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Wang Y, Pang X, Li R, Chen J, Wen C, Zhu H, Long T, Li J, Zheng L, Deng Y, Zheng J, Xu B. Mesenchymal Stem Cells Carrying Viral Fusogenic Protein p14 to Treat Solid Tumors by Inducing Cell-Cell Fusion and Immune Activation. RESEARCH (WASHINGTON, D.C.) 2025; 8:0594. [PMID: 39872128 PMCID: PMC11770199 DOI: 10.34133/research.0594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/29/2025]
Abstract
Background: Chimeric antigen receptor (CAR)-based immune cell therapies attack neighboring cancer cells after receptor recognition but are unable to directly affect distant tumor cells. This limitation may contribute to their inefficiency in treating solid tumors, given the restricted intratumoral infiltration and immunosuppressive tumor microenvironment. Therefore, cell-cell fusion as a cell-killing mechanism might develop a novel cytotherapy aimed at improving the efficacy against solid tumors. Methods: We constructed a fusogenic protein, fusion-associated small transmembrane (FAST) p14 of reptilian reovirus, into cancer cells and mesenchymal stem cells (MSCs), which cocultured with various colon cancer cells and melenoma cells to validate its ability to induce cell fusion and syncytia formation. RNA sequencing, quantitative reverse transcription polymerase chain reaction, and Western blot were performed to elucidate the mechanism of syncytia death. Cell viability assay was employed to assess the killing effects of MSCs carrying the p14 protein (MSCs-p14), which was also identified in the subcutaneous tumor models. Subsequently, the Tet-On system was introduced to enhance the controllability and safety of therapy. Results: Cancer cells incorporated with fusogenic protein p14 FAST from reovirus fused together to form syncytia and subsequently died through apoptosis and pyroptosis. MSCs-p14 cocultured with different cancer cells and effienctly induced cancer cell fusion and caused widespread cancer cell death in vitro. In mouse tumor models, mMSCs-p14 treatment markedly suppressed tumor growth and also enhanced the activity of natural killer cells and macrophages. Controllability and safety of MSCs-p14 therapy were further improved by introducing the tetracycline-controlled transcriptional system. Conclusion: MSC-based cytotherapy carrying viral fusogenic protein in this study kills cancer cells by inducing cell-cell fusion. It has demonstrated definite efficacy in treating solid tumors and is worth considering for clinical development.
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Affiliation(s)
- Yao Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Xunlei Pang
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Department of Gastroenterology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Ruirui Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jiuzhou Chen
- Department of Radiation Oncology, the Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu, China
| | - Chen Wen
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Huihuang Zhu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Tingyu Long
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jianjie Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Lijun Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Youcai Deng
- Department of Clinical Hematology,
College of Pharmacy and Laboratory Medicine Science, Army Medical University, Chongqing 400038, China
| | - Junnian Zheng
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Bo Xu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
- Center of Clinical Oncology,
The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy,
Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
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Chhipa AS, Boscaro V, Gallicchio M, Patel S. The curious case of type I interferon signaling in cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189204. [PMID: 39477031 DOI: 10.1016/j.bbcan.2024.189204] [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: 06/23/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/05/2024]
Abstract
Cytokines are the crucial signaling proteins that mediate the crosstalks between the cells of tumor microenvironment (TME). Interferon-1 (IFN-1) are the important cytokines that are widely known for their tumor suppressive roles comprising of cancer cell intrinsic and extrinsic mechanisms. Despite having known antitumor effects, IFN-1 are also reported to have tumor promoting functions under varying circumstances. This dichotomy in the functions of IFN-1 is largely attributed to the acute and chronic activation of IFN-1 signaling in TME. The chronic activation of IFN-1 signaling in tumor cells results in altered stimulation of downstream pathways that result in the expression of tumor promoting proteins, while the acute IFN-1 signaling activation maintains its tumor inhibiting functions. In the present review, we have discussed the anti- and pro-tumor actions of IFN-1 signaling under acute and chronic IFN-1 signaling activation. We have also discussed the downstream changes in signaling components that result in tumor supportive functions of a constitutive IFN-1 signaling. We have further discussed the possible strategies to overcome the detrimental effects of chronic IFN-1 pathway activation and to successfully employ IFN-1 for their beneficial anti-tumor effects.
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Affiliation(s)
- Abu Sufiyan Chhipa
- Department of Pharmacology, Institute of Pharmacy, Nirma University, 382481 Ahmedabad, India; Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | - Valentina Boscaro
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy
| | | | - Snehal Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, 382481 Ahmedabad, India.
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Zhou P, Ding X, Du X, Wang L, Zhang Y. Targeting Reprogrammed Cancer-Associated Fibroblasts with Engineered Mesenchymal Stem Cell Extracellular Vesicles for Pancreatic Cancer Treatment. Biomater Res 2024; 28:0050. [PMID: 39099892 PMCID: PMC11293949 DOI: 10.34133/bmr.0050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 06/06/2024] [Indexed: 08/06/2024] Open
Abstract
Background: As one of the most aggressive and lethal cancers, pancreatic cancer is highly associated with cancer-associated fibroblasts (CAFs) that influence the development and progression of cancer. Targeted reprogramming of CAFs may be a promising strategy for pancreatic cancer. This study aims to construct engineered extracellular vesicles (EVs) with surface modification of integrin α5 (ITGA5)-targeting peptide and high internal expression of miR-148a-3p by endogenous modification for targeted reprogramming of pancreatic CAFs. Methods: Bone marrow mesenchymal stem cells (BMSCs) and pancreatic CAFs were cocultured to examine the effect of BMSC-derived EVs on the expression levels of CAF markers. miR-148a-3p was identified as a functional molecule. The mechanism of miR-148a-3p was elucidated using the dual-luciferase reporter assay. BMSCs were infected with TERT-encoding and miR-148a-3p-encoding lentiviruses. Subsequently, BMSCs were modified with ITGA5-specific targeting peptide. The supernatant was ultracentrifuged to obtain the engineered EVs (ITGA5-EVs-148a), which were used to reprogram CAFs. Results: BMSCs modulated CAF marker expressions through EVs. miR-148a-3p was up-regulated in BMSCs. The expression of miR-148a-3p in pancreatic CAFs was down-regulated when compared with that in normal fibroblasts (NFs). Mechanistically, ITGA5-EVs-148a effectively suppressed the proliferation and migration of pancreatic CAFs by targeting ITGA5 through the TGF-β/SMAD pathway. ITGA5-EVs-148a was associated with enhanced cellular uptake and exhibited enhanced in vitro and in vivo targeting ability. Moreover, ITGA5-EVs-148a exerted strong reconfiguration effects in inactivating CAFs and reversing tumor-promoting effects in 3D heterospheroid and xenograft pancreatic cancer models. Conclusions: This targeted CAF reprogramming strategy with genetically engineered ITGA5-EVs-148a holds great promise as a precision therapeutics in clinical settings.
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Affiliation(s)
- Pengcheng Zhou
- School of Medicine,
Southeast University, Nanjing 210000, China
- Department of General Surgery,
Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Xian’guang Ding
- State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM),
Nanjing University of Posts and Telecommunications, Nanjing 210023, China
| | - Xuanlong Du
- School of Medicine,
Southeast University, Nanjing 210000, China
| | - Lianhui Wang
- State Key Laboratory of Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM),
Nanjing University of Posts and Telecommunications, Nanjing 210023, China
| | - Yewei Zhang
- Hepatobiliary and Pancreatic Center,
The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
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Mahadiuzzaman ASM, Dain Md Opo FA, Alkarim S. Stem cell-based targeted therapy in pancreatic cancer: Current approaches and future prospects. Tissue Cell 2024; 89:102449. [PMID: 38924893 DOI: 10.1016/j.tice.2024.102449] [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: 01/18/2024] [Revised: 05/22/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024]
Abstract
Despite recent improvements in oncology, diagnosis, and therapy, pancreatic cancer remains extremely difficult to cure due to its aggressive growth pattern with early invasion and distant metastases, chemoresistance, and a lack of effective screening modalities for early detection. Here, novel therapeutic approaches for treating pancreatic cancer are urgently needed. Recently, stem cells have drawn a lot of interest as a possible treatment for pancreatic cancer due to their ability to locate tumors. Though research over the last few decades has revealed some very exciting and promising new treatment approaches, the clinical success of these stem-cell based anti-cancer medicines has been quite limited. The most effective stem cell-mediated therapeutic options will only be available with a deeper understanding of the intricate molecular biology underlying pancreatic cancer and the subsequent identification of cancer stem cells as a novel target that promotes the growth of the cancer and resistance to chemotherapy. This review will highlight the stem cell based anti-cancer therapy targeting pancreatic cancer stem cells and different molecular signaling pathways. A particular focus will be on the therapeutic potential of naïve Stem cells, anti-cancer drug loaded stem cells, genetically engineered stem cells and exosomal miRNA released by stem cells in pancreatic cancer treatment. Similarly, the role of nanotechnology in stem cell based anticancer therapy will be further discussed to better implementation of these cell-based cancer therapy.
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Affiliation(s)
- A S M Mahadiuzzaman
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - F A Dain Md Opo
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Saleh Alkarim
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Embryonic and Cancer Stem Cell Research Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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5
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Taheri M, Tehrani HA, Dehghani S, Alibolandi M, Arefian E, Ramezani M. Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle. Med Res Rev 2024; 44:1596-1661. [PMID: 38299924 DOI: 10.1002/med.22023] [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: 12/08/2022] [Revised: 11/28/2023] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
Targeting actionable mutations in oncogene-driven cancers and the evolution of immuno-oncology are the two prominent revolutions that have influenced cancer treatment paradigms and caused the emergence of precision oncology. However, intertumoral and intratumoral heterogeneity are the main challenges in both fields of precision cancer treatment. In other words, finding a universal marker or pathway in patients suffering from a particular type of cancer is challenging. Therefore, targeting a single hallmark or pathway with a single targeted therapeutic will not be efficient for fighting against tumor heterogeneity. Mesenchymal stem cells (MSCs) possess favorable characteristics for cellular therapy, including their hypoimmune nature, inherent tumor-tropism property, straightforward isolation, and multilineage differentiation potential. MSCs can be loaded with various chemotherapeutics and oncolytic viruses. The combination of these intrinsic features with the possibility of genetic manipulation makes them a versatile tumor delivery vehicle that can be used for in vivo selective tumor delivery of various chemotherapeutic and biological therapeutics. MSCs can be used as biofactory for the local production of chemical or biological anticancer agents at the tumor site. MSC-mediated immunotherapy could facilitate the sustained release of immunotherapeutic agents specifically at the tumor site, and allow for the achievement of therapeutic concentrations without the need for repetitive systemic administration of high therapeutic doses. Despite the enthusiasm evoked by preclinical studies that used MSC in various cancer therapy approaches, the translation of MSCs into clinical applications has faced serious challenges. This manuscript, with a critical viewpoint, reviewed the preclinical and clinical studies that have evaluated MSCs as a selective tumor delivery tool in various cancer therapy approaches, including gene therapy, immunotherapy, and chemotherapy. Then, the novel nanotechnology and bioengineering approaches that can improve the potency of MSC for tumor targeting and overcoming challenges related to their low localization at the tumor sites are discussed.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Dehghani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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6
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Summers BS, Thomas Broome S, Pang TWR, Mundell HD, Koh Belic N, Tom NC, Ng ML, Yap M, Sen MK, Sedaghat S, Weible MW, Castorina A, Lim CK, Lovelace MD, Brew BJ. A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease. Int J Tryptophan Res 2024; 17:11786469241248287. [PMID: 38757094 PMCID: PMC11097742 DOI: 10.1177/11786469241248287] [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: 09/04/2023] [Accepted: 04/03/2024] [Indexed: 05/18/2024] Open
Abstract
Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.
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Affiliation(s)
- Benjamin Sebastian Summers
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Sarah Thomas Broome
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | | | - Hamish D Mundell
- Faculty of Medicine and Health, New South Wales Brain Tissue Resource Centre, School of Medical Sciences, Charles Perkins Centre, University of Sydney, NSW, Australia
| | - Naomi Koh Belic
- School of Life Sciences, University of Technology, Sydney, NSW, Australia
| | - Nicole C Tom
- Formerly of the Department of Physiology, University of Sydney, NSW, Australia
| | - Mei Li Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maylin Yap
- Formerly of the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Monokesh K Sen
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- School of Medicine, Western Sydney University, NSW, Australia
- Faculty of Medicine and Health, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Sara Sedaghat
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Michael W Weible
- School of Environment and Science, Griffith University, Brisbane, QLD, Australia
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia
| | - Alessandro Castorina
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | - Chai K Lim
- Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
| | - Michael D Lovelace
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Bruce J Brew
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
- Departments of Neurology and Immunology, St. Vincent’s Hospital, Sydney, NSW, Australia
- University of Notre Dame, Darlinghurst, Sydney, NSW, Australia
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Stepanov YV, Golovynska I, Ostrovska G, Pylyp L, Dovbynchuk T, Stepanova LI, Gorbach O, Shablii V, Xu H, Garmanchuk LV, Ohulchanskyy TY, Qu J, Solyanik GI. Human mesenchymal stem cells increase LLC metastasis and stimulate or decelerate tumor development depending on injection method and cell amount. Cytometry A 2024; 105:252-265. [PMID: 38038631 DOI: 10.1002/cyto.a.24814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/20/2023] [Accepted: 11/27/2023] [Indexed: 12/02/2023]
Abstract
Mesenchymal stem cells (MSCs) being injected into the body can stimulate or decelerate carcinogenesis. Here, the direction of influence of human placenta-derived MSCs (P-MSCs) on the Lewis lung carcinoma (LLC) tumor development and metastatic potential is investigated in C57BL/6 mice depending on the injection method. After intramuscular co-inoculation of LLC and P-MSCs (LLC + P-MSCs), the growth of primary tumor and angiogenesis are slowed down compared to the control LLC on the 15th day. This is explained by the fact of a decrease in the secretion of proangiogenic factors during in vitro co-cultivation of an equal amount of LLC and P-MSCs. When P-MSCs are intravenously (i.v.) injected in the mice with developing LLC (LLC + P-MSCs(i.v.)), the tumor growth and angiogenesis are stimulated on the 15th day. A highly activated secretion of proangiogenic factors by P-MSCs in a similar in vitro model can explain this. In both the models compared to the control on the 23rd day, there is no significant difference in the tumor growth, while angiogenesis remains correspondingly decelerated or stimulated. However, in both the models, the total volume and number of lung metastases constantly increase compared to the control: it is mainly due to small-size metastases for LLC + P-MSCs(i.v.) and larger ones for LLC + P-MSCs. The increase in the rate of LLC cell dissemination after the injection of P-MSCs is explained by the disordered polyploidy and chromosomal instability, leading to an increase in migration and invasion of cancer cells. After LLC + P-MSCs co-inoculation, the tumor cell karyotype has the most complex and heterogeneous chromosomal structure. These findings indicate a bidirectional effect of P-MSCs on the growth of LLC in the early periods after injection, depending on the injection method, and, correspondingly, the number of contacting cells. However, regardless of the injection method, P-MSCs are shown to increase LLC aggressiveness related to cancer-associated angiogenesis and metastasis activation in the long term.
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Affiliation(s)
- Yurii V Stepanov
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
- Laboratory of Molecular and Cellular Mechanisms of Metastasis, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
| | - Iuliia Golovynska
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Galyna Ostrovska
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Larysa Pylyp
- Clinic of Reproductive Medicine "Nadiya", Kyiv, Ukraine
| | - Taisa Dovbynchuk
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Liudmyla I Stepanova
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Oleksandr Gorbach
- Laboratory of Experimental Oncology, National Cancer Institute of Ukraine, Kyiv, Ukraine
| | - Volodymyr Shablii
- Institute of Molecular Biology and Genetics, NAS of Ukraine, Kyiv, Ukraine
- Institute of Cell Therapy, Kyiv, Ukraine
| | - Hao Xu
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Liudmyla V Garmanchuk
- Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine
| | - Tymish Y Ohulchanskyy
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Junle Qu
- Shenzhen Key Laboratory of Photonics and Biophotonics, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, People's Republic of China
| | - Galina I Solyanik
- Laboratory of Molecular and Cellular Mechanisms of Metastasis, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
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8
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Wu CH, Weng TF, Li JP, Wu KH. Biology and Therapeutic Properties of Mesenchymal Stem Cells in Leukemia. Int J Mol Sci 2024; 25:2527. [PMID: 38473775 DOI: 10.3390/ijms25052527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/08/2024] [Accepted: 02/15/2024] [Indexed: 03/14/2024] Open
Abstract
This comprehensive review delves into the multifaceted roles of mesenchymal stem cells (MSCs) in leukemia, focusing on their interactions within the bone marrow microenvironment and their impact on leukemia pathogenesis, progression, and treatment resistance. MSCs, characterized by their ability to differentiate into various cell types and modulate the immune system, are integral to the BM niche, influencing hematopoietic stem cell maintenance and functionality. This review extensively explores the intricate relationship between MSCs and leukemic cells in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. This review also addresses the potential clinical applications of MSCs in leukemia treatment. MSCs' role in hematopoietic stem cell transplantation, their antitumor effects, and strategies to disrupt chemo-resistance are discussed. Despite their therapeutic potential, the dual nature of MSCs in promoting and inhibiting tumor growth poses significant challenges. Further research is needed to understand MSCs' biological mechanisms in hematologic malignancies and develop targeted therapeutic strategies. This in-depth exploration of MSCs in leukemia provides crucial insights for advancing treatment modalities and improving patient outcomes in hematologic malignancies.
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Affiliation(s)
- Cheng-Hsien Wu
- School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
| | - Te-Fu Weng
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Ju-Pi Li
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- Department of Pathology, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Kang-Hsi Wu
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung 402, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
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Gornostaeva AN, Bobyleva PI, Andreeva ER, Gogiya BS, Buravkova LB. Alteration of PBMC transcriptome profile after interaction with multipotent mesenchymal stromal cells under "physiological" hypoxia. Immunobiology 2024; 229:152766. [PMID: 38091798 DOI: 10.1016/j.imbio.2023.152766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 11/17/2023] [Accepted: 11/22/2023] [Indexed: 01/21/2024]
Abstract
Multipotent mesenchymal stromal cells (MSCs) have demonstrated a pronounced immunosuppressive activity, the manifestation of which depends on the microenvironmental factors, including O2 level. Here we examined the effects of MSCs on transcriptomic profile of allogeneic phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs) after interaction at ambient (20%) or "physiological" hypoxia (5%) O2. As revealed with microarray analysis, PBMC transcriptome at 20% O2 was more affected, which was manifested as differential expression of more than 300 genes, whereas under 5% O2 220 genes were changed. Most of genes at 20% O2 were downregulated, while at hypoxia most of genes were upregulated. Altered gene patterns were only partly overlapped at different O2 levels. A set of altered genes at hypoxia only was of particular interest. According to Gene Ontology a part of above genes was responsible for adhesion, cell communication, and immune response. At both oxygen concentrations, MSCs demonstrated effective immunosuppression manifested as attenuation of T cell activation and proliferation as well as anti-inflammatory shift of cytokine profile. Thus, MSC-mediated immunosuppression is executed with greater efficacy at a "physiological" hypoxia, since the same result has been achieved through a change in the expression of a fewer genes in target PBMCs.
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Affiliation(s)
- A N Gornostaeva
- Cell Physiology Laboratory, Institute of Biomedical Problems, Russian Academy of Sciences, Khoroshevskoye shosse 76a, 123007 Moscow, Russia.
| | - P I Bobyleva
- Cell Physiology Laboratory, Institute of Biomedical Problems, Russian Academy of Sciences, Khoroshevskoye shosse 76a, 123007 Moscow, Russia
| | - E R Andreeva
- Cell Physiology Laboratory, Institute of Biomedical Problems, Russian Academy of Sciences, Khoroshevskoye shosse 76a, 123007 Moscow, Russia
| | - B Sh Gogiya
- Department of Herniology and Plastic Surgery, A. V. Vishnevsky Institute of Surgery, Bolshaya Serpukhovskaya Str, 27, 117997 Moscow, Russia
| | - L B Buravkova
- Cell Physiology Laboratory, Institute of Biomedical Problems, Russian Academy of Sciences, Khoroshevskoye shosse 76a, 123007 Moscow, Russia
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10
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Alhattab DM, Isaioglou I, Alshehri S, Khan ZN, Susapto HH, Li Y, Marghani Y, Alghuneim AA, Díaz-Rúa R, Abdelrahman S, Al-Bihani S, Ahmed F, Felimban RI, Alkhatabi H, Alserihi R, Abedalthagafi M, AlFadel A, Awidi A, Chaudhary AG, Merzaban J, Hauser CAE. Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system. Biomater Res 2023; 27:111. [PMID: 37932837 PMCID: PMC10626721 DOI: 10.1186/s40824-023-00457-9] [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: 08/28/2023] [Accepted: 10/29/2023] [Indexed: 11/08/2023] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a hematological malignancy that remains a therapeutic challenge due to the high incidence of disease relapse. To better understand resistance mechanisms and identify novel therapies, robust preclinical models mimicking the bone marrow (BM) microenvironment are needed. This study aimed to achieve an automated fabrication process of a three-dimensional (3D) AML disease model that recapitulates the 3D spatial structure of the BM microenvironment and applies to drug screening and investigational studies. METHODS To build this model, we investigated a unique class of tetramer peptides with an innate ability to self-assemble into stable hydrogel. An automated robotic bioprinting process was established to fabricate a 3D BM (niche-like) multicellular AML disease model comprised of leukemia cells and the BM's stromal and endothelial cellular fractions. In addition, monoculture and dual-culture models were also fabricated. Leukemia cell compatibility, functionalities (in vitro and in vivo), and drug assessment studies using our model were performed. In addition, RNAseq and gene expression analysis using TaqMan arrays were also performed on 3D cultured stromal cells and primary leukemia cells. RESULTS The selected peptide hydrogel formed a highly porous network of nanofibers with mechanical properties similar to the BM extracellular matrix. The robotic bioprinter and the novel quadruple coaxial nozzle enabled the automated fabrication of a 3D BM niche-like AML disease model with controlled deposition of multiple cell types into the model. This model supported the viability and growth of primary leukemic, endothelial, and stromal cells and recapitulated cell-cell and cell-ECM interactions. In addition, AML cells in our model possessed quiescent characteristics with improved chemoresistance attributes, resembling more the native conditions as indicated by our in vivo results. Moreover, the whole transcriptome data demonstrated the effect of 3D culture on enhancing BM niche cell characteristics. We identified molecular pathways upregulated in AML cells in our 3D model that might contribute to AML drug resistance and disease relapse. CONCLUSIONS Our results demonstrate the importance of developing 3D biomimicry models that closely recapitulate the in vivo conditions to gain deeper insights into drug resistance mechanisms and novel therapy development. These models can also improve personalized medicine by testing patient-specific treatments.
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Affiliation(s)
- Dana M Alhattab
- Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
- KAUST Smart Health Initiative (KSHI), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Ioannis Isaioglou
- Cell Migration and Signaling Laboratory, Bioscience Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Salwa Alshehri
- Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Zainab N Khan
- Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
- Red Sea Research Center (RSRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Hepi H Susapto
- Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Yanyan Li
- Cell Migration and Signaling Laboratory, Bioscience Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Yara Marghani
- Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Arwa A Alghuneim
- Cell Migration and Signaling Laboratory, Bioscience Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Rubén Díaz-Rúa
- Core Laboratories, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Sherin Abdelrahman
- Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia
| | - Shuroug Al-Bihani
- Core Laboratories, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Farid Ahmed
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Raed I Felimban
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Heba Alkhatabi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
- Hematology Research Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Raed Alserihi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Malak Abedalthagafi
- Department of Pathology and Laboratory Medicine, Emory School of Medicine, Atlanta, USA
| | - AlShaibani AlFadel
- Division of Hematology, Stem Cell Transplantation & Cellular Therapy, Oncology Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Abdalla Awidi
- Cell Therapy Center, The University of Jordan, Amman, Jordan
- Medical School, The University of Jordan, Amman, Jordan
- Jordan University Hospital, Amman, Jordan
| | - Adeel Gulzar Chaudhary
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Jasmeen Merzaban
- Cell Migration and Signaling Laboratory, Bioscience Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Charlotte A E Hauser
- Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
- KAUST Smart Health Initiative (KSHI), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
- Red Sea Research Center (RSRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
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11
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Jahani S, Zare N, Mirzaei Y, Arefnezhad R, Zarei H, Goleij P, Bagheri N. Mesenchymal stem cells and ovarian cancer: Is there promising news? J Cell Biochem 2023; 124:1437-1448. [PMID: 37682985 DOI: 10.1002/jcb.30471] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/24/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023]
Abstract
Ovarian cancer (OC) is described as a heterogeneous complex condition with high mortality, weak prognosis, and late-stage presentation. OC has several subgroups based on different indices, like the origin and histopathology. The current treatments against OC include surgery followed by chemotherapy and radiotherapy; however, these methods have represented diverse side effects without enough effectiveness on OC. Recently, mesenchymal stem cell (MSC)-based therapy has acquired particular attention for treating diverse problems, such as cancer. These multipotent stem cells can be obtained from different sources, such as the umbilical cord, adipose tissues, bone marrow, and placenta, and their efficacy has been investigated against OC. Hence, in this narrative review, we aimed to review and discuss the present studies about the effects of various sources of MSCs on OC with a special focus on involved mechanisms.
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Affiliation(s)
| | - Nabi Zare
- Coenzyme R Research Institute, Tehran, Iran
| | - Yousef Mirzaei
- Department of Medical Biochemical Analysis, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq
| | | | - Hooman Zarei
- Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pouya Goleij
- Department of Genetics, Sana Institute of Higher Education, Sari, Iran
- International Network of Stem Cell (INSC), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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12
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Giuli L, Santopaolo F, Pallozzi M, Pellegrino A, Coppola G, Gasbarrini A, Ponziani FR. Cellular therapies in liver and pancreatic diseases. Dig Liver Dis 2023; 55:563-579. [PMID: 36543708 DOI: 10.1016/j.dld.2022.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/21/2022] [Accepted: 11/22/2022] [Indexed: 04/29/2023]
Abstract
Over the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue regeneration, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine.
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Affiliation(s)
- Lucia Giuli
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Maria Pallozzi
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Pellegrino
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gaetano Coppola
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Università Cattolica del Sacro Cuore, Rome, Italy
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13
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The Role of Mesenchymal Stem Cells and Exosomes in Tumor Development and Targeted Antitumor Therapies. Stem Cells Int 2023; 2023:7059289. [PMID: 36824409 PMCID: PMC9943627 DOI: 10.1155/2023/7059289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 01/17/2023] [Accepted: 02/03/2023] [Indexed: 02/17/2023] Open
Abstract
Mesenchymal stem cells (MSCs) can be isolated from various tissues in adults and differentiated into cells of the osteoblasts, adipocytes, chondrocytes, and myocytes. Recruitments of MSCs towards tumors have a crucial contribution to tumor development. However, the role of MSCs in the tumor microenvironment is uncertain. In addition, due to its tropism to the tumor and low immunogenic properties, more and more pieces of evidence indicate that MSCs may be an ideal carrier for antitumor biologics such as cytokines, chemotherapeutic agents, and oncolytic viruses. Here, we review the existing knowledge on the anti- and protumorigenic effect of MSCs and their extracellular vesicles and exosomes, the role of MSCs, and their extracellular vesicles and exosomes as antitumor vectors.
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14
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Ma Z, Hua J, Liu J, Zhang B, Wang W, Yu X, Xu J. Mesenchymal Stromal Cell-Based Targeted Therapy Pancreatic Cancer: Progress and Challenges. Int J Mol Sci 2023; 24:ijms24043559. [PMID: 36834969 PMCID: PMC9966548 DOI: 10.3390/ijms24043559] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/18/2023] [Accepted: 02/01/2023] [Indexed: 02/12/2023] Open
Abstract
Pancreatic cancer is an aggressive malignancy with high mortality rates and poor prognoses. Despite rapid progress in the diagnosis and treatment of pancreatic cancer, the efficacy of current therapeutic strategies remains limited. Hence, better alternative therapeutic options for treating pancreatic cancer need to be urgently explored. Mesenchymal stromal cells (MSCs) have recently received much attention as a potential therapy for pancreatic cancer owing to their tumor-homing properties. However, the specific antitumor effect of MSCs is still controversial. To this end, we aimed to focus on the potential anti-cancer treatment prospects of the MSC-based approach and summarize current challenges in the clinical application of MSCs to treat pancreatic cancer.
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Affiliation(s)
- Zhilong Ma
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
- Correspondence: (X.Y.); (J.X.); Tel.: +86-021-64175590 (X.Y.); +86-021-64031446 (J.X.)
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong’An Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, No. 270 Dong’An Road, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
- Correspondence: (X.Y.); (J.X.); Tel.: +86-021-64175590 (X.Y.); +86-021-64031446 (J.X.)
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15
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Jiang Z, Xu Y, Fu M, Zhu D, Li N, Yang G. Genetically modified cell spheroids for tissue engineering and regenerative medicine. J Control Release 2023; 354:588-605. [PMID: 36657601 DOI: 10.1016/j.jconrel.2023.01.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 01/11/2023] [Accepted: 01/12/2023] [Indexed: 01/21/2023]
Abstract
Cell spheroids offer cell-to-cell interactions and show advantages in survival rate and paracrine effect to solve clinical and biomedical inquiries ranging from tissue engineering and regenerative medicine to disease pathophysiology. Therefore, cell spheroids are ideal vehicles for gene delivery. Genetically modified spheroids can enhance specific gene expression to promote tissue regeneration. Gene deliveries to cell spheroids are via viral vectors or non-viral vectors. Some new technologies like CRISPR/Cas9 also have been used in genetically modified methods to deliver exogenous gene to the host chromosome. It has been shown that genetically modified cell spheroids had the potential to differentiate into bone, cartilage, vascular, nerve, cardiomyocytes, skin, and skeletal muscle as well as organs like the liver to replace the diseased organ in the animal and pre-clinical trials. This article reviews the recent articles about genetically modified spheroid cells and explains the fabrication, applications, development timeline, limitations, and future directions of genetically modified cell spheroid.
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Affiliation(s)
- Zhiwei Jiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Yi Xu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Mengdie Fu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Danji Zhu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Na Li
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Guoli Yang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China.
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16
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Development of minimally invasive cancer immunotherapy using anti-disialoganglioside GD2 antibody-producing mesenchymal stem cells for a neuroblastoma mouse model. Pediatr Surg Int 2022; 39:43. [PMID: 36484857 DOI: 10.1007/s00383-022-05310-z] [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] [Accepted: 11/17/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE Mouse IgG anti-disialoganglioside GD2 antibody-secreting mouse mesenchymal stem cells (anti-GD2-MSCs) were developed, and their anti-tumor effects were validated in an in vivo neuroblastoma mouse model. METHODS Anti-GD2 antibody constructs were generated, incorporating FLAG-tagged single-chain fragment variables against GD2 fused to a linker sequence, and a fragment of a stationary portion was changed from human IgG to mouse IgG and GFP protein. The construct was lentivirally introduced into mouse MSCs. A syngeneic mouse model was established through the subcutaneous transplantation of a tumor tissue fragment from a TH-MYCN transgenic mouse, and the homing effects of anti-GD2-MSCs were validated by In vivo imaging system imaging. The syngeneic model was divided into three groups according to topical injection materials: anti-GD2-MSCs with IL-2, IL-2, and PBS. The tumors were removed, and natural killer (NK) cells were counted. RESULTS Anti-GD2-MSCs showed homing effects in syngeneic models. The growth rate of subcutaneous tumors was significantly suppressed by anti-GD2-MSCs with IL-2 (p < 0.05). Subcutaneous tumor immunostaining showed an increased NK cell infiltration in the same group (p < 0.01). CONCLUSION Anti-GD2-MSCs using mouse IgG showed a homing effect and significant tumor growth suppression in syngeneic models. Anti-GD2-MSC-based cellular immunotherapy could be a novel therapeutic strategy for intractable neuroblastoma.
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17
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Antoon R, Wang XH, Saleh AH, Warrington J, Hedley DW, Keating A. Pancreatic cancer growth promoted by bone marrow mesenchymal stromal cell-derived IL-6 is reversed predominantly by IL-6 blockade. Cytotherapy 2022; 24:699-710. [PMID: 35473998 DOI: 10.1016/j.jcyt.2021.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 11/17/2021] [Accepted: 12/06/2021] [Indexed: 12/26/2022]
Abstract
Pancreatic cancer is a highly lethal cancer characterized by local invasiveness, early metastasis, recurrence and high resistance to current therapies. Extensive stroma or desmoplasia is a key histological feature of the disease, and interactions between cancer and stromal cells are critical for pancreatic cancer development and progression. Mesenchymal stromal cells [MSCs] exhibit preferential tropism to primary and metastatic tumor sites and may either suppress or support tumor growth. Although MSCs represent a potential source of pancreatic cancer stroma, their contribution to pancreatic tumor growth remains poorly known. Here, we show that bone marrow MSCs significantly contribute to pancreatic cancer growth in vitro and in vivo. Furthermore, MSCs create a pro-carcinogenic microenvironment through the release of key factors mediating growth and angiogenesis, including interleukin (IL)-6, IL-8, vascular endothelial growth factor and activation of STAT3 signaling in tumor cells. IL-6 released by MSCs was largely responsible for the pro-tumorigenic effects of MSCs. Knockdown of IL-6 expression in MSCs by small interfering RNA (siRNA) abolished the MSC growth-promoting effect in vitro, reducing tumor cell proliferation and clonogenic potential. In addition, in a heterotopic nude mouse model of human pancreatic tumor xenografts, blockade of IL-6 with the anti-IL-6 receptor antibody, tocilizumab, or of its downstream effector STAT3 with the small molecule STAT3 inhibitor S3I-201, abrogated MSC-mediated tumor promotion and delayed tumor formation significantly. Our data demonstrate that MSCs promote pancreatic cancer growth, with IL-6 produced by MSCs playing a pivotal role.
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Affiliation(s)
- Roula Antoon
- Krembil Research Institute, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | | | - Amr H Saleh
- Krembil Research Institute, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | | | - David W Hedley
- Princess Margaret Cancer Centre, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Armand Keating
- Krembil Research Institute, Toronto, ON, Canada; Princess Margaret Cancer Centre, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
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18
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Yang T, Tang S, Peng S, Ding G. The Effects of Mesenchymal Stem Cells on Oral Cancer and Possible Therapy Regime. Front Genet 2022; 13:949770. [PMID: 35846142 PMCID: PMC9280436 DOI: 10.3389/fgene.2022.949770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are characterized by self-renewal, rapid proliferation, multipotent differentiation, and low immunogenicity. In addition, the tropism of MSCs towards injured tissues and tumor lesions makes them attractive candidates as cell carriers for therapeutic agent delivery and genetic material transfer. The interaction between tumor cells and MSCs in the tumor microenvironment plays an important role in tumor progression. Oral cancer is one of the most common malignant diseases in the head and neck. Although considerable improvements in the treatment of oral cancer were achieved, more effective and safer novel agents and treatments are still needed, and deeper studies on the etiology, pathology, and treatment of the oral cancer are desirable. In the past decades, many studies have reported the beneficial effects of MSCs-based therapies in the treatment of various diseases, including oral cancers. Meanwhile, other studies demonstrated that MSCs may enhance the growth and metastasis of oral cancer. In this paper, we reviewed the research progress of the effects of MSCs on oral cancers, the underlying mechanisms, and their potential applications in the treatment of oral cancers.
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Masoudi MR, Rafati A. Immunogenicity against hepatitis C virus with mesenchymal stem cells of inbreed BALB/c mice sub cloned with HCVcp protein gene. Transpl Immunol 2022; 74:101651. [PMID: 35764239 DOI: 10.1016/j.trim.2022.101651] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/09/2022] [Accepted: 06/22/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND AND AIM Hepatitis C is one of the leading causes of liver disease in the world and despite extensive research, there is still no vaccine against it. Researchers have identified cell-based therapies as an alternative strategy in advanced liver disorders. The aim of this study was to transfer the hepatitis C virus core protein (HCVcp) gene into mesenchymal stem cells and to evaluate its immunogenicity after injection into mice. MATERIALS AND METHODS The present study had two experimental and animal stages. In the first step, by designing a vector containing the HCVcp gene and transferring it into the mesenchymal stem cell, gene expression and protein production by the mesenchymal stem cell manipulated by PCR and SDS-PAGE were confirmed. In the second stage, by injecting manipulated mesenchymal stem cells into mice, the level of humoral immune stimulation and splenocytes proliferation was assessed by the ELISA commercial kit. RESULTS According to molecular studies, the expression of HCVcp was confirmed by mesenchymal stem cells. Also, splenocytes proliferation rate (0.316 ± 0.029) and antibody titer (284 ± 47) in mice treated with manipulated mesenchymal stem cells were significantly increased compared to the control group. CONCLUSION The results of the present study showed that the use of genetically engineered mesenchymal stem cells while maintaining the immunomodulatory properties of these cells can stimulate specific immune system responses against hepatitis C central protein.
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Affiliation(s)
- Mahmood Reza Masoudi
- Department of Internal Medicine, Sirjan School of Medical Sciences, Sirjan, Iran
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Chen YC, Lan YW, Huang SM, Yen CC, Chen W, Wu WJ, Staniczek T, Chong KY, Chen CM. Human amniotic fluid mesenchymal stem cells attenuate pancreatic cancer cell proliferation and tumor growth in an orthotopic xenograft mouse model. Stem Cell Res Ther 2022; 13:235. [PMID: 35659367 PMCID: PMC9166578 DOI: 10.1186/s13287-022-02910-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 05/20/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer and chemotherapy ineffectively treats PDAC, leading to the requirement for alternative tumor-targeted treatment. Human amniotic fluid mesenchymal stem cells (hAFMSCs) have been revealed to suppress tumor growth in various cancers and they are a strong candidate for treating PDAC. METHODS To evaluate the effects of hAFMSCs on human pancreatic carcinoma cells (PANC1, AsPC1 and BxPC3 cell lines) and the possible mechanism involved, an in vitro cell coculture system was used. A PANC1 orthotopic xenograft mouse model was established and hAFMSCs were injected intravenously at 4 weeks post-xenograft. RESULTS An in vitro coculture assay showed that hAFMSCs inhibited PANC1 cell proliferation by inducing S phase cell cycle arrest and increased cell apoptosis in a time-dependent manner. In PANC1 cells, hAFMSCs caused the downregulation of Cyclin A and Cyclin B1 as well as the upregulation of p21 (CDKN1A) at 24 h post coculture. The upregulation of pro-apoptotic factors Caspase-3/-8 and Bax at 24 h post coculture reduced the migration and invasion ability of PANC1 cells through inhibiting the epithelial-mesenchymal transition (EMT) process. In a PANC1 orthotopic xenograft mouse model, a single injection of hAFMSCs showed significant tumor growth inhibition with evidence of the modulation of cell cycle and pro-apoptotic regulatory genes and various genes involved in matrix metallopeptidase 7 (MMP7) signaling-triggered EMT process. Histopathological staining showed lower Ki67 levels in tumors from hAFMSCs-treated mice. CONCLUSIONS Our data demonstrated that hAFMSCs strongly inhibit PDAC cell proliferation, tumor growth and invasion, possibly by altering cell cycle arrest and MMP7 signaling-triggered EMT.
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Affiliation(s)
- Ying-Cheng Chen
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Kuo Kuang Rd, Taichung, 402 Taiwan
| | - Ying-Wei Lan
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Kuo Kuang Rd, Taichung, 402 Taiwan
| | - Shiaw-Min Huang
- Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, 300 Taiwan
| | - Chih-Ching Yen
- Department of Internal Medicine, China Medical University Hospital, and College of Health Care, China Medical University, Taichung, 404 Taiwan
| | - Wei Chen
- Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Wan-Ju Wu
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Kuo Kuang Rd, Taichung, 402 Taiwan
| | - Theresa Staniczek
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Kuo Kuang Rd, Taichung, 402 Taiwan
- Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, and Center of Excellence in Dermatology, Heidelberg University, 69117 Mannheim, Germany
| | - Kowit-Yu Chong
- Department of Medical Biotechnology and Laboratory Science and Division of Biotechnology, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan 333 Taiwan
| | - Chuan-Mu Chen
- Department of Life Sciences, and Ph.D. Program in Translational Medicine, College of Life Sciences, National Chung Hsing University, Kuo Kuang Rd, Taichung, 402 Taiwan
- The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, 402 Taiwan
- Rong Hsing Research Center for Translational Medicine, Taichung Veterans General Hospital, Taichung, 407 Taiwan
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21
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Belmar-López C, Vassaux G, Medel-Martinez A, Burnet J, Quintanilla M, Ramón y Cajal S, Hernandez-Losa J, De la Vieja A, Martin-Duque P. Mesenchymal Stem Cells Delivery in Individuals with Different Pathologies: Multimodal Tracking, Safety and Future Applications. Int J Mol Sci 2022; 23:ijms23031682. [PMID: 35163605 PMCID: PMC8835939 DOI: 10.3390/ijms23031682] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/27/2022] [Accepted: 01/27/2022] [Indexed: 02/05/2023] Open
Abstract
Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. As most of the individuals joining clinical trials that use MSCs for cancer and other pathologies are carefully recruited and do not suffer from other diseases, here we decided to study the safety and application of iv-injected MSCs in animals simultaneously induced with different inflammatory pathologies (diabetes, wound healing and tumors). We studied this by in vitro and in vivo approaches using different gene reporters (GFP, hNIS, and f-Luc) and non-invasive techniques (PET, BLI, or fluorescence). Our results found that MSCs reached different organs depending on the previously induced pathology. Moreover, we evaluated the property of MSCs to target tumors as vectors to deliver adenoviruses, including the interaction between tumor microenvironment and MSCs on their arrival. Mechanisms such as transdifferentiation, MSC fusion with cells, or paracrine processes after MSCs homing were studied, increasing the knowledge and safety of this new therapy for cancer.
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Affiliation(s)
- Carolina Belmar-López
- Instituto Aragonés de Ciencias de la Salud/IIS Aragón, 50009 Zaragoza, Spain; (C.B.-L.); (A.M.-M.)
| | - Georges Vassaux
- Institut de Pharmacologie Moléculaire et Cellulaire, INSERM, CNRS, Université Côte d’Azur, 06560 Valbonne, France;
| | - Ana Medel-Martinez
- Instituto Aragonés de Ciencias de la Salud/IIS Aragón, 50009 Zaragoza, Spain; (C.B.-L.); (A.M.-M.)
| | - Jerome Burnet
- Cancer Research UK, Queen Mary University of London, London E1 4NS, UK;
| | - Miguel Quintanilla
- Instituto de Investigaciones Biomedicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain;
| | - Santiago Ramón y Cajal
- Pathology Department, Hospital Universitari Vall d’Hebron, 08035 Barcelona, Spain; (S.R.y.C.); (J.H.-L.)
| | - Javier Hernandez-Losa
- Pathology Department, Hospital Universitari Vall d’Hebron, 08035 Barcelona, Spain; (S.R.y.C.); (J.H.-L.)
| | - Antonio De la Vieja
- Endocrine Tumors Unit, Unidad Funcional de Investigación en Enfermedades Endocrinas (UFIEC), Instituto de Salud Carlos III (ISCIII), 28222 Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Correspondence: (A.D.l.V.); (P.M.-D.)
| | - Pilar Martin-Duque
- Instituto Aragonés de Ciencias de la Salud/IIS Aragón, 50009 Zaragoza, Spain; (C.B.-L.); (A.M.-M.)
- Fundación ARAID, 50018 Zaragoza, Spain
- Networking Research Center in Biomaterials, Bioengineering and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (A.D.l.V.); (P.M.-D.)
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22
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Niknam MR, Attari F. The Potential Applications of Stem Cells for Cancer Treatment. Curr Stem Cell Res Ther 2022; 17:26-42. [PMID: 35048802 DOI: 10.2174/1574888x16666210810100858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/26/2021] [Accepted: 06/01/2021] [Indexed: 01/10/2023]
Abstract
:
Scientists encounter many obstacles in traditional cancer therapies, including the side effects
on the healthy cells, drug resistance, tumor relapse, the short half-life of employed drugs in
the blood circulation, and the improper delivery of drugs toward the tumor site. The unique traits of
stem cells (SCs) such as self-renewal, differentiation, tumor tropism, the release of bioactive
molecules, and immunosuppression have opened a new window for utilizing SCs as a novel tool in
cancer treatment. In this regard, engineered SCs can secrete anti-cancer proteins or express enzymes
used in suicide gene therapy which locally induce apoptosis in neoplastic cells via the bystander
effect. These cells also stand as proper candidates to serve as careers for drug-loaded nanoparticles
or to play suitable hosts for oncolytic viruses. Moreover, they harbor great potential to be
employed in immunotherapy and combination therapy. However, tactful strategies should be devised
to allow easier transplantation and protection of SCs from in vivo immune responses. In spite
of the great hope concerning SCs application in cancer therapy, there are shortcomings and challenges
to be addressed. This review tends to elaborate on recent advances on the various applications
of SCs in cancer therapy and existing challenges in this regard.
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Affiliation(s)
- Malikeh Rad Niknam
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Farnoosh Attari
- Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
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23
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Delinassios JG, Hoffman RM. The cancer-inhibitory effects of proliferating tumor-residing fibroblasts. Biochim Biophys Acta Rev Cancer 2021; 1877:188673. [PMID: 34953931 DOI: 10.1016/j.bbcan.2021.188673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/09/2021] [Accepted: 12/17/2021] [Indexed: 11/19/2022]
Abstract
Initiation, local progression, and metastasis of cancer are associated with specific morphological, molecular, and functional changes in the extracellular matrix and the fibroblasts within the tumor microenvironment (TME). In the early stages of tumor development, fibroblasts are an obstacle that cancer cells must surpass or nullify to progress. Thus, in early tumor progression, specific signaling from cancer cells activates bio-pathways, which abolish the innate anticancer properties of fibroblasts and convert a high proportion of them to tumor-promoting cancer-associated fibroblasts (CAFs). Following this initial event, a wide spectrum of gene expression changes gradually leads to the development of a stromal fibroblast population with complex heterogeneity, creating fibroblast subtypes with characteristic profiles, which may alternate between being tumor-promotive and tumor-suppressive, topologically and chronologically in the TME. These fibroblast subtypes form the tumor's histological landscape including areas of cancer growth, inflammation, angiogenesis, invasion fronts, proliferating and non-proliferating fibroblasts, cancer-cell apoptosis, fibroblast apoptosis, and necrosis. These features reflect general deregulation of tissue homeostasis within the TME. This review discusses fundamental and current knowledge that has established the existence of anticancer fibroblasts within the various interacting elements of the TME. It is proposed that the maintenance of fibroblast proliferation is an essential parameter for the activation of their anticancer capacity, similar to that by which normal fibroblasts would be activated in wound repair, thus maintaining tissue homeostasis. Encouragement of research in this direction may render new means of cancer therapy and a greater understanding of tumor progression.
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Affiliation(s)
- John G Delinassios
- International Institute of Anticancer Research, 1(st) km Kapandritiou-Kalamou Rd., Kapandriti, 19014 Attica, Greece.
| | - Robert M Hoffman
- Department of Surgery, University of California, 9300 Campus Point Drive, La Jolla, CA 92037, USA; AntiCancer Inc., 7917 Ostrow St, San Diego, CA 92111, USA.
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Fathi E, Vandghanooni S, Montazersaheb S, Farahzadi R. Mesenchymal stem cells promote caspase-3 expression of SH-SY5Y neuroblastoma cells via reducing telomerase activity and telomere length. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1583-1589. [PMID: 35317118 PMCID: PMC8917842 DOI: 10.22038/ijbms.2021.59400.13187] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 10/26/2021] [Indexed: 01/14/2023]
Abstract
OBJECTIVES The use of mesenchymal stem cells in malignancies has attracted much attention due to their ability to deliver anticancer agents to tumors, including cytokines, chemokines, etc. This study aimed to investigate the effect of MSCs on the neuroblastoma SH-SY5Y cells through proliferation/apoptosis, senescence assessment, telomere length, and telomerase activity in vitro. BAX and BCL2 were also examined as potential signaling pathways in this process. MATERIALS AND METHODS For this reason, two cell populations (MSCs and SH-SY5Y cells) were co-cultured on trans-well plates for 7 days. In a subsequent step, SH-SY5Y cells were harvested from both control and experimental groups and subjected to flow cytometry, ELISA, real-time PCR, PCR-ELISA TRAP assay, and Western blotting assay for Ki67/Caspase3 investigation, β-Galactosidase assessment, telomere length, and telomerase activity assay. Also, expression of genes and proteins through real-time PCR and Western blotting demonstrated the involvement of the aforementioned signaling pathways in this process. RESULTS It was found that MSCs contributed significantly to decrease and increase of Ki-67 and Caspase-3, respectively. Also, MSCs dramatically reduced the length of telomere and telomerase activity and increased the β-Galactosidase activity in a significant manner. In addition, significant increase and decrease were also seen in BAX and BCL2 gene and protein expressions, respectively. CONCLUSION These findings revealed that close interaction between MSCs and neuroblastoma cells causes inhibition of the SH-SY5Y cell proliferation and promotes cell senescence via BAX and caspase-3 cascade pathways.
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Affiliation(s)
- Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Liu H, Deng S, Han L, Ren Y, Gu J, He L, Liu T, Yuan ZX. Mesenchymal stem cells, exosomes and exosome-mimics as smart drug carriers for targeted cancer therapy. Colloids Surf B Biointerfaces 2021; 209:112163. [PMID: 34736220 DOI: 10.1016/j.colsurfb.2021.112163] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 10/10/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity to differentiate into several cell types under appropriate conditions. They also possess remarkable antitumor features that make them a novel choice to treat cancers. Accumulating evidence suggest that the MSCs-derived extracellular vesicles, known as exosomes, play an essential role in the therapeutic effects of MSCs mainly by carrying biologically active factors. However, limitations such as low yield of exosomes and difficulty in isolation and purification hinder their clinical applications. To overcome these issues, research on development of exosome-mimics has attracted great attention. This systematic review represents, to the best of our knowledge, the first thorough evaluations of the innate antineoplastic features of MSCs-derived exosomes or exosome-mimics, the methods of drug loading, application as drug delivery system and their impacts on targeted cancer therapy. Importantly, we dissect the commonalities and differences as well as address the shortcomings of work accumulated over the last two decades and discuss how this information can serve as a guide map for optimal experimental design implementation ultimately aiding the effective transition into clinical trials.
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Affiliation(s)
- Hongmei Liu
- College of Pharmacy, Southwest Minzu University, Chengdu 610041, China
| | - Shichen Deng
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, Sichuan, China
| | - Lu Han
- College of Pharmacy, Southwest Minzu University, Chengdu 610041, China
| | - Yan Ren
- College of Pharmacy, Southwest Minzu University, Chengdu 610041, China
| | - Jian Gu
- College of Pharmacy, Southwest Minzu University, Chengdu 610041, China
| | - Lili He
- College of Pharmacy, Southwest Minzu University, Chengdu 610041, China.
| | - Tianqing Liu
- NICM Health Research Institute, Western Sydney University, Westmead, Australia.
| | - Zhi-Xiang Yuan
- College of Pharmacy, Southwest Minzu University, Chengdu 610041, China.
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Iida Y, Yoshikawa R, Murata A, Kotani H, Kazuki Y, Oshimura M, Matsuzaki Y, Harada M. Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells. J Immunother Cancer 2021; 8:jitc-2020-000582. [PMID: 32675195 PMCID: PMC7368496 DOI: 10.1136/jitc-2020-000582] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2020] [Indexed: 12/12/2022] Open
Abstract
Background Mesenchymal stem/stromal cells (MSC) accumulate and reside in tumor sites. Methods Taking advantage of this feature in anticancer therapy, immortalized murine MSC (iMSC) were genetically altered to produce chemokine (C-C motif) ligand 19 (iMSC/CCL19), which attracts dendritic cells (DC) and T lymphocytes. Thereafter, iMSC/CCL19 were examined for their therapeutic efficacy using a syngeneic CT26 colon carcinoma cell line. Results Co-injection of iMSC/CCL19 into mice significantly suppressed the in vivo growth of CT26 cells compared with that of CCL19-expressing immortalized fibroblasts (iFib/CCL19). This anticancer effect was not observed when injected in CT26-bearing nude mice. Co-injected iMSC/CCL19 survived longer than iFib/CCL19 in the tumor sites. In a therapeutic model, local injection of iMSC/CCL19 suppressed the tumor growth, and increased IFN (interferon)-γ+ CD8+ T cells and CCR7+ DC infiltration in tumor site was observed when treated with iMSC/CCL19, but not with iMSC. This antitumor effect was completely negated by depletion of CD4+ cells and partially negated by depletion of CD8+ cells. Furthermore, the antitumor effects induced by local injection of iMSC/CCL19 were augmented by additional therapy with anti-programmed death (PD)-ligand 1 (PD-L1) antibody, but not with anti-PD-1 antibody. This combination therapy cured most of the tumors in CT26-bearing mice. Conclusion These results suggest that local therapy with iMSC/CCL19 can suppress tumor growth via effective recruitment of CCR7+ DC into tumor sites and increase IFN-γ+ CD8+ T cells, and that combination with anti-PD-L1 antibody therapy can be a powerful anticancer therapy.
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Affiliation(s)
- Yuichi Iida
- Immunology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan
| | - Rintaro Yoshikawa
- Life Science, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Shimane, Japan
| | - Akihiko Murata
- Molecular and Cellular Biology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Hitoshi Kotani
- Immunology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan
| | - Yasuhiro Kazuki
- Biomedical Science, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
| | - Mitsuo Oshimura
- Chromosome Engineering Research Center, Tottori University, Yonago, Tottori, Japan
| | - Yumi Matsuzaki
- Life Science, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Shimane, Japan
| | - Mamoru Harada
- Immunology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Japan
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Ferrara B, Pignatelli C, Cossutta M, Citro A, Courty J, Piemonti L. The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options. Cancers (Basel) 2021; 13:cancers13174442. [PMID: 34503252 PMCID: PMC8430646 DOI: 10.3390/cancers13174442] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 01/18/2023] Open
Abstract
The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.
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Affiliation(s)
- Benedetta Ferrara
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - Cataldo Pignatelli
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - Mélissande Cossutta
- INSERM U955, Immunorégulation et Biothérapie, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil, 94010 Créteil, France; (M.C.); (J.C.)
- AP-HP, Centre d’Investigation Clinique Biothérapie, Groupe Hospitalo-Universitaire Chenevier Mondor, 94010 Créteil, France
| | - Antonio Citro
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - José Courty
- INSERM U955, Immunorégulation et Biothérapie, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil, 94010 Créteil, France; (M.C.); (J.C.)
- AP-HP, Centre d’Investigation Clinique Biothérapie, Groupe Hospitalo-Universitaire Chenevier Mondor, 94010 Créteil, France
| | - Lorenzo Piemonti
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
- Correspondence:
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Hassanzadeh A, Altajer AH, Rahman HS, Saleh MM, Bokov DO, Abdelbasset WK, Marofi F, Zamani M, Yaghoubi Y, Yazdanifar M, Pathak Y, Chartrand MS, Jarahian M. Mesenchymal Stem/Stromal Cell-Based Delivery: A Rapidly Evolving Strategy for Cancer Therapy. Front Cell Dev Biol 2021; 9:686453. [PMID: 34322483 PMCID: PMC8311597 DOI: 10.3389/fcell.2021.686453] [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: 03/26/2021] [Accepted: 06/10/2021] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem/stromal cell (MSC)-based therapy has become an attractive and advanced scientific research area in the context of cancer therapy. This interest is closely linked to the MSC-marked tropism for tumors, suggesting them as a rational and effective vehicle for drug delivery for both hematological and solid malignancies. Nonetheless, the therapeutic application of the MSCs in human tumors is still controversial because of the induction of several signaling pathways largely contributing to tumor progression and metastasis. In spite of some evidence supporting that MSCs may sustain cancer pathogenesis, increasing proofs have indicated the suppressive influences of MSCs on tumor cells. During the last years, a myriad of preclinical and some clinical studies have been carried out or are ongoing to address the safety and efficacy of the MSC-based delivery of therapeutic agents in diverse types of malignancies. A large number of studies have focused on the MSC application as delivery vehicles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), chemotherapeutic drug such as gemcitabine (GCB), paclitaxel (PTX), and doxorubicin (DOX), prodrugs such as 5-fluorocytosine (5-FC) and ganciclovir (GCV), and immune cell-activating cytokines along with oncolytic virus. In the current review, we evaluate the latest findings rendering the potential of MSCs to be employed as potent gene/drug delivery vehicle for inducing tumor regression with a special focus on the in vivo reports performed during the last two decades.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Marwan Mahmood Saleh
- Department of Biophysics, College of Applied Sciences, University of Anbar, Ramadi, Iraq
| | - Dmitry O. Bokov
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Yoda Yaghoubi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Yashwant Pathak
- Professor and Associate Dean for Faculty Affairs, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
- Adjunct Professor, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
| | | | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany
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Hassanzadeh A, Shamlou S, Yousefi N, Nikoo M, Verdi J. Genetically-Modified Stem Cell in Regenerative Medicine and Cancer Therapy; A New Era. Curr Gene Ther 2021; 22:23-39. [PMID: 34238158 DOI: 10.2174/1566523221666210707125342] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/20/2021] [Accepted: 04/25/2021] [Indexed: 11/22/2022]
Abstract
Recently, genetic engineering by various strategies to stimulate gene expression in a specific and controllable mode is a speedily growing therapeutic approach. Genetic modification of human stem or progenitor cells, such as embryonic stem cells (ESCs), neural progenitor cells (NPCs), mesenchymal stem/stromal cells (MSCs), and hematopoietic stem cells (HSCs) for direct delivery of specific therapeutic molecules or genes has been evidenced as an opportune plan in the context of regenerative medicine due to their supported viability, proliferative features, and metabolic qualities. On the other hand, a large number of studies have investigated the efficacy of modified stem cells in cancer therapy using cells from various sources, disparate transfection means for gene delivery, different transfected yields, and wide variability of tumor models. Accordingly, cell-based gene therapy holds substantial aptitude for the treatment of human malignancy as it could relieve signs or even cure cancer succeeding expression of therapeutic or suicide transgene products; however, there exist inconsistent results in this regard. Herein, we deliver a brief overview of stem cell potential to use in cancer therapy and regenerative medicine and importantly discuss stem cells based gene delivery competencies to stimulate tissue repair and replacement in concomitant with their potential to use as an anti-cancer therapeutic strategy, focusing on the last two decades in vivo studies.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Shamlou
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Niloufar Yousefi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Marzieh Nikoo
- Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Javad Verdi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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30
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Attia N, Mashal M, Puras G, Pedraz JL. Mesenchymal Stem Cells as a Gene Delivery Tool: Promise, Problems, and Prospects. Pharmaceutics 2021; 13:843. [PMID: 34200425 PMCID: PMC8229096 DOI: 10.3390/pharmaceutics13060843] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/24/2021] [Accepted: 05/31/2021] [Indexed: 12/13/2022] Open
Abstract
The cell-based approach in gene therapy arises as a promising strategy to provide safe, targeted, and efficient gene delivery. Owing to their unique features, as homing and tumor-tropism, mesenchymal stem cells (MSCs) have recently been introduced as an encouraging vehicle in gene therapy. Nevertheless, non-viral transfer of nucleic acids into MSCs remains limited due to various factors related to the main stakeholders of the process (e.g., nucleic acids, carriers, or cells). In this review, we have summarized the main types of nucleic acids used to transfect MSCs, the pros and cons, and applications of each. Then, we have emphasized on the most efficient lipid-based carriers for nucleic acids to MSCs, their main features, and some of their applications. While a myriad of studies have demonstrated the therapeutic potential for engineered MSCs therapy in various illnesses, optimization for clinical use is an ongoing challenge. On the way of improvement, genetically modified MSCs have been combined with various novel techniques and tools (e.g., exosomes, spheroids, 3D-Bioprinting, etc.,) aiming for more efficient and safe applications in biomedicine.
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Affiliation(s)
- Noha Attia
- Laboratory of Pharmaceutics, NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (N.A.); (M.M.)
- Department of Basic Sciences, The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda
- The Center of Research and Evaluation, The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda
- Histology and Cell Biology Department, Faculty of Medicine, University of Alexandria, Alexandria 21561, Egypt
| | - Mohamed Mashal
- Laboratory of Pharmaceutics, NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (N.A.); (M.M.)
- The Center of Research and Evaluation, The American University of Antigua-College of Medicine, Coolidge 1451, Antigua and Barbuda
| | - Gustavo Puras
- Laboratory of Pharmaceutics, NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (N.A.); (M.M.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01006 Vitoria-Gasteiz, Spain
- Laboratory of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
| | - Jose Luis Pedraz
- Laboratory of Pharmaceutics, NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (N.A.); (M.M.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01006 Vitoria-Gasteiz, Spain
- Laboratory of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
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31
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Ni Y, Zhou X, Yang J, Shi H, Li H, Zhao X, Ma X. The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment. Front Cell Dev Biol 2021; 9:637675. [PMID: 34095111 PMCID: PMC8173135 DOI: 10.3389/fcell.2021.637675] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 04/19/2021] [Indexed: 02/05/2023] Open
Abstract
Cancer cells resistance to various therapies remains to be a key challenge nowadays. For a long time, scientists focused on tumor cells themselves for the mechanisms of acquired drug resistance. However, recent evidence showed that tumor microenvironment (TME) is essential for regulating immune escape, drug resistance, progression and metastasis of malignant cells. Reciprocal interactions between cancer cells and non-malignant cells within this milieu often reshape the TME and promote drug resistance. Therefore, advanced knowledge about these sophisticated interactions is significant for the design of effective therapeutic approaches. In this review, we highlight cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory lymphocytes (Tregs), mesenchymal stem cells (MSCs), cancer-associated adipocytes (CAAs), and tumor endothelial cells (TECs) existing in TME, as well as their multiple cross-talk with tumor cells, which eventually endows tumor cells with therapeutic resistance.
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Affiliation(s)
- Yanghong Ni
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xiaoting Zhou
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Jia Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Houhui Shi
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Hongyi Li
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
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32
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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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34
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Chen X, Wang Y, Jiang S. The Effect of Sirtuin 2 (Sirt2) Overexpressing Bone Marrow Mesenchymal Stem Cells on the Growth of Human Epidermal Growth Factor Receptor 2 (Her-2) Breast Cancer Cells and Its Mechanism. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Our study investigates the effect of high expression of Sirt2 in MSCs (MSCs-Sirt2) on Her-2 breast cancer cell proliferation. A mouse subcutaneous xenograft tumor model was established and MSCssirt2 analysis was performed on nude mice. TUNEL staining, flow cytometry, western-blot, real-time
PCR and immunohistochemistry were used to detect cancer cell apoptosis. The number of NK cells infiltrated by flow cytometry detected the tumor tissue of tumor-bearing mice, and its killing activity on tumor-bearing mice was detected by isotope labeling and release method. The levels of TNF-α,
IFN-γ, IL-8, IL-6 and IL-10 were detected by ELISA. Caspase-3 level was decreased in the MSCs group (P <0.01) while increased in the MSCs-sirt2 group (P <0.001). However, PCNA expression showed an opposite profile in the Her-2 group and MSCs-sirt2 group compared to
Caspase-3 level (P <0.01). The tumor volume and weight in the MSCs-sirt2 group was significantly reduced (P < 0.01), while increased in the MSCs group significantly (P < 0.05). The number of Ki-67-positive tumor cells in MSCs-sirt2 group was significantly reduced
(P <0.01) and increased in MSCs group (P < 0.001) with oppositive number of TUNEL-positive tumor cells in the MSCs-sirt2 group and MSCs group (P <0.01). IFN-γ level showed an upward trend (P <0.001). The NK cell toxicity of MSCs-Sirt2 group was
significantly higher (P <0.001). MSCs-Sirt2 has an inhibitory effect on Her-2 breast cancer cell growth by enhancing the local inflammatory response of NK cells.
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Affiliation(s)
- Xiaolin Chen
- Department of Pharmacy, Chongqing Jiangjin District Central Hospital, Chingqing, 402260, China
| | - Yan Wang
- Department of Cardiothoracic Surgery, Chongqing Jiangjin District Central Hospital, Chingqing, 402260, China
| | - Sunlu Jiang
- Minimally Invasive Interventional Center, Hubei Cancer Hospital, Wuhan, Hubei, 430000, China
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35
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Mesenchymal stem/stromal cells: Developmental origin, tumorigenesis and translational cancer therapeutics. Transl Oncol 2020; 14:100948. [PMID: 33190044 PMCID: PMC7672320 DOI: 10.1016/j.tranon.2020.100948] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/27/2020] [Accepted: 11/05/2020] [Indexed: 12/20/2022] Open
Abstract
While a large and growing body of research has demonstrated that mesenchymal stem/stromal cells (MSCs) play a dual role in tumor growth and inhibition, studies exploring the capability of MSCs to contribute to tumorigenesis are rare. MSCs are key players during tumorigenesis and cancer development, evident in their faculty to increase cancer stem cells (CSCs) population, to generate the precursors of certain forms of cancer (e.g. sarcoma), and to induce epithelial-mesenchymal transition to create the CSC-like state. Indeed, the origin and localization of the native MSCs in their original tissues are not known. MSCs are identified in the primary tumor sites and the fetal and extraembryonic tissues. Acknowledging the developmental origin of MSCs and tissue-resident native MSCs is essential for better understanding of MSC contributions to the cellular origin of cancer. This review stresses that the plasticity of MSCs can therefore instigate further risk in select therapeutic strategies for some patients with certain forms of cancer. Towards this end, to explore the safe and effective MSC-based anti-cancer therapies requires a strong understanding of the cellular and molecular mechanisms of MSC action, ultimately guiding new strategies for delivering treatment. While clinical trial efforts using MSC products are currently underway, this review also provides new insights on the underlying mechanisms of MSCs to tumorigenesis and focuses on the approaches to develop MSC-based anti-cancer therapeutic applications.
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36
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Wilhelm C, Scherzad A, Bregenzer M, Meyer T, Gehrke T, Kleinsasser N, Hagen R, Hackenberg S. Interaction of head and neck squamous cell carcinoma cells and mesenchymal stem cells under hypoxia and normoxia. Oncol Lett 2020; 20:229. [PMID: 32968451 DOI: 10.3892/ol.2020.12092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) exhibit strong tropism towards tumor tissue. While MSCs generally surround tumors, they can also infiltrate tumors and thereby influence their proliferation. Interactions between MSCs and tumor cells are usually tested under normoxia, but the majority of solid tumors, including head and neck squamous cell carcinoma (HNSCC), are also characterized by hypoxic areas. Hence, the present study aimed to assess the interaction between MSCs and tumor cells under hypoxic conditions. MSCs were cultivated under normoxia and hypoxia, and conditioned media were used to cultivate the HNSCC cell line FaDu. The cell cycle distribution and viability of MSCs and the proliferation of FaDu cells were analyzed under normoxia and hypoxia, and changes in cytokine levels in the conditioned media were evaluated. No cell cycle changes were observed for MSCs after 24 h of cultivation under hypoxia, but the cell viability had declined. Hypoxia also led to a decrease in the proliferation of FaDu cells; however, FaDu cells proliferated faster after 48 h under hypoxia compared with normoxic conditions. This effect was reversed after incubation under normoxia for 72 h and hypoxia for 72 h. While these changes constituted a trend, these differences were not statistically significant. A cytokine assay showed an increase in interleukin (IL)-6 in the hypoxic medium. Overall, the results indicated that there was an interaction between MSCs and tumor cells. The presence or absence of oxygen seemed to influence the functionality of MSCs and their protumorigenic properties, in which IL-6 was identified as a potential mediator. Since MSCs are a component of the tumor stroma, further in vitro and in vivo studies are needed to investigate this interaction in order to develop novel approaches for tumor therapy.
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Affiliation(s)
- Christian Wilhelm
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Agmal Scherzad
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Maximilian Bregenzer
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Till Meyer
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Thomas Gehrke
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Norbert Kleinsasser
- Department of Otorhinolaryngology, Head and Neck Surgery, Kepler University, A-4020 Linz, Austria
| | - Rudolf Hagen
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
| | - Stephan Hackenberg
- Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Julius Maximilian University of Wuerzburg, D-97080 Wuerzburg, Germany
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Costa LA, Eiro N, Fraile M, Gonzalez LO, Saá J, Garcia-Portabella P, Vega B, Schneider J, Vizoso FJ. Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses. Cell Mol Life Sci 2020; 78:447-467. [PMID: 32699947 PMCID: PMC7375036 DOI: 10.1007/s00018-020-03600-0] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/02/2020] [Accepted: 07/13/2020] [Indexed: 12/11/2022]
Abstract
Mesenchymal stem cells (MSC) are present in all organs and tissues. Several studies have shown the therapeutic potential effect of MSC or their derived products. However, the functional heterogeneity of MSC constitutes an important barrier for transferring these capabilities to the clinic. MSC heterogeneity depends on their origin (biological niche) or the conditions of potential donors (age, diseases or unknown factors). It is accepted that many culture conditions of the artificial niche to which they are subjected, such as O2 tension, substrate and extracellular matrix cues, inflammatory stimuli or genetic manipulations can influence their resulting phenotype. Therefore, to attain a more personalized and precise medicine, a correct selection of MSC is mandatory, based on their functional potential, as well as the need to integrate all the existing information to achieve an optimal improvement of MSC features in the artificial niche.
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Affiliation(s)
- Luis A Costa
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - Noemi Eiro
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - María Fraile
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - Luis O Gonzalez
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain.,Department of Anatomical Pathology, Fundación Hospital de Jove, Gijón, Spain
| | - Jorge Saá
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - Pablo Garcia-Portabella
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - Belén Vega
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain
| | - José Schneider
- Department of Obstetrics and Gynecology, University of Valladolid, Valladolid, Spain
| | - Francisco J Vizoso
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33920, Gijón, Asturias, Spain.
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Fujishiro A, Iwasa M, Fujii S, Maekawa T, Andoh A, Tohyama K, Takaori-Kondo A, Miura Y. Menatetrenone facilitates hematopoietic cell generation in a manner that is dependent on human bone marrow mesenchymal stromal/stem cells. Int J Hematol 2020; 112:316-330. [PMID: 32572826 DOI: 10.1007/s12185-020-02916-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 06/06/2020] [Accepted: 06/11/2020] [Indexed: 12/24/2022]
Abstract
Vitamin K2 in the form of menatetrenone has clinical benefits for osteoporosis and cytopenia. Given the dominant role of mesenchymal-osteolineage cells in the regulation of hematopoiesis, we investigated whether menatetrenone alters the hematopoiesis-supportive capability of human bone marrow mesenchymal stromal/stem cells (BM-MSCs). Menatetrenone up-regulated fibronectin protein expression in BM-MSCs without affecting their proliferation and differentiation capabilities. In addition, menatetrenone treatment of BM-MSCs enhanced generation of the CD34+ cell population in co-cultures through acceleration of the cell cycle. This effect was associated with cell-cell interactions mediated by VLA-4 and fibronectin. This proposal was supported by cytokine array and quantitative real-time PCR analyses, in which there were no significant differences between the expression levels of hematopoiesis-associated soluble factors in naïve and menatetrenone-treated BM-MSCs. Profiling of hematopoietic cells in co-cultures with menatetrenone-treated BM-MSCs demonstrated that they included significantly more CD34+CD38+ hematopoietic progenitor cells and cells skewed toward myeloid and megakaryocytic lineages than those in co-cultures with untreated BM-MSCs. Notably, myelodysplastic syndrome-derived cells were induced to undergo apoptosis when co-cultured with BM-MSCs, and this effect was enhanced by menatetrenone. Overall, our findings indicate that pharmacological treatment with menatetrenone bestows a unique hematopoiesis-supportive capability on BM-MSCs, which may contribute to the clinical improvement of cytopenia.
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Affiliation(s)
- Aya Fujishiro
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. .,Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan.
| | - Masaki Iwasa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.,Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan
| | - Sumie Fujii
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Hematology and Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Taira Maekawa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Akira Andoh
- Division of Gastroenterology and Hematology, Department of Medicine, Shiga University of Medical Science, Setatsukinowacho, Otsu, Shiga, 520-2192, Japan
| | - Kaoru Tohyama
- Department of Laboratory Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan
| | - Akifumi Takaori-Kondo
- Department of Hematology and Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yasuo Miura
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.,Department of Hematology and Oncology, Kyoto University Graduate School for Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
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LI A, ZHANG T, GAO J. [Progress on utilizing mesenchymal stem cells as cellular delivery system for targeting delivery of as drug/gene for anti-tumor therapy]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020; 49:20-34. [PMID: 32621413 PMCID: PMC8800717 DOI: 10.3785/j.issn.1008-9292.2020.02.22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/15/2020] [Indexed: 06/11/2023]
Abstract
Mesenchymal stem cells (MSCs) have the inherent tumor-homing ability with the attraction of multiple chemokines released by tumor tissues or tumor microenvironments, which can be utilized as promising cellular carriers for targeted delivery of anti-tumor drugs and genes. In most circumstances, large amount of systemicly administrated MSCs will be firstly trapped by lungs, following with re-distribution and homing to tumor tissues after lung clearance. Several approaches like enhanced interactions between chemokines and receptors on MSCs or reducing the retention of MSCs by changes of administration methods are firstly reviewed for improving the homing of MSCs towards tumor tissues. Additionally, the potentials and gains of utilizing MSCs to carry several chemotherapeutics, such as doxorubicin, paclitaxel and gemcitabine are summarized, showing the advantages of overcoming the short half-life and poor tumor targeting of these chemotherapeutics. Moreover, the applications of MSCs to protect and deliver therapeutic genes to tumor sites for selectively tumor cells eliminating or promoting immune system are highlighted. In addition, the potentials of using MSCs for tumor-targeting delivery of diagnostic and therapeutic agents are addressed. We believed that the continuous improvement and optimization of this stem cells-based cellular delivery system will provide a novel delivery strategy and option for tumor treatment.
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Li JN, Li W, Cao LQ, Liu N, Zhang K. Efficacy of mesenchymal stem cells in the treatment of gastrointestinal malignancies. World J Gastrointest Oncol 2020; 12:365-382. [PMID: 32368316 PMCID: PMC7191336 DOI: 10.4251/wjgo.v12.i4.365] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/03/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs), which are a kind of stem cell, possess an immune privileged nature, tumour homing features, and multi-lineage differentiation ability. MSCs have been studied in many fields, such as tissue engineering, nervous system diseases, and cancer treatment. In recent years, an increasing number of researchers have focused on the effects of MSCs on various kinds of tumours. However, the concrete anticancer efficacy of MSCs is still controversial. Gastrointestinal (GI) malignancies are the major causes of cancer-related death worldwide. The interactions of MSCs and GI cancer cells in specific conditions have attracted increasing attention. In this review, we introduce the characteristics of MSCs and analyse the effects of MSCs on GI malignancies, including gastric cancer, hepatoma, pancreatic cancer, and colorectal cancer. In addition, we also provide our perspectives on why MSCs may play different roles in GI malignancies and further research directions to increase the treatment efficacy of MSCs on GI malignancies.
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Affiliation(s)
- Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Wei Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Lan-Qing Cao
- Department of Pathology, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Ning Liu
- Department of Central Laboratory, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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Liu J, Shi Y, Han J, Zhang Y, Cao Z, Cheng J. Quantitative Tracking Tumor Suppression Efficiency of Human Umbilical Cord-Derived Mesenchymal Stem Cells by Bioluminescence Imaging in Mice Hepatoma Model. Int J Stem Cells 2020; 13:104-115. [PMID: 31887848 PMCID: PMC7119203 DOI: 10.15283/ijsc19098] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 10/07/2019] [Accepted: 11/07/2019] [Indexed: 01/02/2023] Open
Abstract
Background and Objectives Tracking of the tumor progression by MSCs-based therapy is being increasingly important in evaluating relative therapy effectively. Herein, Bioluminescence imaging (BLI) technology was used to dynamically and quantitatively track the hepatocellular carcinoma suppressive effects by human umbilical cord mesenchymal stem cells (UC-MSCs). Methods and Results The stem cells present typical phenotypic characteristics and differentiation ability by morphology and flow cytometry analysis of marker expression. Then, the growth inhibition effect of conditioned medium and UC-MSC on H7402 cells was studied. It is found both the conditioned medium and UC-MSC can effectively decrease the proliferation of H7402 cells compared with the control group. Meanwhile, the relative migration of UC-MSC to H7402 is also increased through the transwell migration assay. In addition, a mice hepatoma tumor model was built by H7402 cells which can express a pLenti-6.3/DEST-CMV-luciferase 2-mKate2 gene. The effect of stem cells on growth inhibition of tumor in a mice transplantation model was dynamically monitored by bioluminescence imaging within 5 weeks. It has shown the bioluminescence signal intensity of the tumor model was significantly higher than that of the UC-MSC co-acting tumor model, indicating that the inhibition of UC-MSC on liver cancer resulted in low expression of bioluminescent signals. Conclusions The microenvironment of UC-MSCs can effectively inhibit the growth of liver cancer cells, and this therapeutic effect can be dynamically and quantitatively monitored in vivo by BLI. This is of great significance for the imaging research and application of stem cells in anticancer therapy.
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Affiliation(s)
- Jingjing Liu
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yupeng Shi
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing Han
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Zhang
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenghao Cao
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingliang Cheng
- Department of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Wu Z, Liu W, Wang Z, Zeng B, Peng G, Niu H, Chen L, Liu C, Hu Q, Zhang Y, Pan M, Wu L, Liu M, Liu X, Liang D. Mesenchymal stem cells derived from iPSCs expressing interleukin-24 inhibit the growth of melanoma in the tumor-bearing mouse model. Cancer Cell Int 2020; 20:33. [PMID: 32015693 PMCID: PMC6990536 DOI: 10.1186/s12935-020-1112-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 01/17/2020] [Indexed: 02/06/2023] Open
Abstract
Background Interleukin-24 (IL-24) is a therapeutic gene for melanoma, which can induce melanoma cell apoptosis. Mesenchymal stem cells (MSCs) show promise as a carrier to delivery anti-cancer factors to tumor tissues. Induced pluripotent stem cells (iPSCs) are an alternative source of mesenchymal stem cells (MSCs). We previously developed a novel non-viral gene targeting vector to target IL-24 to human iPSCs. This study aims to investigate whether MSCs derived from the iPSCs with the site-specific integration of IL-24 can inhibit the growth of melanoma in a tumor-bearing mouse model via retro-orbital injection. Methods IL-24-iPSCs were differentiated into IL-24-iMSCs in vitro, of which cellular properties and potential of differentiation were characterized. The expression of IL-24 in the IL-24-iMSCs was measured by qRT-PCR, Western Blotting, and ELISA analysis. IL-24-iMSCs were transplanted into the melanoma-bearing mice by retro-orbital intravenous injection. The inhibitory effect of IL-24-iMSCs on the melanoma cells was investigated in a co-culture system and tumor-bearing mice. The molecular mechanisms underlying IL-24-iMSCs in exerting anti-tumor effect were also explored. Results iPSCs-derived iMSCs have the typical profile of cell surface markers of MSCs and have the ability to differentiate into osteoblasts, adipocytes, and chondroblasts. The expression level of IL-24 in IL-24-iMSCs reached 95.39 ng/106 cells/24 h, which is significantly higher than that in iMSCs, inducing melanoma cells apoptosis more effectively in vitro compared with iMSCs. IL-24-iMSCs exerted a significant inhibitory effect on the growth of melanoma in subcutaneous mouse models, in which the migration of IL-24-iMSCs to tumor tissue was confirmed. Additionally, increased expression of Bax and Cleaved caspase-3 and down-regulation of Bcl-2 were observed in the mice treated with IL-24-iMSCs. Conclusion MSCs derived from iPSCs with the integration of IL-24 at rDNA locus can inhibit the growth of melanoma in tumor-bearing mouse models when administrated via retro-orbital injection.
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Affiliation(s)
- Zheng Wu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Wei Liu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Zujia Wang
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Baitao Zeng
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Guangnan Peng
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Hongyan Niu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Linlin Chen
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Cong Liu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Qian Hu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Yuxuan Zhang
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Mengmeng Pan
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Lingqian Wu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.,3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China
| | - Mujun Liu
- 2Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan China.,3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China
| | - Xionghao Liu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.,3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China
| | - Desheng Liang
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.,3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China
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Therapeutic Mesenchymal Stromal Cells for Immunotherapy and for Gene and Drug Delivery. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 16:204-224. [PMID: 32071924 PMCID: PMC7012781 DOI: 10.1016/j.omtm.2020.01.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess several fairly unique properties that, when combined, make them ideally suited for cellular-based immunotherapy and as vehicles for gene and drug delivery for a wide range of diseases and disorders. Key among these are: (1) their relative ease of isolation from a variety of tissues; (2) the ability to be expanded in culture without a loss of functionality, a property that varies to some degree with tissue source; (3) they are relatively immune-inert, perhaps obviating the need for precise donor/recipient matching; (4) they possess potent immunomodulatory functions that can be tailored by so-called licensing in vitro and in vivo; (5) the efficiency with which they can be modified with viral-based vectors; and (6) their almost uncanny ability to selectively home to damaged tissues, tumors, and metastases following systemic administration. In this review, we summarize the latest research in the immunological properties of MSCs, their use as immunomodulatory/anti-inflammatory agents, methods for licensing MSCs to customize their immunological profile, and their use as vehicles for transferring both therapeutic genes in genetic disease and drugs and genes designed to destroy tumor cells.
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Attia N, Mashal M. Mesenchymal Stem Cells: The Past Present and Future. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1312:107-129. [PMID: 33159306 DOI: 10.1007/5584_2020_595] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The biomedical applications of mesenchymal stem cells (MSCs) have gained expanding attention over the past three decades. MSCs are easily obtained from various tissue types (e.g. bone marrow, fat, cord blood, etc.), are capable of self-renewal, and could be induced to differentiate into several cell lineages for countless biomedical applications. In addition, when transplanted, MSCs are not detected by immune surveillance, thus do not lead to graft rejection. Moreover, they can home towards affected tissues and induce their therapeutic effect in a cell-base and/or a cell-free manner. These properties, and many others, have made MSCs appealing therapeutic cell candidates (for cell and/or gene therapy) in myriad clinical conditions. However, similar to any other therapeutic tool, MSCs still have their own limitations and grey areas that entail more research for better understanding and optimization. Herein, we present a brief overview of various pre-clinical/clinical applications of MSCs in regenerative medicine and discuss limitations and future challenges.
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Affiliation(s)
- Noha Attia
- Department of Basic Sciences, The American University of Antigua-College of Medicine, Coolidge, Antigua and Barbuda. .,The Center of research and evaluation, The American University of Antigua-College of Medicine, Coolidge, Antigua and Barbuda. .,Histology and Cell Biology Department, Faculty of Medicine, University of Alexandria, Alexandria, Egypt. .,NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
| | - Mohamed Mashal
- The Center of research and evaluation, The American University of Antigua-College of Medicine, Coolidge, Antigua and Barbuda.,NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
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Galland S, Stamenkovic I. Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression. J Pathol 2019; 250:555-572. [PMID: 31608444 PMCID: PMC7217065 DOI: 10.1002/path.5357] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/03/2019] [Accepted: 10/04/2019] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem or stromal cells (MSCs) are pluripotent cells implicated in a broad range of physiological events, including organogenesis and maintenance of tissue homeostasis as well as tissue regeneration and repair. Because their current definition is somewhat loose – based primarily on their ability to differentiate into a variety of mesenchymal tissues, adhere to plastic, and express, or lack, a handful of cell surface markers – MSCs likely encompass several subpopulations, which may have diverse properties. Their diversity may explain, at least in part, the pleiotropic functions that they display in different physiological and pathological settings. In the context of tissue injury, MSCs can respectively promote and attenuate inflammation during the early and late phases of tissue repair. They may thereby act as sensors of the inflammatory response and secrete mediators that boost or temper the response as required by the stage of the reparatory and regenerative process. MSCs are also implicated in regulating tumor development, in which they are increasingly recognized to play a complex role. Thus, MSCs can both promote and constrain tumor progression by directly affecting tumor cells via secreted mediators and cell–cell interactions and by modulating the innate and adaptive immune response. This review summarizes our current understanding of MSC involvement in tumor development and highlights the mechanistic underpinnings of their implication in tumor growth and progression. © 2020 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Sabine Galland
- Laboratory of Experimental Pathology, Institute of Pathology, CHUV, Lausanne, Switzerland
| | - Ivan Stamenkovic
- Laboratory of Experimental Pathology, Institute of Pathology, CHUV, Lausanne, Switzerland
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Potentials of "stem cell-therapy" in pancreatic cancer: An update. Pancreatology 2019; 19:1034-1042. [PMID: 31668563 DOI: 10.1016/j.pan.2019.09.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 08/22/2019] [Accepted: 09/28/2019] [Indexed: 02/07/2023]
Abstract
In recent times, cell-therapies like T-activated cells, dendritic cells and natural killer cells have shown increasing promise in treating cancers as evidenced by both animal and human studies in the literature. In addition, stem cells are also being considered as potent anti-cancer agents since they act through multi-pronged approaches (chemokines, cytokines, paracrine action). In this review, we have attempted to discuss the inferences of studies that have used different sub-types of stem cells namely mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs) and neural stem cells (NSCs) in in-vitro/in-vivo mice and/or human studies as a treatment modality for pancreatic cancer. Pancreatic cancers are diagnosed in late/metastatic stages hence limiting its progress to partial/disease-free status. Recent literature supports evidences of stem cell therapy in pancreatic cancer with promising results; yet their impact remains inconclusive due to limited studies in human subjects. With reference to the treatment options for pancreatic cancer, the most studied sub-type of stem cells was HSCs as evident from the available clinical trials. The suggested mechanism of the HSC-transplantation is presumably via the graft-versus-tumor effect that elicits an anti-tumor immune response activated by the T-cell repertoires. On the other hand, the property of MSCs like tropism, migration to tumor site and activation of host immune cells by its secretome, appear to be able to regulate pancreatic tumor microenvironment. Further, drug delivery potential could be mediated via engineered MSCs to enhance the bioavailability of drug/prodrug at tumor site. Conclusively, stem cells have shown great potentials as next-generation therapeutic options.
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Maniwa J, Fumino S, Kimura K, Tanaka T, Higashi M, Kishida T, Mazda O, Tajiri T. Novel mesenchymal stem cell delivery system as targeted therapy against neuroblastoma using the TH-MYCN mouse model. J Pediatr Surg 2019; 54:2600-2605. [PMID: 31627888 DOI: 10.1016/j.jpedsurg.2019.08.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 08/24/2019] [Indexed: 12/14/2022]
Abstract
PURPOSE Mesenchymal stem cells (MSCs) are reported to migrate toward damaged tissues or tumors. We previously reported the in vivo short-term (1 day) tumor-homing effect of xenogeneic human MSCs (hMSCs) using the TH-MYCN mouse neuroblastoma model (MYCN-TgM). In this study, we analyzed the long-term tumor-homing effect of allogeneic mouse MSCs (mMSCs) and explored the antitumor effect and drug delivery function of mMSCs. METHODS mMSCs were administered intraperitoneally (i.p.) to MYCN-TgM and traced by an in vivo imaging system (IVIS). We administered green fluorescent protein (GFP)-transduced mMSCs into MYCN-TgM i.p. and examined the cell survival by immunohistochemistry. We also administered interferon beta-transduced mMSCs (mMSCs-IFN-β) to MYCN-TgM i.p. and measured the concentration of IFN-β in the tumor and organs by an enzyme-linked immunosorbent assay (ELISA). The survival curves of MYCN-TgM administered every week was analyzed. RESULTS The IVIS revealed the accumulation of fluorescence was observed in the tumor both in vivo and after excision. Immunohistochemistry using anti-GFP antibody revealed that the mMSCs existed within the tumor until 14 days but not in the organs. The ELISA showed increased concentrations of IFN-β only in the tumors, with the values gradually diminishing over 14 days. The mMSCs-IFN-β group survived significantly longer than the control group (p < 0.03), while the mMSCs-alone group did not show a survival advantage. CONCLUSIONS Allogeneic mMSCs showed a homing ability for mouse neuroblastoma and existed within the tumor for as long as two weeks. This may be a candidate drug delivery vehicle for antitumor agents against neuroblastoma.
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Affiliation(s)
- Junnosuke Maniwa
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Shigehisa Fumino
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Koseki Kimura
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoko Tanaka
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mayumi Higashi
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tsunao Kishida
- Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Osam Mazda
- Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tatsuro Tajiri
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Park JH, Kim OH, Kim KH, Hong HE, Seo H, Choi HJ, Ahn J, Lee TY, Kim SJ. Isolation of Secretome with Enhanced Antifibrotic Properties from miR-214-Transfected Adipose-Derived Stem Cells. J Korean Med Sci 2019; 34:e273. [PMID: 31760709 PMCID: PMC6875435 DOI: 10.3346/jkms.2019.34.e273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/23/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Secretome refers to the total set of molecules secreted or surface-shed by stem cells. The limitations of stem cell research have led numerous investigators to turn their attention to the use of secretome instead of stem cells. In this study, we intended to reinforce antifibrotic properties of the secretome released from adipose-derived stem cells (ASCs) transfected with miR-214. METHODS We generated miR-214-transfected ASCs, and extracted the secretome (miR214-secretome) from conditioned media of the transfected ASCs through a series of ultrafiltrations. Subsequently, we intravenously injected the miR-214-secretome into mice with liver fibrosis, and determined the effects of miR-214-secretome on liver fibrosis. RESULTS Compared with that by naïve secretome, liver fibrosis was ameliorated by intravenous infusion of miR-214-secretome into mice with liver fibrosis, which was demonstrated by significantly lower expression of fibrosis-related markers (alpha-smooth muscle actin, transforming growth factor-β, and metalloproteinases-2) in the livers as well as lower fibrotic scores in the special stained livers compared with naïve secretome. The infusion of miR-214-secretome also led to lesser local and systemic inflammation, higher expression of an antioxidant enzyme (superoxide dismutase), and higher liver proliferative and synthetic function. CONCLUSION MicroRNA-214 transfection stimulates ASCs to release the secretome with higher antifibrotic and anti-inflammatory properties. miR-214-secretome is thus expected to be one of the prominent ways of overcoming liver fibrosis, if further studies consistently validate its safety and efficiency.
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Affiliation(s)
- Jung Hyun Park
- Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Ok Hee Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Kee Hwan Kim
- Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Ha Eun Hong
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Haeyeon Seo
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Joseph Ahn
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Tae Yun Lee
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Say June Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul, Korea.
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Du L, Liang Q, Ge S, Yang C, Yang P. The growth inhibitory effect of human gingiva-derived mesenchymal stromal cells expressing interferon-β on tongue squamous cell carcinoma cells and xenograft model. Stem Cell Res Ther 2019; 10:224. [PMID: 31358054 PMCID: PMC6664557 DOI: 10.1186/s13287-019-1320-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 06/17/2019] [Accepted: 06/30/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Interferon-β (IFN-β) is a cytokine with pleiotropic cellular functions, including antiviral, antiproliferative, and immunomodulatory activities. IFN-β inhibits multiple tumor cell growth in vitro. However, the contradiction between the therapeutic dose of IFN-β and its maximally tolerated dose is still inextricable in vivo. Human gingiva-derived mesenchymal stromal cells (GMSCs) represent promising vehicles for cancer gene therapy. This study evaluated the potential of GMSCs genetically engineered to produce IFN-β as a targeted gene delivery system to treat tongue squamous cell carcinoma (TSCC) in vitro and in vivo. METHODS A lentiviral vector encoding IFN-β was constructed and transfected into GMSCs to obtain IFN-β gene-modified GMSCs (GMSCs/IFN-β). Enzyme-linked immunosorbent assay (ELISA) was used to measure the IFN-β concentration in conditioned medium (CM) from GMSCs/IFN-β. The Cell Counting Kit-8 (CCK8), colony formation assay, and flow cytometry were used to detect the effects of GMSCs/IFN-β on TSCC cell line CAL27 cell growth and apoptosis in vitro. TSCC xenograft model was developed by subcutaneous injection of CAL27 cells into BALB/c nude mouse, and the role of intravenously injected GMSCs/IFN-β in engrafting in TSCC and controlling tumor progression was measured in vivo. RESULTS GMSCs/IFN-β expressed a high level of IFN-β. Both CCK8 and colony forming assay showed that GMSCs/IFN-β significantly inhibited the proliferation of CAL27 cells compared with the GMSCs, GMSCs/vector, or DMEM group. Flow cytometry analysis demonstrated that the CAL27 cell apoptosis rate was higher in the GMSCs/IFN-β group than in the other three groups. The in vivo experiment revealed that GMSCs/IFN-β engrafted selectively in TSCC xenograft and expressed a high level of IFN-β. There were smaller tumor volume and lower number of Ki67-positive cells in the GMSCs/IFN-β group than in the GMSCs, GMSCs/vector, or phosphate-buffered saline (PBS) group. Interestingly, GMSCs and GMSCs/vector also presented the potential of CAL27 cell growth inhibition in vitro and in vivo, although such an effect was weaker than GMSCs/IFN-β. CONCLUSIONS GMSCs/IFN-β inhibits the proliferation of TSCC cells in vitro and in vivo. These results provide evidence that delivery of IFN-β by GMSCs may be a promising approach to develop an effective treatment option for TSCC therapy.
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Affiliation(s)
- Lingqian Du
- Department of Stomatology, The Second Hospital of Shandong University, Jinan, 250033 Shandong People’s Republic of China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44 West Wenhua Road, Jinan, 250012 Shandong People’s Republic of China
| | - Qianyu Liang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44 West Wenhua Road, Jinan, 250012 Shandong People’s Republic of China
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, People’s Republic of China
| | - Shaohua Ge
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44 West Wenhua Road, Jinan, 250012 Shandong People’s Republic of China
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, People’s Republic of China
| | - Chengzhe Yang
- Department of Oral & Maxillofacial Surgery, Qilu Hospital and Institute of Stomatology, Shandong University, 107 Wenhua Road West, Jinan, 250012 Shandong People’s Republic of China
| | - Pishan Yang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, 44 West Wenhua Road, Jinan, 250012 Shandong People’s Republic of China
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, People’s Republic of China
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50
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An anticancer effect of umbilical cord-derived mesenchymal stem cell secretome on the breast cancer cell line. Cell Tissue Bank 2019; 20:423-434. [PMID: 31338647 DOI: 10.1007/s10561-019-09781-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 07/17/2019] [Indexed: 12/13/2022]
Abstract
Nowadays, Mesenchymal stem cells (MSCs) have become one of the most attractive tools for treating tumors, due to their specific characteristics, the most prominent of which are tropism toward tumor. These cells will exert their effects through their secretion. In this study, our aim was to evaluate the anti-cancer effect of umbilical cord-derived mesenchymal cells (UCMSC) secretome, on MCF-7 tumor cells. MSCs were extracted from the umbilical cord of mothers, having normal delivery or cesarean section. After culture, the supernatants of these cells were collected and freeze-dried. The cytotoxic effect of freeze-dried secretome was examined at different concentrations on MCF-7 and the optimum concentrations (IC50) were calculated, using MTT assay. These results were confirmed by BrdU assay. The effect of induction of apoptosis of the MSC secretome on MCF-7 was determined, using annexin V/PI method by flow cytometry. The results of our study indicate that the isolation and growth time of UCMSCs of mothers who were naturally delivered was lower than those who received cesarean section. Co-culture studies showed that MSCs had cytotoxic effects on MCF-7 cells. The MSC secretome also showed cytotoxic effects on the MCF-7 cell line, this effect was mediated by induction of apoptosis, which was dose-dependent with an IC50 of 10 mg/mL.
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