRATION ClinicalTrials.gov. NCT03346967, Registered November 20, 2017.
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Affiliation(s)
- Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Health Care System, Hanoi, Vietnam.
| | - Phuong T M Dam
- Vinmec Hightech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Hoang-Phuong Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Health Care System, Hanoi, Vietnam
| | - Tan-Sinh Thi Nguyen
- Vinmec Times City International Hospital, 458 Minh Khai Street, Hanoi, Vietnam
| | - Huong Minh To
- Vinmec Times City International Hospital, 458 Minh Khai Street, Hanoi, Vietnam
| | - Hung Ba Nguyen
- Vinmec Times City International Hospital, 458 Minh Khai Street, Hanoi, Vietnam
| | - Ngoc-Anh Luu
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Health Care System, Hanoi, Vietnam
| | - Duc M Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Health Care System, Hanoi, Vietnam
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37
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Luan Y, Kong X, Feng Y. Mesenchymal stem cells therapy for acute liver failure: Recent advances and future perspectives. LIVER RESEARCH 2021; 5:53-61. [PMID: 39959343 PMCID: PMC11791815 DOI: 10.1016/j.livres.2021.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/16/2021] [Accepted: 03/24/2021] [Indexed: 12/21/2022]
Abstract
Acute liver failure (ALF) is a life-threatening disease characterized by the rapid development of hepatocyte death and a systemic inflammatory response, which leads to high mortality. Despite the prevention of ALF complications, therapeutic effectiveness remains limited because of the rapid disease progression. Thus, there is a need to explore various therapeutic approaches. Currently, the only effective treatment is liver transplantation; However, the lack of donors, surgical complications, immunosuppression, and high medical costs limit its clinical application. Recently, mesenchymal stem cells (MSCs) have been found to exert hepatoprotective effects in ALF through suppression of inflammation, immunoregulation, promotion of mitosis, anti-apoptosis effects, and alleviation of the metabolic and oxidative stress imbalance. In this review, we summarize the advantages and disadvantages of MSCs from different sources and their molecular mechanisms in ALF treatment, along with future perspectives that may provide guidance to improve the current status of MSCs therapy for ALF.
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Affiliation(s)
- Yuling Luan
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoni Kong
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Feng
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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38
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Saeedi M, Nezhad MS, Mehranfar F, Golpour M, Esakandari MA, Rashmeie Z, Ghorbani M, Nasimi F, Hoseinian SN. Biological Aspects and Clinical Applications of Mesenchymal Stem Cells: Key Features You Need to be Aware of. Curr Pharm Biotechnol 2021; 22:200-215. [PMID: 32895040 DOI: 10.2174/1389201021666200907121530] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 11/22/2022]
Abstract
Mesenchymal Stem Cells (MSCs), a form of adult stem cells, are known to have a selfrenewing property and the potential to specialize into a multitude of cells and tissues such as adipocytes, cartilage cells, and fibroblasts. MSCs can migrate and home to the desired target zone where inflammation is present. The unique characteristics of MSCs in repairing, differentiation, regeneration, and the high capacity of immune modulation have attracted tremendous attention for exerting them in clinical purposes, as they contribute to the tissue regeneration process and anti-tumor activity. The MSCs-based treatment has demonstrated remarkable applicability towards various diseases such as heart and bone malignancies, and cancer cells. Importantly, genetically engineered MSCs, as a stateof- the-art therapeutic approach, could address some clinical hurdles by systemic secretion of cytokines and other agents with a short half-life and high toxicity. Therefore, understanding the biological aspects and the characteristics of MSCs is an imperative issue of concern. Herein, we provide an overview of the therapeutic application and the biological features of MSCs against different inflammatory diseases and cancer cells. We further shed light on MSCs' physiological interaction, such as migration, homing, and tissue repairing mechanisms in different healthy and inflamed tissues.
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Affiliation(s)
- Mohammad Saeedi
- Department of Laboratory Science, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Muhammad S Nezhad
- Stem Cells and Regenerative Medicine Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mehranfar
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahdieh Golpour
- School of Paramedical Sciences, Semnan University of Medical Sciences, Sorkheh, Semnan, Iran
| | - Mohammad A Esakandari
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Zahra Rashmeie
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Maryam Ghorbani
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Nasimi
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Seyed N Hoseinian
- Department of Laboratory Science, Faculty of medicine, Semnan University of Medical Sciences, Semnan, Iran
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Aslam N, Abusharieh E, Abuarqoub D, Alhattab D, Jafar H, Alshaer W, Masad RJ, Awidi AS. An In Vitro Comparison of Anti-Tumoral Potential of Wharton's Jelly and Bone Marrow Mesenchymal Stem Cells Exhibited by Cell Cycle Arrest in Glioma Cells (U87MG). Pathol Oncol Res 2021; 27:584710. [PMID: 34257532 PMCID: PMC8262206 DOI: 10.3389/pore.2021.584710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 02/12/2021] [Indexed: 12/18/2022]
Abstract
The therapeutic potential of mesenchymal stem cells (MSCs) for various malignancies is currently under investigation due to their unique properties. However, many discrepancies regarding their anti-tumoral or pro-tumoral properties have raised uncertainty about their application for anti-cancer therapies. To investigate, if the anti-tumoral or pro-tumoral properties are subjective to the type of MSCs under different experimental conditions we set out these experiments. Three treatments namely cell lysates (CL), serum-free conditioned media and FBS conditioned media (FBSCM) from each of Wharton’s Jelly MSCs and Bone Marrow-MSCs were applied to evaluate the anti-tumoral or pro-tumoral effect on the glioma cells (U87MG). The functional analysis included; Morphological evaluation, proliferation and migration potential, cell cycle analysis, and apoptosis for glioma cells. The fibroblast cell line was added to investigate the stimulatory or inhibitory effect of treatments on the proliferation of the normal cell. We found that cell lysates induced a generalized inhibitory effect on the proliferation of the glioma cells and the fibroblasts from both types of MSCs. Similarly, both types of conditioned media from two types of MSCs exerted the same inhibitory effect on the proliferation of the glioma cells. However, the effect of two types of conditioned media on the proliferation of fibroblasts was stimulatory from BM-MSCs and variable from WJ-MSCs. Moreover, all three treatments exerted a likewise inhibitory effect on the migration potential of the glioma cells. Furthermore, we found that the cell cycle was arrested significantly at the G1 phase after treating cells with conditioned media which may have led to inhibit the proliferative and migratory abilities of the glioma cells (U87MG). We conclude that cell extracts of MSCs in the form of secretome can induce specific anti-tumoral properties in serum-free conditions for the glioma cells particularly the WJ-MSCs and the effect is mediated by the cell cycle arrest at the G1 phase.
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Affiliation(s)
- Nazneen Aslam
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Elham Abusharieh
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Pharmaceutical science, Faculty of Pharmacy, The University of Jordan, Amman, Jordan
| | - Duaa Abuarqoub
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra. Amman, Jordan
| | - Dana Alhattab
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Laboratory for Nanomedicine, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Hanan Jafar
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Anatomy and Histology, School of Medicine, The University of Jordan, Amman, Jordan
| | - Walhan Alshaer
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Razan J Masad
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Abdalla S Awidi
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Medicine, School of Medicine, The University of Jordan, Amman, Jordan.,Department of Hematology and Oncology, Jordan University Hospital, The University of Jordan, Amman, Jordan.,Department of Hematology and Oncology, The University of Jordan, Amman, Jordan
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Teotia AK, Qayoom I, Singh P, Mishra A, Jaiman D, Seppälä J, Lidgren L, Kumar A. Exosome-Functionalized Ceramic Bone Substitute Promotes Critical-Sized Bone Defect Repair in Rats. ACS APPLIED BIO MATERIALS 2021; 4:3716-3726. [DOI: 10.1021/acsabm.1c00311] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Arun K. Teotia
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 201806, India
| | - Irfan Qayoom
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 201806, India
| | - Prerna Singh
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 201806, India
- Center for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kanpur 201806, India
| | - Ankita Mishra
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 201806, India
| | - Deepika Jaiman
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 201806, India
| | - Jukka Seppälä
- Polymer Technology, School of Chemical Engineering, Aalto University, Espoo 02150, Finland
| | - Lars Lidgren
- Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund 221 85, Sweden
| | - Ashok Kumar
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 201806, India
- Center for Environmental Science and Engineering, Indian Institute of Technology Kanpur, Kanpur 201806, India
- Center for Nanoscience, Indian Institute of Technology Kanpur, Kanpur 201806, India
- The Mehta Family Centre for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur 208016, India
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41
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Ravan AP, Goudarzi F, Rafieemehr H, Bahmani M, Rad F, Jafari M, Mahmoodi M. Human umbilical cord-mesenchymal stem cells conditioned medium attenuates CCl 4 induced chronic liver fibrosis. TOXIN REV 2021. [DOI: 10.1080/15569543.2019.1590849] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Alireza Pouyandeh Ravan
- Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Farjam Goudarzi
- Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hassan Rafieemehr
- Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahdi Bahmani
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fariba Rad
- Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Mohammad Jafari
- Department of Pathology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Marzieh Mahmoodi
- Department of Biostatistics, School of Health and Nutrition, Bushehr University of Medical Sciences, Bushehr, Iran
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Kim GB, Shon OJ, Seo MS, Choi Y, Park WT, Lee GW. Mesenchymal Stem Cell-Derived Exosomes and Their Therapeutic Potential for Osteoarthritis. BIOLOGY 2021; 10:285. [PMID: 33915850 PMCID: PMC8066608 DOI: 10.3390/biology10040285] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/28/2021] [Accepted: 03/29/2021] [Indexed: 12/18/2022]
Abstract
Exosomes are nano-sized vesicles (50-150 nm in diameter) that contain nucleic acids (e.g., microRNA and messenger RNA), functional proteins, and bioactive lipids. They are secreted by various types of cells, including B cells, T cells, reticulocytes, dendritic cells, mast cells, epithelial cells, and mesenchymal stem cells (MSCs). They perform a wide variety of functions, including the repair of damaged tissues, regulation of immune responses, and reduction in inflammation. When considering the limitations of MSCs, including issues in standardization and immunogenicity, MSC-derived exosomes have advantages such as small dimensions, low immunogenicity, and lack of requirement for additional procedures for culture expansion or delivery. MSC-derived exosomes have shown outstanding therapeutic effects through chondro-protective and anti-inflammatory properties. MSC-derived exosomes may enable a new therapeutic paradigm for the treatment of osteoarthritis. However, further research is needed to prove their clinical effectiveness and feasibility.
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Affiliation(s)
- Gi Beom Kim
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University, Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea; (G.B.K.); (O.-J.S.); (W.T.P.)
| | - Oog-Jin Shon
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University, Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea; (G.B.K.); (O.-J.S.); (W.T.P.)
| | - Min-Soo Seo
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea;
| | - Young Choi
- Department of Orthopedic Surgery, Kosin University College of Medicine, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seogu, Busan 49267, Korea;
| | - Wook Tae Park
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University, Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea; (G.B.K.); (O.-J.S.); (W.T.P.)
| | - Gun Woo Lee
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University, Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea; (G.B.K.); (O.-J.S.); (W.T.P.)
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43
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Jiao Z, Ma Y, Zhang Q, Wang Y, Liu T, Liu X, Piao C, Liu B, Wang H. The adipose-derived mesenchymal stem cell secretome promotes hepatic regeneration in miniature pigs after liver ischaemia-reperfusion combined with partial resection. Stem Cell Res Ther 2021; 12:218. [PMID: 33781342 PMCID: PMC8008619 DOI: 10.1186/s13287-021-02284-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Background Hepatic ischaemia-reperfusion injury (HIRI) is inevitable in complicated liver surgery and is a major factor leading to postoperative complications and liver dysfunction. Studies have shown that the paracrine mechanisms of stem cell may be essential to tissue repair and functional improvement after transplantation. However, the role of the adipose-derived mesenchymal stem cell secretome (ASC-secretome) in liver regeneration in large animals remains to be determined. Methods Twenty-four miniature pigs were subjected to laparoscopic liver ischaemia-reperfusion combined with partial hepatectomy and divided into the following four groups: the saline group, the DMEM group, the ASC group and the ASC-secretome group. Serum and liver tissue samples were collected before the operation and at 1, 3 and 7 days after the operation, and changes in tissue pathology, serum inflammation, liver function, angiogenesis-related factors and liver tissue regeneration-related genes and proteins were evaluated. Results Detailed histological analysis showed that ASCs and the ASC-secretome changed pathological damage to liver tissue after liver ischaemia-reperfusion combined with partial hepatectomy (1 and 3 days: p < 0.01). Compared with the saline and DMEM control groups, the ASC-secretome group had significantly reduced expression levels of ALP (1 and 3 days: p < 0.05), ALT (1 day: p < 0.01; 3 days: p < 0.05) and AST (1 and 3 days: p < 0.01), which promoted the recovery of liver function. Moreover, detection of the expression levels of TNF-α and IL-1β (1 day: p < 0.01; 3 days: p < 0.05), IL-6 (1 and 3 days: p < 0.05) and IL-10 (1 and 3 days: p < 0.01) in serum confirmed that the ASC-secretome had obvious anti-inflammatory effects. In addition, the ASC-secretome increased the expression levels of ANG-1 (3 days: p < 0.01), ANG-2 (3 and 7 days: p < 0.01) and VEGF (1 and 7 days: p < 0.05; 3 days: p < 0.01) and promoted angiogenesis during liver regeneration. Moreover, it promoted the mRNA expression of HGF and Cyclin D1 (1 and 3 days: p < 0.01); increased the levels of p-STAT3 (1 and 3 days: p < 0.01), PCNA and Ki67 (1 and 3 days: p < 0.01; 7 days: p < 0.05); inhibited the negative feedback of SOCS3 (1 and 3 days: p < 0.01); and decreased the mRNA expression of TGF-β (3 days: p < 0.01). The cytokines and growth factors detected in the ASC-secretome included TNF-α, IL-6, IL-1β, ANG-1, ANG-2, VEGF and b-FGF. Conclusion The ASC-secretome alleviates the inflammatory response induced by ischaemia-reperfusion combined with partial hepatectomy in miniature pigs and promotes liver regeneration.
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Affiliation(s)
- Zhihui Jiao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.,College of Wildlife and Protected Area, Northeast Forestry University, Harbin, People's Republic of China
| | - Yajun Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Qianzhen Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Yue Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Tao Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Xiaoning Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Chenxi Piao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Boyang Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.,College of Wildlife and Protected Area, Northeast Forestry University, Harbin, People's Republic of China
| | - Hongbin Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
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Kim HJ, Kim OH, Hong HE, Lee SC, Kim SJ. Harnessing adipose‑derived stem cells to release specialized secretome for the treatment of hepatitis B. Int J Mol Med 2021; 47:15. [PMID: 33448314 PMCID: PMC7834954 DOI: 10.3892/ijmm.2021.4848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 12/09/2020] [Indexed: 11/09/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have the function of repairing damaged tissue, which is known to be mediated by the secretome, the collection of secretory materials shed from MSCs. Adjusting the culture conditions of MSCs can lead to a significant difference in the composition of the secretome. It was hypothesized that pre‑sensitization of MSCs with specific disease‑causing agents could harness MSCs to release the therapeutic materials specialized for the disease. To validate this hypothesis, the present study aimed to generate a 'disease‑specific secretome' for hepatitis caused by hepatitis B virus using hepatitis BX antigen (HBx) as a disease‑causing material. Secretary materials (HBx‑IS) were collected following the stimulation of adipose‑derived stem cells (ASCs) with 100‑fold diluted culture media of AML12 hepatocytes that had been transfected with pcDNA‑HBx for 24 h. An animal model of hepatitis B was generated by injecting HBx into mice, and the mice were subsequently intravenously administered a control secretome (CS) or HBx‑IS. Compared with the CS injection, the HBx‑IS injection significantly reduced the serum levels of interleukin‑6 and tumor necrosis factor‑α (pro‑inflammatory cytokines). Western blot analysis and immunohistochemistry of the liver specimens revealed that the HBx‑IS injection led to a higher expression of liver regeneration‑related markers, including hepatocyte growth factor and proliferating cell nuclear antigen, a lower expression of pro‑apoptotic markers, such as cleaved caspase 3 and Bim in mouse livers, and a lower expression of pro‑inflammatory markers (F4/80 and CD68) compared to the CS injection. HBx‑IS exhibited higher liver regenerative, anti‑inflammatory and anti‑apoptotic properties, particularly in the mouse model of hepatitis B compared to CS. This suggests that the secretome obtained by stimulating ASCs with disease‑causing agents may have a more prominent therapeutic effect on the specific disease than the naïve secretome.
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Affiliation(s)
- Hee Ju Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591
| | - Ok-Hee Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea
| | - Ha-Eun Hong
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea
| | - Sang Chul Lee
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea
- Department of Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon 34943, Republic of Korea
| | - Say-June Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea
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Baig MT, Ghufran H, Mehmood A, Azam M, Humayun S, Riazuddin S. Vitamin E pretreated Wharton's jelly-derived mesenchymal stem cells attenuate CCl 4-induced hepatocyte injury in vitro and liver fibrosis in vivo. Biochem Pharmacol 2021; 186:114480. [PMID: 33617844 DOI: 10.1016/j.bcp.2021.114480] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/02/2021] [Accepted: 02/16/2021] [Indexed: 12/22/2022]
Abstract
Oxidative microenvironment in fibrotic liver alleviates the efficacious outcome of mesenchymal stem cells (MSCs)-based cell therapy. Recent evidence suggests that pharmacological pretreatment is a rational approach to harness the MSCs with higher therapeutic potential. Here, we investigated whether Vitamin E pretreatment can boost the antifibrotic effects of Wharton's jelly-derived MSCs (WJMSCs). We used rat liver-derived hepatocytes injured by CCl4 treatment in co-culture system with Vitamin E pretreated-WJMSCs (Vit E-WJMSCs) to evaluate the hepatoprotective effect of Vit E-WJMSCs. After 24 h of co-culturing, we found that Vit E-WJMSCs rescued injured hepatocytes as hepatocyte injury-associated medium (AST, ALT, and ALP) and mRNA (Cyp2e1, Hif1-α, and Il-1β) markers reduced to normal levels. Subsequently, CCl4-induced liver fibrosis rat models were employed to examine the antifibrotic potential of Vit E-WJMSCs. After 1 month of cell transplantation, it was revealed that Vit E-WJMSCs transplantation ceased fibrotic progression, as evident by improved hepatic architecture and functions, more significantly in comparison to naïve WJMSCs. In addition, Vit E-WJMSCs transplantation decreased the expressions of fibrosis-associated gene (Tgf-β1, α-Sma, and Col1α1) markers in the liver parenchyma. Intriguingly, the results of tracing experiments discovered that more WJMSCs engrafted in the Vit E-WJMSCs treated rat livers compared to naïve WJMSCs treated livers. These findings implicate that pretreatment of WJMSCs with Vitamin E improves their tolerance to hostile niche of fibrotic liver; thereby further enhancing their efficacy for hepatic fibrosis.
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Affiliation(s)
- Maria Tayyab Baig
- National Centre of Excellence in Molecular Biology, University of Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Hafiz Ghufran
- National Centre of Excellence in Molecular Biology, University of Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Azra Mehmood
- National Centre of Excellence in Molecular Biology, University of Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Maryam Azam
- National Centre of Excellence in Molecular Biology, University of Punjab, 87-West Canal Bank Road, Lahore, Pakistan
| | - Shamsa Humayun
- Fatima Jinnah Medical University, Sir Ganga Ram Hospital, Lahore, Pakistan
| | - Sheikh Riazuddin
- National Centre of Excellence in Molecular Biology, University of Punjab, 87-West Canal Bank Road, Lahore, Pakistan; Allama Iqbal Medical Research Centre, Jinnah Burn and Reconstructive Surgery Centre, Lahore, Pakistan.
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Therapeutic Potential of Mesenchymal Stromal Cells and Extracellular Vesicles in the Treatment of Radiation Lesions-A Review. Cells 2021; 10:cells10020427. [PMID: 33670501 PMCID: PMC7922519 DOI: 10.3390/cells10020427] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 02/08/2021] [Accepted: 02/13/2021] [Indexed: 12/14/2022] Open
Abstract
Ionising radiation-induced normal tissue damage is a major concern in clinic and public health. It is the most limiting factor in radiotherapy treatment of malignant diseases. It can also cause a serious harm to populations exposed to accidental radiation exposure or nuclear warfare. With regard to the clinical use of radiation, there has been a number of modalities used in the field of radiotherapy. These includes physical modalities such modified collimators or fractionation schedules in radiotherapy. In addition, there are a number of pharmacological agents such as essential fatty acids, vasoactive drugs, enzyme inhibitors, antioxidants, and growth factors for the prevention or treatment of radiation lesions in general. However, at present, there is no standard procedure for the treatment of radiation-induced normal tissue lesions. Stem cells and their role in tissue regeneration have been known to biologists, in particular to radiobiologists, for many years. It was only recently that the potential of stem cells was studied in the treatment of radiation lesions. Stem cells, immediately after their successful isolation from a variety of animal and human tissues, demonstrated their likely application in the treatment of various diseases. This paper describes the types and origin of stem cells, their characteristics, current research, and reviews their potential in the treatment and regeneration of radiation induced normal tissue lesions. Adult stem cells, among those mesenchymal stem cells (MSCs), are the most extensively studied of stem cells. This review focuses on the effects of MSCs in the treatment of radiation lesions.
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Tani S, Okada H, Chung UI, Ohba S, Hojo H. The Progress of Stem Cell Technology for Skeletal Regeneration. Int J Mol Sci 2021; 22:1404. [PMID: 33573345 PMCID: PMC7866793 DOI: 10.3390/ijms22031404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/22/2021] [Accepted: 01/28/2021] [Indexed: 01/05/2023] Open
Abstract
Skeletal disorders, such as osteoarthritis and bone fractures, are among the major conditions that can compromise the quality of daily life of elderly individuals. To treat them, regenerative therapies using skeletal cells have been an attractive choice for patients with unmet clinical needs. Currently, there are two major strategies to prepare the cell sources. The first is to use induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs), which can recapitulate the skeletal developmental process and differentiate into various skeletal cells. Skeletal tissues are derived from three distinct origins: the neural crest, paraxial mesoderm, and lateral plate mesoderm. Thus, various protocols have been proposed to recapitulate the sequential process of skeletal development. The second strategy is to extract stem cells from skeletal tissues. In addition to mesenchymal stem/stromal cells (MSCs), multiple cell types have been identified as alternative cell sources. These cells have distinct multipotent properties allowing them to differentiate into skeletal cells and various potential applications for skeletal regeneration. In this review, we summarize state-of-the-art research in stem cell differentiation based on the understanding of embryogenic skeletal development and stem cells existing in skeletal tissues. We then discuss the potential applications of these cell types for regenerative medicine.
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Affiliation(s)
- Shoichiro Tani
- Sensory & Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (S.T.); (H.O.)
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
| | - Hiroyuki Okada
- Sensory & Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (S.T.); (H.O.)
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
| | - Ung-il Chung
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Shinsuke Ohba
- Department of Cell Biology, Institute of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan;
| | - Hironori Hojo
- Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
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Liang W, Chen X, Zhang S, Fang J, Chen M, Xu Y, Chen X. Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines. Cell Mol Biol Lett 2021; 26:3. [PMID: 33472580 PMCID: PMC7818947 DOI: 10.1186/s11658-020-00246-5] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 12/27/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial-mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites.
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Affiliation(s)
- Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan, 316000, Zhejiang, People's Republic of China.
| | - Xiaozhen Chen
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Songou Zhang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Jian Fang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Meikai Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Yifan Xu
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Xuerong Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
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Wu X, Zhang S, Lai J, Lu H, Sun Y, Guan W. Therapeutic Potential of Bama Pig Adipose-Derived Mesenchymal Stem Cells for the Treatment of Carbon Tetrachloride-Induced Liver Fibrosis. EXP CLIN TRANSPLANT 2020; 18:823-831. [PMID: 33349209 DOI: 10.6002/ect.2020.0108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Liver fibrosis is inevitable in the healing process of liver injury. Liver fibrosis will develop into liver cirrhosis unless the damaging factors are removed. This study investigated the potential therapy of Bama pig adipose-derived mesenchymal stem cells in a carbon tetrachloride-induced liver fibrosis Institute of Cancer Research strain mice model. MATERIALS AND METHODS Adipose-derived mesenchymal stem cells were injected intravenously into the tails of mice of the Institute of Cancer Research strain that had been treated with carbon tetrachloride for 4 weeks. Survival rate, migration, and proliferation of adipose-derived mesenchymal stem cells in the liver were observed by histochemistry, fluorescent labeling, and serological detection. RESULTS At 1, 2, and 3 weeks after adipose-derived mesenchymal stem cell injection, liver fibrosis was significantly ameliorated. The injected adipose-derived mesenchymal stem cells had hepatic differentiation potential in vivo, and the survival rate of adipose-derived mesenchymal stem cells declined over time. CONCLUSIONS The findings in this study confirmed that adipose-derived mesenchymal stem cells derived from the Bama pig can be used in the treatment of liver fibrosis, and the grafted adipose-derived mesenchy-mal stem cells can migrate, survive, and differentiate into hepatic cells in vivo.
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Affiliation(s)
- Xinran Wu
- From the Sport and Exercise Sciences Centre, University of Malaya, Kuala Lumpur, Malaysia
| | - Shuang Zhang
- From the Scientific Experimental Research Center, Harbin Sport University, Nangang District, Harbin, Heilongjiang Province, China
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50
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Gugjoo MB, Hussain S, Amarpal, Shah RA, Dhama K. Mesenchymal Stem Cell-Mediated Immuno-Modulatory and Anti- Inflammatory Mechanisms in Immune and Allergic Disorders. ACTA ACUST UNITED AC 2020; 14:3-14. [PMID: 32000656 PMCID: PMC7509741 DOI: 10.2174/1872213x14666200130100236] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 01/25/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023]
Abstract
Background: Mesenchymal Stem Cells (MSCs) are present in almost all the tissues of the body and act as the backbone of the internal tissue homeostasis. Among their various characteristic features, immuno-modulatory and/ anti-inflammatory properties play an important role in therapeutics. Objective: The current topic focuses on the characterization and immuno-modulatory and/ anti-inflammatory properties of MSCs. To present and discuss the current status of MSCs immuno-modulatory properties. Methods: Available literature on MSCs properties and patents have been detailed, critically interpreted, and discussed based upon available literature. The main focus has been on their characteristic immuno-modulatory and anti-inflammatory properties though some of the basic characterization markers have also been detailed. The databases searched for the literature include PubMed, Med Line, PubMed Central, Science Direct and a few other scientific databases. Results: MSCs are present in a very limited concentration in the tissues, and as such their culture expansion becomes imperative. MSCs immuno-modulatory and anti-inflammatory roles are achieved through direct cell-cell contact and / by the release of certain factors. Such properties are controlled by micro-environment upon which currently very limited control can be exerted. Besides, further insights in the xeno-protein free culture media as against the fetal bovine serum is required. Conclusion: MSCs have been well-isolated, cultured and characterized from numerous tissues of the body. The majority of the studies have shown MSCs as immuno-compromised with immunomodulatory and / or anti-inflammatory properties except some of the latest studies that have failed to achieve the desired results and thus, demand further research. Further research is required in the area to translate the results into clinical application.
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Affiliation(s)
- Mudasir B Gugjoo
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Shahid Hussain
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Amarpal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243 122, Uttar Pradesh, India
| | - Riaz A Shah
- Divison of Animal Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Kuldeep Dhama
- Division of Pathology, ICARIndian Veterinary Research Institute, Izatnagar, Bareilly, 243 122, Uttar Pradesh, India
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