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Movahed ZG, Mansouri K, Mohsen AH, Matin MM. Bone marrow mesenchymal stem cells enrich breast cancer stem cell population via targeting metabolic pathways. Med Oncol 2025; 42:90. [PMID: 40045066 DOI: 10.1007/s12032-025-02632-5] [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: 10/26/2024] [Accepted: 02/13/2025] [Indexed: 03/29/2025]
Abstract
The role of cancer cell metabolic reprogramming in the formation and maintenance of cancer stem cells (CSCs) has been well established. This reprogramming involves alterations in the metabolic pathways of cancer cells, leading to the acquisition of stem cell-like properties such as self-renewal and differentiation. This study aimed to investigate the potential effects of bone marrow mesenchymal stem cells (BM-MSCs) on the enrichment of breast CSCs. Exosomes (Exo) and conditioned media (CM) were isolated from BM-MSCs for use in this experimental study. The impact of BM-MSCs-Exo and BM-MSCs-CM on the expression of stemness genes NANOG and OCT-4, as well as CD24 and CD44 markers, was assessed in MCF-7 and MDA-MB-231 cell cultures to identify CSCs. Furthermore, the effects of BM-MSCs-Exo and BM-MSCs-CM on cancer cell metabolism were evaluated by examining changes in glycolysis, the pentose phosphate pathway (PPP), and amino acid profiles. Additionally, the influence of BM-MSCs-Exo and BM-MSCs-CM on tumor growth in vivo was also investigated. The analysis of stemness marker expression in cells treated with BM-MSCs-Exo and BM-MSCs-CM revealed an increase in stemness characteristics compared to the control group. Furthermore, the examination of changes in cell metabolism following these treatments showed alterations in glycolysis, PPP, and amino acid metabolism pathways. Additionally, it was demonstrated that BM-MSCs-Exo and BM-MSCs-CM can promote tumor growth in mice following transplantation of 4T1 cells. These findings suggest that BM-MSCs-Exo and BM-MSCs-CM can enrich the population of CSCs in MCF-7 and MDA-MB-231 cells by targeting metabolic pathways, however, further studies are required to elicit the exact mechanisms of these phenomena.
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Affiliation(s)
- Zahra Ghanbari Movahed
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Bākhtarān, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Health Technology Institute, School of Medicine, Kermanshah University of Medical Sciences, P.O. Box 67145-1673, Bākhtarān, Iran.
| | - Ali Hamrahi Mohsen
- Institute of Biochemistry and Biophysics, Faculty of Science, University of Tehran, Tehran, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
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Taeb S, Rostamzadeh D, Amini SM, Rahmati M, Golshekan M, Abedinzade M, Ahmadi E, Neha S, Najafi M. Revolutionizing Cancer Treatment: Harnessing the Power of Mesenchymal Stem Cells for Precise Targeted Therapy in the Tumor Microenvironment. Curr Top Med Chem 2025; 25:243-262. [PMID: 38797895 DOI: 10.2174/0115680266299112240514103048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 04/03/2024] [Accepted: 04/16/2024] [Indexed: 05/29/2024]
Abstract
In recent years, mesenchymal stem cells (MSCs) have emerged as promising anti-- cancer mediators with the potential to treat several cancers. MSCs have been modified to produce anti-proliferative, pro-apoptotic, and anti-angiogenic molecules that could be effective against a variety of malignancies. Additionally, customizing MSCs with cytokines that stimulate pro-tumorigenic immunity or using them as vehicles for traditional chemical molecules with anti-cancer characteristics. Even though the specific function of MSCs in tumors is still challenged, promising outcomes from preclinical investigations of MSC-based gene therapy for a variety of cancers inspire the beginning of clinical trials. In addition, the tumor microenvironment (TME) could have a substantial influence on normal tissue stem cells, which can affect the treatment outcomes. To overcome the complications of TME in cancer development, MSCs could provide some signs of hope for converting TME into unequivocal therapeutic tools. Hence, this review focuses on engineered MSCs (En-MSCs) as a promising approach to overcoming the complications of TME.
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Affiliation(s)
- Shahram Taeb
- Department of Radiology, School of Paramedical Sciences, Guilan University of Medical Sciences, Rasht, Iran
| | - Davoud Rostamzadeh
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Seyed Mohammad Amini
- Radiation Biology Research center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Rahmati
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Mostafa Golshekan
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Mahmoud Abedinzade
- Department of Medical Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Elham Ahmadi
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Singh Neha
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, Connecticut, USA
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Zhou B, Qin Q, Fang Y, Liu X, Zhang M, Wang S, Zhong L, Guo R. Exosomes from human bone marrow MSCs alleviate PD-1/PD-L1 inhibitor-induced myocardial injury in melanoma mice by regulating macrophage polarization and pyroptosis. Life Sci 2024; 358:123108. [PMID: 39374773 DOI: 10.1016/j.lfs.2024.123108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 09/30/2024] [Accepted: 10/01/2024] [Indexed: 10/09/2024]
Abstract
Myocarditis, which can be triggered by immune checkpoint inhibitor (ICI) treatment, represents a critical and severe adverse effect observed in cancer therapy. Thus, elucidating the underlying mechanism and developing effective strategies to mitigate its harmful impact is of utmost importance. The objective of this study is to investigate the potential role and regulatory mechanism of exosomes derived from human bone marrow mesenchymal stem cells (hBMSC-Exos) in providing protection against myocardial injury induced by ICIs. We observed that the administration of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor BMS-1 in tumor-bearing mice led to evident cardiac dysfunction and myocardial injury, which were closely associated with M1 macrophage polarization and cardiac pyroptosis. Remarkably, these adverse effects were significantly alleviated through tail-vein injection of hBMSC-Exos. Moreover, either BMS-1 or hBMSC-Exos alone demonstrated the ability to reduce tumor size, while the combination of hBMSC-Exos with BMS-1 treatment not only effectively improved the probability of tumor inhibition but also alleviated cardiac anomalies induced by BMS-1.
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Affiliation(s)
- Bingqian Zhou
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Qin Qin
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Yue Fang
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Xiaoyu Liu
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Mengyu Zhang
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Shuo Wang
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China
| | - Li Zhong
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Rui Guo
- College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China; The Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, Baoding 071002, China.
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Doyle K, Sutter M, Rodriguez M, Hassan AE, Kumar P, Brown E. Proliferative Effects of Mesenchymal Stromal Cells on Neuroblastoma Cell Lines: Are They Tumor Promoting or Tumor Inhibiting? J Pediatr Surg 2024; 59:1582-1590. [PMID: 38490883 PMCID: PMC12007663 DOI: 10.1016/j.jpedsurg.2024.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 02/12/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND Neuroblastoma is a common pediatric malignancy with poor survival for high-risk disease. Mesenchymal stromal cells (MSCs) have innate tumor-homing properties, enabling them to serve as a cellular delivery vehicle, but MSCs have demonstrated variable effects on tumor growth. We compared how placental MSCs (PMSCs) and bone marrow-derived MSCs (BM-MSCs) affect proliferation of neuroblastoma (NB) cells in vitro. METHODS Indirect co-culture assessed proliferative effects of 18 MSCs (early-gestation PMSCs (n = 9), term PMSCs (n = 5), BM-MSCs (n = 4) on three high-risk NB cell lines (NB1643, SH-SY5Y, and CHLA90). Controls were NB cells cultured in media alone. Proliferation was assessed using MTS assay and measured by fold change (fc) over controls. PMSCs were sub-grouped by neuroprotective effect: strong (n = 7), intermediate (n = 3), and weak (n = 4). The relationship between MSC type, PMSC neuroprotection, and PMSC gestational age on NB cell proliferation was assessed. RESULTS NB cell proliferation varied between MSC groups. BM-MSCs demonstrated lower proliferative effects than PMSCs (fc 1.18 vs 1.44, p < 0.001). Neither gestational age nor neuroprotection significantly predicted degree of proliferation. Proliferative effects of MSCs varied among NB cell lines. BM-MSCs had less effect on CHLA90 (fc 1.01) compared to NB1643 (fc 1.33) and SH-SY5Y (fc 1.20). Only NB1643 showed a difference between early and term PMSCs (p = 0.04). CONCLUSION Effects of MSCs on NB cell proliferation vary by MSC source and NB cell line. BM-MSCs demonstrated lower proliferative effects than most PMSCs. MSC neuroprotection was not correlated with proliferation. Improved understanding of MSC proliferation-promoting mechanisms may provide valuable insight into selection of cells best suited as drug delivery vehicles. LEVEL OF EVIDENCE N/A. TYPE OF STUDY Original Research.
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Affiliation(s)
- Kathleen Doyle
- Department of Surgery, University of California-Davis, Sacramento, CA, USA.
| | - Maria Sutter
- Center for Surgical Bioengineering, Department of Surgery, University of California-Davis, Sacramento, CA, USA
| | - Monica Rodriguez
- Center for Surgical Bioengineering, Department of Surgery, University of California-Davis, Sacramento, CA, USA
| | | | - Priyadarsini Kumar
- Center for Surgical Bioengineering, Department of Surgery, University of California-Davis, Sacramento, CA, USA
| | - Erin Brown
- Department of Surgery, Division of Pediatric Surgery, University of California-Davis, Sacramento, CA, USA
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Wang KH, Chang YH, Ding DC. Bone Marrow Mesenchymal Stem Cells Promote Ovarian Cancer Cell Proliferation via Cytokine Interactions. Int J Mol Sci 2024; 25:6746. [PMID: 38928452 PMCID: PMC11203416 DOI: 10.3390/ijms25126746] [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: 04/03/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) are key players in promoting ovarian cancer cell proliferation, orchestrated by the dynamic interplay between cytokines and their interactions with immune cells; however, the intricate crosstalk among BMSCs and cytokines has not yet been elucidated. Here, we aimed to investigate interactions between BMSCs and ovarian cancer cells. We established BMSCs with a characterized morphology, surface marker expression, and tri-lineage differentiation potential. Ovarian cancer cells (SKOV3) cultured with conditioned medium from BMSCs showed increased migration, invasion, and colony formation, indicating the role of the tumor microenvironment in influencing cancer cell behavior. BMSCs promoted SKOV3 tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice, increasing tumor growth. The co-injection of BMSCs increased the phosphorylation of p38 MAPK and GSK-3β in SKOV3 tumors. Co-culturing SKOV3 cells with BMSCs led to an increase in the expression of cytokines, especially MCP-1 and IL-6. These findings highlight the influence of BMSCs on ovarian cancer cell behavior and the potential involvement of specific cytokines in mediating these effects. Understanding these mechanisms will highlight potential therapeutic avenues that may halt ovarian cancer progression.
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Affiliation(s)
- Kai-Hung Wang
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan;
| | - Yu-Hsun Chang
- Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan;
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 970, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan
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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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Kang QM, Wang J, Chen SM, Song SR, Yu SC. Glioma-associated mesenchymal stem cells. Brain 2024; 147:755-765. [PMID: 37850820 DOI: 10.1093/brain/awad360] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 09/06/2023] [Accepted: 10/05/2023] [Indexed: 10/19/2023] Open
Abstract
Recent studies have revealed that glioma-associated mesenchymal stem cells play instrumental roles in tumorigenesis and tumour progression and cannot be ignored as a cellular component of the glioma microenvironment. Nevertheless, the origin of these cells and their roles are poorly understood. The only relevant studies have shown that glioma-associated mesenchymal stem cells play a large role in promoting tumour proliferation, invasion and angiogenesis. This review provides a comprehensive summary of their discovery and definition, origin, differences from other tissue-derived mesenchymal stem cells, spatial distribution, functions and prognostic and therapeutic opportunities to deepen the understanding of these cells and provide new insight into the treatment of glioma.
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Affiliation(s)
- Qing-Mei Kang
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Chongqing, 400038, China
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing, 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing, 400038, China
- Jin-feng Laboratory, Chongqing, 401329, China
| | - Jun Wang
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Chongqing, 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing, 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing, 400038, China
- Jin-feng Laboratory, Chongqing, 401329, China
| | - Shi-Man Chen
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Chongqing, 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing, 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing, 400038, China
- Jin-feng Laboratory, Chongqing, 401329, China
| | - Si-Rong Song
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Chongqing, 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing, 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing, 400038, China
- Jin-feng Laboratory, Chongqing, 401329, China
| | - Shi-Cang Yu
- Department of Stem Cell and Regenerative Medicine, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Chongqing, 400038, China
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Chongqing, 400038, China
- Key Laboratory of Cancer Immunopathology, Ministry of Education, Chongqing, 400038, China
- Jin-feng Laboratory, Chongqing, 401329, China
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Salaudeen MA, Allan S, Pinteaux E. Hypoxia and interleukin-1-primed mesenchymal stem/stromal cells as novel therapy for stroke. Hum Cell 2024; 37:154-166. [PMID: 37987924 PMCID: PMC10764391 DOI: 10.1007/s13577-023-00997-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/11/2023] [Indexed: 11/22/2023]
Abstract
Promising preclinical stroke research has not yielded meaningful and significant success in clinical trials. This lack of success has prompted the need for refinement of preclinical studies with the intent to optimize the chances of clinical success. Regenerative medicine, especially using mesenchymal stem/stromal cells (MSCs), has gained popularity in the last decade for treating many disorders, including central nervous system (CNS), such as stroke. In addition to less stringent ethical constraints, the ample availability of MSCs also makes them an attractive alternative to totipotent and other pluripotent stem cells. The ability of MSCs to differentiate into neurons and other brain parenchymal and immune cells makes them a promising therapy for stroke. However, these cells also have some drawbacks that, if not addressed, will render MSCs unfit for treating ischaemic stroke. In this review, we highlighted the molecular and cellular changes that occur following an ischaemic stroke (IS) incidence and discussed the physiological properties of MSCs suitable for tackling these changes. We also went further to discuss the major drawbacks of utilizing MSCs in IS and how adequate priming using both hypoxia and interleukin-1 can optimize the beneficial properties of MSCs while eliminating these drawbacks.
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Affiliation(s)
- Maryam Adenike Salaudeen
- Faculty of Biology, Medicine, and Health, Division of Neuroscience, University of Manchester, Manchester, UK
- Department of Pharmacology and Therapeutics, Ahmadu Bello University, Zaria, Nigeria
| | - Stuart Allan
- Faculty of Biology, Medicine, and Health, Division of Neuroscience, University of Manchester, Manchester, UK
| | - Emmanuel Pinteaux
- Faculty of Biology, Medicine, and Health, Division of Neuroscience, University of Manchester, Manchester, UK.
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Sengul F, Vatansev H, Ozturk B. Investigation the effects of bee venom and H-dental-derived mesenchymal stem cells on non-small cell lung cancer cells (A549). Mol Biol Rep 2023; 51:2. [PMID: 38057592 DOI: 10.1007/s11033-023-09002-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 10/13/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Lung cancer, one of the most common oncological diseases worldwide, continues to be the leading cause of cancer-related deaths. The development of new approaches for lung cancer, which still has a low survival rate despite medical advances, is of great importance. METHODS AND RESULTS In this study, bee venom (BV), conditioned medium of MSCs isolated from dental follicles (MSC-CM) and cisplatin were applied at different doses and their effects on A549 cell line were evaluated. Dental follicles were used as a source of MSCs source and differentiation kits, and characterization studies (flow cytometry) were performed. Cell viability was measured by the MTT method and apoptosis was measured by an Annexin V-FITC/PI kit on flow cytometer. IC50 dose values were determined according to the 24th hour and were determined as 15.8 µg/mL for BV, 10.78% for MSC-CM and 5.77 µg/mL for cisplatin. IC50 values found for BV and MSC-CM were also given in combination and the effects were observed. It was found that the applied substances caused BV to decrease in cell viability and induced apoptosis in cells. In addition to the induction of apoptosis in BV, MSC-CM, and combined use, all three applications led to an increase in Bax protein expression and a decrease in Bcl-2 protein expression. The molecular mechanism of anticancer activity through inhibition of Bax and Bcl-2 proteins and the NF-κB signaling pathway may be suggested. CONCLUSION Isolated MSCs in our study showed anticancer activity and BV and MSC-CM showed synergistic antiproliferative and apoptotic effects.
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Affiliation(s)
- Fatma Sengul
- Department of Biochemistry, Faculty of Pharmacy, University of Adiyaman, Central Classroom C Block Floor:3, 02040, Adiyaman, Turkey.
| | - Husamettin Vatansev
- Department of Medical Biochemistry, Faculty of Medicine, University of Selçuk, Alaeddin Keykubat Campus, 42131, Konya, Turkey
| | - Bahadir Ozturk
- Department of Medical Biochemistry, Faculty of Medicine, University of Selçuk, Alaeddin Keykubat Campus, 42131, Konya, Turkey
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10
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Qi C, Shi H, Fan M, Chen W, Yao H, Jiang C, Meng L, Pang S, Lin R. Microvesicles from bone marrow-derived mesenchymal stem cells promote Helicobacter pylori-associated gastric cancer progression by transferring thrombospondin-2. Cell Commun Signal 2023; 21:274. [PMID: 37798762 PMCID: PMC10552243 DOI: 10.1186/s12964-023-01127-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/09/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Our previous study found that bone marrow-derived mesenchymal stem cells (BMSCs) promote Helicobacter pylori (H pylori)-associated gastric cancer (GC) progression by secreting thrombospondin-2 (THBS2). Extracellular vesicles (EVs) are important carriers for intercellular communication, and EVs secreted by BMSCs have been shown to be closely related to tumor development. The aim of this study was to investigate whether BMSC-derived microvesicles (MVs, a main type of EV) play a role in H. pylori-associated GC by transferring THBS2. METHODS BMSCs and THBS2-deficient BMSCs were treated with or without the supernatant of H. pylori for 12 h at a multiplicity of infection of 50, and their EVs were collected. Then, the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on the GC cell line MGC-803 were assessed by in vitro proliferation, migration, and invasion assays. In addition, a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model were constructed to evaluate the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on GC development and metastasis in vivo. RESULTS BMSC-derived MVs could be readily internalized by MGC-803 cells. BMSC-derived MVs after H. pylori treatment significantly promoted their proliferation, migration and invasion in vitro (all P < 0.05) and promoted tumor development and metastasis in a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model in vivo (all P < 0.05). The protein expression of THBS2 was significantly upregulated after H. pylori treatment in BMSC-derived MVs (P < 0.05). Depletion of the THBS2 gene reduces the tumor-promoting ability of BMSC-MVs in an H. pylori infection microenvironment both in vitro and in vivo. CONCLUSION Overall, these findings indicate that MVs derived from BMSCs can promote H. pylori-associated GC development and metastasis by delivering the THBS2 protein. Video Abstract.
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Affiliation(s)
- Cuihua Qi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
- Department of Gastroenterology, The First Affiliated Hospital of Shihezi University, Shihezi, 832002 China
| | - Huiying Shi
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Mengke Fan
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Weigang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shihezi University, Shihezi, 832002 China
| | - Hailing Yao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Chen Jiang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Lingjun Meng
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Suya Pang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 4300222 China
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11
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Khan S, Mahgoub S, Fallatah N, Lalor PF, Newsome PN. Liver Disease and Cell Therapy: Advances Made and Remaining Challenges. Stem Cells 2023; 41:739-761. [PMID: 37052348 PMCID: PMC10809282 DOI: 10.1093/stmcls/sxad029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 02/27/2023] [Indexed: 04/14/2023]
Abstract
The limited availability of organs for liver transplantation, the ultimate curative treatment for end stage liver disease, has resulted in a growing and unmet need for alternative therapies. Mesenchymal stromal cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties have therefore emerged as a promising therapeutic agent in treating inflammatory liver disease. Significant strides have been made in exploring their biological activity. Clinical application of MSC has shifted the paradigm from using their regenerative potential to one which harnesses their immunomodulatory properties. Reassuringly, MSCs have been extensively investigated for over 30 years with encouraging efficacy and safety data from translational and early phase clinical studies, but questions remain about their utility. Therefore, in this review, we examine the translational and clinical studies using MSCs in various liver diseases and their impact on dampening immune-mediated liver damage. Our key observations include progress made thus far with use of MSCs for clinical use, inconsistency in the literature to allow meaningful comparison between different studies and need for standardized protocols for MSC manufacture and administration. In addition, the emerging role of MSC-derived extracellular vesicles as an alternative to MSC has been reviewed. We have also highlighted some of the remaining clinical challenges that should be addressed before MSC can progress to be considered as therapy for patients with liver disease.
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Affiliation(s)
- Sheeba Khan
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Sara Mahgoub
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Nada Fallatah
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Patricia F Lalor
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
| | - Philip N Newsome
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
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12
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Lu X, Guo H, Wei X, Lu D, Shu W, Song Y, Qiu N, Xu X. Current Status and Prospect of Delivery Vehicle Based on Mesenchymal Stem Cell-Derived Exosomes in Liver Diseases. Int J Nanomedicine 2023; 18:2873-2890. [PMID: 37283714 PMCID: PMC10239634 DOI: 10.2147/ijn.s404925] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 05/10/2023] [Indexed: 06/08/2023] Open
Abstract
With the improvement of the average life expectancy and increasing incidence of obesity, the burden of liver disease is increasing. Liver disease is a serious threat to human health. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stem cells (MSCs) can be used as an alternative therapy for liver disease, especially liver cirrhosis, liver failure, and liver transplantation complications. However, MSCs may have potential tumorigenic effects. Exosomes derived from MSCs (MSC-Exos), as the important intercellular communication mode of MSCs, contain various proteins, nucleic acids, and DNA. MSC-Exos can be used as a delivery system to treat liver diseases through immune regulation, apoptosis inhibition, regeneration promotion, drug delivery, and other ways. Good histocompatibility and material exchangeability make MSC-Exos a new treatment for liver diseases. This review summarizes the latest research on MSC-Exos as delivery vehicles in different liver diseases, including liver injury, liver failure, liver fibrosis, hepatocellular carcinoma (HCC), and ischemia and reperfusion injury. In addition, we discuss the advantages, disadvantages, and clinical application prospects of MSC-Exos-based delivery vectors in the treatment of liver diseases.
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Affiliation(s)
- Xinfeng Lu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Haijun Guo
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Wenzhi Shu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Yisu Song
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Nasha Qiu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
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13
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Wang M, Li J, Wang D, Xin Y, Liu Z. The effects of mesenchymal stem cells on the chemotherapy of colorectal cancer. Biomed Pharmacother 2023; 160:114373. [PMID: 36753960 DOI: 10.1016/j.biopha.2023.114373] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/09/2023] Open
Abstract
Colorectal cancer (CRC) has been the third commonest cancer in the world. The prognosis of patients with CRC is related to the molecular subtypes and gene mutations, which is prone to recurrence, metastasis, and drug resistance. Mesenchymal stem cells (MSCs) are a group of progenitor ones with the capabilities of self-renewal， multi-directional differentiation, and tissue re-population, which could be isolated from various kinds of tissues and be differentiated into diverse cell types. In recent years, MSCs are applied for mechanisms study of tissue repairing, graft-versus-host disease (GVHD) and autoimmune-related disease, and tumor development, with the advantages of anti-inflammation, multi-lineage differentiation, and homing capability. Integrating the chemotherapy and MSCs therapy might provide a novel treatment approach for CRC patients. In this review, we summarize the current progress in the integrated treatment of integrating the MSCs and chemotherapy for CRC.
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Affiliation(s)
- Meiqi Wang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Dongxin Wang
- Department of Anesthesiology, Jilin Cancer Hospital, Jilin, China
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China
| | - Zhuo Liu
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
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14
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Al-Awsi GRL, Alsaikhan F, Margiana R, Ahmad I, Patra I, Najm MAA, Yasin G, Rasulova I, Hammid AT, Kzar HH, Al-Gazally ME, Siahmansouri H. Shining the light on mesenchymal stem cell-derived exosomes in breast cancer. Stem Cell Res Ther 2023; 14:21. [PMID: 36750912 PMCID: PMC9906907 DOI: 10.1186/s13287-023-03245-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 01/18/2023] [Indexed: 02/09/2023] Open
Abstract
In women, breast cancer (BC) is the second most frequently diagnosed cancer and the leading cause of cancer death. Mesenchymal stem cells (MSCs) are a subgroup of heterogeneous non-hematopoietic fibroblast-like cells that have the ability to differentiate into multiple cell types. Recent studies stated that MSCs can migrate into the tumor sites and exert various effect on tumor growth and development. Multiple researches have demonstrated that MSCs can favor tumor growth, while other groups have indicated that MSCs inhibit tumor development. Emerging evidences showed exosomes (Exo) as a new mechanism of cell communication which are essential for the crosstalk between MSCs and BC cells. MSC-derived Exo (MSCs-Exo) could mimic the numerous effects on the proliferation, metastasis, and drug response through carrying a wide scale of molecules, such as proteins, lipids, messenger RNAs, and microRNAs to BC cells. Consequently, in the present literature, we summarized the biogenesis and cargo of Exo and reviewed the role of MSCs-Exo in development of BC.
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Affiliation(s)
- Ghaidaa Raheem Lateef Al-Awsi
- grid.517728.e0000 0004 9360 4144Department of Radiological Techniques, Al-Mustaqbal University College, Babylon, Iraq
| | - Fahad Alsaikhan
- grid.449553.a0000 0004 0441 5588College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Kingdom of Saudi Arabia
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. .,Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. .,Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia. .,Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
| | - Irfan Ahmad
- grid.412144.60000 0004 1790 7100Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | | | - Mazin A. A. Najm
- grid.513203.6Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Ghulam Yasin
- grid.411501.00000 0001 0228 333XDepartment of Botany, Bahauddin Zakariya University, Multan, Pakistan
| | - Iroda Rasulova
- Independent Researcher, “Kasmed” Private Medical Centre, Tashkent, Uzbekistan
| | - Ali Thaeer Hammid
- grid.513683.a0000 0004 8495 7394Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja’afar Al-Sadiq University, Baghdad, Iraq
| | - Hamzah H. Kzar
- Veterinary Medicine College, Al-Qasim Green University, Al-Qasim, Iraq
| | | | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Isaković J, Šerer K, Barišić B, Mitrečić D. Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force? Front Bioeng Biotechnol 2023; 11:1139359. [PMID: 36926687 PMCID: PMC10011535 DOI: 10.3389/fbioe.2023.1139359] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Neurological disorders are recognized as major causes of death and disability worldwide. Because of this, they represent one of the largest public health challenges. With awareness of the massive burden associated with these disorders, came the recognition that treatment options were disproportionately scarce and, oftentimes, ineffective. To address these problems, modern research is increasingly looking into novel, more effective methods to treat neurological patients; one of which is cell-based therapies. In this review, we present a critical analysis of the features, challenges, and prospects of one of the stem cell types that can be employed to treat numerous neurological disorders-mesenchymal stem cells (MSCs). Despite the fact that several studies have already established the safety of MSC-based treatment approaches, there are still some reservations within the field regarding their immunocompatibility, heterogeneity, stemness stability, and a range of adverse effects-one of which is their tumor-promoting ability. We additionally examine MSCs' mechanisms of action with respect to in vitro and in vivo research as well as detail the findings of past and ongoing clinical trials for Parkinson's and Alzheimer's disease, ischemic stroke, glioblastoma multiforme, and multiple sclerosis. Finally, this review discusses prospects for MSC-based therapeutics in the form of biomaterials, as well as the use of electromagnetic fields to enhance MSCs' proliferation and differentiation into neuronal cells.
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Affiliation(s)
- Jasmina Isaković
- Omnion Research International, Zagreb, Croatia.,Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Klara Šerer
- University of Zagreb School of Medicine, Zagreb, Croatia
| | - Barbara Barišić
- University of Zagreb School of Dental Medicine, Zagreb, Croatia
| | - Dinko Mitrečić
- Department of Histology and Embryology, University of Zagreb School of Medicine, Zagreb, Croatia.,Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
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16
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Yüce M, Albayrak E. Hyperthermia-stimulated tonsil-mesenchymal stromal cells suppress hematological cancer cells through downregulation of IL-6. J Cell Biochem 2022; 123:1966-1979. [PMID: 36029519 DOI: 10.1002/jcb.30322] [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: 10/06/2021] [Revised: 08/01/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022]
Abstract
There are contradictory reports on the use of mesenchymal stromal cells (MSCs) in cancer therapy. Variable outcomes have been associated with several factors including cancer pathology, experimental procedure, MSC source tissue, and individual genetic differences. It is also known that MSCs exert their therapeutic effects with various paracrine factors released from these cells. The profiles of the factors released from MSCs are altered by heat shock, hypoxia, oxidative stress, starvation or various agents such as inflammatory cytokines, and their therapeutic potential is affected. In this study, the antitumor potential of conditioned media (CM), which contains paracrine factors, of mild hyperthermia-stimulated mesenchymal stromal cells derived from lymphoid organ tonsil tissue (T-MSC) was investigated in comparison with CM obtained from T-MSCs grew under normal culture conditions. CM was obtained from T-MSCs that were successfully isolated from palatine tonsil tissue and characterized. The cytotoxic effect of CM on the growth of hematological cancer cell lines at different concentrations (1:1 and 1:2) was demonstrated by methylthiazoldiphenyl-tetrazolium bromide analysis. In addition, the apoptotic effect of T-MSC-CM treatment was evaluated on the cancer cells using Annexin-V/PI detection method by flow cytometry. The pro/anti-apoptotic and cytokine-related gene expressions were also analyzed by real-time polymerase chain reaction post T-MSC-CM treatment. In conclusion, we demonstrated that the factors released from hyperthermia-stimulated T-MSCs induced apoptosis in hematological cancer cell lines in a dose-dependent manner. Importantly, our results at the transcriptional level support that the factors and cytokines released from hyperthermia-stimulated T-MSC may exert antitumoral effects in cancer cells by downregulation of IL-6 that promotes tumorigenesis. These findings reveal that T-MSC-CM can be a powerful cell-free therapeutical strategy for cancer therapy.
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Affiliation(s)
- Melek Yüce
- Stem Cell Research & Application Center, Ondokuz Mayıs University, Kurupelit Campus, Atakum/Samsun, Turkey
| | - Esra Albayrak
- Stem Cell Research & Application Center, Ondokuz Mayıs University, Kurupelit Campus, Atakum/Samsun, Turkey
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17
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Sirithammajak S, Manochantr S, Tantrawatpan C, Tantikanlayaporn D, Kheolamai P. Human Mesenchymal Stem Cells Derived from the Placenta and Chorion Suppress the Proliferation while Enhancing the Migration of Human Breast Cancer Cells. Stem Cells Int 2022; 2022:4020845. [PMID: 36406002 PMCID: PMC9674426 DOI: 10.1155/2022/4020845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 10/21/2022] [Accepted: 10/31/2022] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND Breast cancer is the most frequently diagnosed malignancy among women, resulting from abnormal proliferation of mammary epithelial cells. The highly vascularized nature of breast tissue leads to a high incidence of breast cancer metastases, resulting in a poor survival rate. Previous studies suggest that human mesenchymal stem cells (hMSCs) play essential roles in the growth, metastasis, and drug responses of many cancers, including breast cancer. However, hMSCs from different sources may release different combinations of cytokines that affect breast cancer differently. METHODS In this study, we have isolated hMSCs from the placenta (PL-hMSCs) and the chorion (CH-hMSCs) and determined how these hMSCs affect the proliferation, migration, invasion, and gene expression of two human breast cancer cells, MCF-7 and MDA-MB-231, as well as the possible mechanisms underlying those effects. RESULTS The results showed that the soluble factors derived from PL-hMSCs and CH-hMSCs inhibited the proliferation of MCF-7 and MDA-MB-231 cells but increased the migration of MDA-MB-231 cells. The study of gene expression showed that PL-hMSCs and CH-hMSCs downregulated the expression levels of the protooncogene CyclinD1 while upregulating the expression levels of tumor suppressor genes, P16 and P21 in MCF-7 and MDA-MB-231 cells. Furthermore, hMSCs from both sources also increased the expression levels of MYC, SNAI1, and TWIST, which promote the epithelial-mesenchymal transition and migration of breast cancer cells in both cell lines. The functional study suggests that the suppressive effect of CH-hMSCs and PL-hMSCs on MCF-7 and MDA-MB231 cell proliferation was mediated, at least in part, through IFN-γ. CONCLUSIONS Our study suggests that CH-hMSCs and PL-hMSCs inhibited breast cancer cell proliferation by negatively regulating CYCLIND1 expression and upregulating the expression of the P16 and P21 genes. In contrast, hMSCs from both sources enhanced breast cancer cell migration, possibly by increasing the expression of MYC, SNAI1, and TWIST genes in those cells.
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Affiliation(s)
- Sarawut Sirithammajak
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Sirikul Manochantr
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Chairat Tantrawatpan
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Duangrat Tantikanlayaporn
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Pakpoom Kheolamai
- Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
- Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani 12120, Thailand
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18
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He J, Yao X, Mo P, Wang K, Yang ZL, Tian NN, Zhu XQ, Zhao J, Pang RQ, Ruan GP, Pan XH. Lack of tumorigenesis and protumorigenic activity of human umbilical cord mesenchymal stem cells in NOD SCID mice. BMC Cancer 2022; 22:307. [PMID: 35317758 PMCID: PMC8941803 DOI: 10.1186/s12885-022-09431-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 03/08/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The tumorigenesis of infused umbilical cord mesenchymal stem cells (UC-MSCs) is being preclinically evaluated. METHODS We observed tumor formation in NOD SCID mice after a single subcutaneous injection of hUC-MSCs and the effect of these cells on tumor growth in tumor-bearing mice. Three generations (P5, P7, and P10) of hUC-MSCs (1 × 107) from two donors (hUC-MSC1 and hUC-MSC2) were inoculated subcutaneously into NOD SCID mice. Subcutaneous transplantation models were established in NOD SCID mice with human cervical cancer HeLa cells (solid tumor) and human B cell lymphoma Raji cells (hematological tumor). Then, the animals were euthanized, gross dissection was performed, and tissues were collected. Various organs were observed microscopically to identify pathological changes and tumor metastasis. RESULTS In the tumorigenesis experiment, no general anatomical abnormalities were observed. In the tumor promotion experiment, some animals in the HeLa groups experienced tumor rupture, and one animal died in each of the low- and medium-dose hUC-MSC groups. The results may have occurred due to the longer feeding time, and the tumor may have caused spontaneous infection and death. Pathological examination revealed no metastasis to distant organs in any group. In the Raji tumor model, some animals in each group experienced tumor rupture, and one animal in the medium-dose hUC-MSC group died, perhaps due to increased tumor malignancy. Thus, hUC-MSCs neither promoted nor inhibited tumor growth. No cancer cell metastasis was observed in the heart, liver, spleen, lungs, kidneys or other important organs, except that pulmonary venule metastasis was observed in 1 animal in the model group. CONCLUSIONS Injected hUC-MSCs were not tumorigenic and did not significantly promote or inhibit solid or hematological tumor growth or metastasis in NOD SCID mice.
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Affiliation(s)
- Jie He
- Kunming Medical University, 920th Hospital Clinical College, Yunnan Province, Kunming, 650000, China
| | - Xiang Yao
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Ping Mo
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Kai Wang
- Kunming Medical University, 920th Hospital Clinical College, Yunnan Province, Kunming, 650000, China
| | - Zai-Ling Yang
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Ni-Ni Tian
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Xiang-Qing Zhu
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Jing Zhao
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Rong-Qing Pang
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China
| | - Guang-Ping Ruan
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China.
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China.
| | - Xing-Hua Pan
- Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, 650032, Yunnan Province, China.
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Kunming, 650032, Yunnan Province, China.
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19
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Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, Hua D, Shao C, Shi Y. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther 2022; 7:92. [PMID: 35314676 PMCID: PMC8935608 DOI: 10.1038/s41392-022-00932-0] [Citation(s) in RCA: 328] [Impact Index Per Article: 109.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 11/18/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
AbstractMesenchymal stromal/stem cells (MSCs) possess multi-lineage differentiation and self-renewal potentials. MSCs-based therapies have been widely utilized for the treatment of diverse inflammatory diseases, due to the potent immunoregulatory functions of MSCs. An increasing body of evidence indicates that MSCs exert their therapeutic effects largely through their paracrine actions. Growth factors, cytokines, chemokines, extracellular matrix components, and metabolic products were all found to be functional molecules of MSCs in various therapeutic paradigms. These secretory factors contribute to immune modulation, tissue remodeling, and cellular homeostasis during regeneration. In this review, we summarize and discuss recent advances in our understanding of the secretory behavior of MSCs and the intracellular communication that accounts for their potential in treating human diseases.
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20
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Wang FD, Zhou J, Chen EQ. Molecular Mechanisms and Potential New Therapeutic Drugs for Liver Fibrosis. Front Pharmacol 2022; 13:787748. [PMID: 35222022 PMCID: PMC8874120 DOI: 10.3389/fphar.2022.787748] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis is the pathological process of excessive extracellular matrix deposition after liver injury and is a precursor to cirrhosis, hepatocellular carcinoma (HCC). It is essentially a wound healing response to liver tissue damage. Numerous studies have shown that hepatic stellate cells play a critical role in this process, with various cells, cytokines, and signaling pathways engaged. Currently, the treatment targeting etiology is considered the most effective measure to prevent and treat liver fibrosis, but reversal fibrosis by elimination of the causative agent often occurs too slowly or too rarely to avoid life-threatening complications, especially in advanced fibrosis. Liver transplantation is the only treatment option in the end-stage, leaving us with an urgent need for new therapies. An in-depth understanding of the mechanisms of liver fibrosis could identify new targets for the treatment. Most of the drugs targeting critical cells and cytokines in the pathogenesis of liver fibrosis are still in pre-clinical trials and there are hardly any definitive anti-fibrotic chemical or biological drugs available for clinical use. In this review, we will summarize the pathogenesis of liver fibrosis, focusing on the role of key cells, associated mechanisms, and signaling pathways, and summarize various therapeutic measures or drugs that have been trialed in clinical practice or are in the research stage.
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Affiliation(s)
| | | | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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21
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Yang M, Chen J, Chen L. The roles of mesenchymal stem cell-derived exosomes in diabetes mellitus and its related complications. Front Endocrinol (Lausanne) 2022; 13:1027686. [PMID: 36339446 PMCID: PMC9633677 DOI: 10.3389/fendo.2022.1027686] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetes mellitus is a type of metabolic disease characterized by hyperglycemia, primarily caused by defects in insulin secretion, insulin action, or both. Long-term chronic hyperglycemia can lead to diabetes-related complications, causing damage, dysfunction, and failure of different organs. However, traditional insulin and oral drug therapy can only treat the symptoms but not delay the progressive failure of pancreatic beta cells or prevent the emergence of diabetic complications. Mesenchymal stem cells have received extensive attention due to their strong immunoregulatory functions and regeneration effects. Mesenchymal stem cell-derived exosomes (MSC-Exos) have been proposed as a novel treatment for diabetic patients as they have demonstrated superior efficiency to mesenchymal stem cells. This review summarizes the therapeutic effects, mechanisms, challenges, and future prospects of MSC-Exos in treating diabetes mellitus and its related complications. This review supports the potential use of MSC-Exos in future regenerative medicine to overcome the current difficulties in clinical treatment, particularly in treating diabetes.
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Affiliation(s)
- Mengmeng Yang
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
| | - Jun Chen
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
- *Correspondence: Jun Chen, ; Li Chen,
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China
- Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
- *Correspondence: Jun Chen, ; Li Chen,
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22
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Wang KH, Chang YH, Harnod T, Ding DC. Endometrial Cancer-Infiltrating Mesenchymal Stem Cells Exhibit Immunosuppressive Effects. Cell Transplant 2022; 31:9636897221104452. [PMID: 35712817 PMCID: PMC9210080 DOI: 10.1177/09636897221104452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Endometrial cancer is the most common gynecologic cancer with high heterogeneity. However, there are limited treatment options for advanced endometrial carcinoma. In recent years, immunotherapy has broadly been used for the treatment of various cancers. However, the efficacy of immunotherapy against endometrial cancer is limited. The tumor microenvironment, including mesenchymal stem cells (MSCs), may contribute to tumor progression through cancer cells themselves and through cells of the immune system. We successfully isolated endometrial cancer–derived MSCs (EmCaMSCs) from patients and found that the population of MSCs in tumor tissues was approximately 1%–5%. The population of MSCs correlated with the stage of the disease. EmCaMSCs expressed MSC markers and exhibited trilineage differentiation ability. The programmed death ligands PD-L1 and PD-L2 were highly expressed in EmCaMSCs; their expression could be further enhanced by tumor necrosis factor-α and interferon-γ. When cocultured with peripheral blood mononuclear cells (PBMCs), anti-CD3, and anti-CD28, EmCaMSCs inhibited the proliferation of PBMCs, which were partially rescued by treatment with anti-PD-L1 antibodies. From the profile of conditioned medium of EmCaMSCs, we discovered that interleukin (IL)-8 and insulin-like growth factor–binding protein 6 could also rescue the proliferation of PBMCs. Furthermore, EmCaMSCs cocultured with IL-2-induced PBMCs exhibited decreased expression of CD56, CD4, and CD8 and showed decreased cytotoxicity toward K562 cells and endometrial cancer cells. Overall, EmCaMSCs were isolated successfully from endometrial cancer tissues and exhibited immunosuppressive effects and may be targeted for the treatment of endometrial cancer by anti-cytokine and immune checkpoint inhibitors. The percentage of MSCs in tumor stroma might predict the prognosis of endometrial cancer.
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Affiliation(s)
- Kai-Hung Wang
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien
| | - Yu-Hsun Chang
- Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien
| | - Tomor Harnod
- Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien.,Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien
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23
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Yassine S, Alaaeddine N. Mesenchymal Stem Cell Exosomes and Cancer: Controversies and Prospects. Adv Biol (Weinh) 2021; 6:e2101050. [PMID: 34939371 DOI: 10.1002/adbi.202101050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/11/2021] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) have displayed a novel therapeutic strategy for a wide range of diseases and conditions. Their secretome and exosome-based paracrine activity are considered as the main processes harboring their diverse therapeutic properties. Several investigations have examined the effects of MSC-derived exosomes on cancer growth, yet, controversial results have always emerged. Although MSC-derived exosomes are able to rigorously enforce the repression of cancer proliferation and progression, it is shown that MSCs exosomal activity displays numerous protumorigenic effects. This discrepancy over the dual effects of MSCs on cancer growth may be mediated by many factors including experimental design, stem cells origins, culture conditions, in addition to cancer-MSCs cross-talks. Despite the controversial effects of MSCs on carcinogenesis, scientists are able to overcome a number of obstacles by modifying MSCs to deliver antioncogenic miRNAs, anticancer drugs, and oncolytic viruses into tumor sites. This review discusses the controversial effects of MSC-derived exosomes on tumorigenesis, investigates the main causes that underlie this discrepancy, summarizes the pattern of engineered-MSCs, and finally highlights how future studies should advance the research in the field of MSCs-based cancer therapies in order to accelerate the transition from preclinical studies to clinical practice.
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Affiliation(s)
- Sirine Yassine
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, 1100, Lebanon
| | - Nada Alaaeddine
- Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, 1100, Lebanon
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24
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Bie Q, Zhai R, Chen Y, Li Y, Xie N, Wang B, Yuan P, Zhou X, Cong H, Chang X, Xiong H, Zhang B. Sox9 Is Crucial for Mesenchymal Stem Cells to Enhance Cutaneous Wound Healing. Int J Stem Cells 2021; 14:465-474. [PMID: 34456192 PMCID: PMC8611311 DOI: 10.15283/ijsc21078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/09/2021] [Accepted: 07/08/2021] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Human umbilical cord mesenchymal stem cells (HUC-MSCs) are promising candidates for cell-based therapy in regenerative medicine or other diseases due to their superior characteristics, including higher proliferation, faster self-renewal ability, lower immunogenicity, a noninvasive harvest procedure, easy expansion in vitro, and ethical access, compared with stem cells from other sources. METHODS AND RESULTS In the present study, we knocked down the expression of SOX9 in HUC-MSCs by lentivirus interference and found that knockdown of SOX9 inhibited the proliferation and migration of HUC-MSCs and influenced the expression of cytokines (IL-6 and IL-8), growth factors (GM-CSF and VEGF) and stemness-related genes (OCT4 and SALL4). In addition, the repair effect of skin with burn injury in rats treated with HUC-MSCs transfected with sh-control was better than that rats treated with HUC-MSCs transfected with shSOX9 or PBS, and the accessory structures of the skin, including hair follicles and glands, were greater than those in the other groups. We found that knockdown of the expression of SOX9 obviously inhibited the expression of Ki67, CK14 and CK18. CONCLUSIONS In conclusion, this study will provide a guide for modifying HUC-MSCs by bioengineering technology in the future.
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Affiliation(s)
- Qingli Bie
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
| | - Ruixia Zhai
- Department of Obstetric, Affiliated Hospital of Jining
Medical University, Jining Medical University, Jining,
China
| | - Yanrong Chen
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
| | - Yingao Li
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
| | - Na Xie
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
| | - Baoyi Wang
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
| | - Poyun Yuan
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
| | - Xinjie Zhou
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
| | - Haiyan Cong
- Department of Central Lab, Weihai Municipal Hospital,
Cheeloo College of Medicine, Weihai, China
| | - Xin Chang
- Department of Central Lab, Weihai Municipal Hospital,
Cheeloo College of Medicine, Weihai, China
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Jining
Medical University, Jining, China
| | - Bin Zhang
- Department of Laboratory Medicine, Affiliated Hospital of
Jining Medical University, Jining Medical University, Jining,
China
- Institute of Forensic Medicine and Laboratory Medicine,
Jining Medical University, Jining, China
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25
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Horst EN, Bregenzer ME, Mehta P, Snyder CS, Repetto T, Yang-Hartwich Y, Mehta G. Personalized models of heterogeneous 3D epithelial tumor microenvironments: Ovarian cancer as a model. Acta Biomater 2021; 132:401-420. [PMID: 33940195 PMCID: PMC8969826 DOI: 10.1016/j.actbio.2021.04.041] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/15/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023]
Abstract
Intractable human diseases such as cancers, are context dependent, unique to both the individual patient and to the specific tumor microenvironment. However, conventional cancer treatments are often nonspecific, targeting global similarities rather than unique drivers. This limits treatment efficacy across heterogeneous patient populations and even at different tumor locations within the same patient. Ultimately, this poor efficacy can lead to adverse clinical outcomes and the development of treatment-resistant relapse. To prevent this and improve outcomes, it is necessary to be selective when choosing a patient's optimal adjuvant treatment. In this review, we posit the use of personalized, tumor-specific models (TSM) as tools to achieve this remarkable feat. First, using ovarian cancer as a model disease, we outline the heterogeneity and complexity of both the cellular and extracellular components in the tumor microenvironment. Then we examine the advantages and disadvantages of contemporary cancer models and the rationale for personalized TSM. We discuss how to generate precision 3D models through careful and detailed analysis of patient biopsies. Finally, we provide clinically relevant applications of these versatile personalized cancer models to highlight their potential impact. These models are ideal for a myriad of fundamental cancer biology and translational studies. Importantly, these approaches can be extended to other carcinomas, facilitating the discovery of new therapeutics that more effectively target the unique aspects of each individual patient's TME. STATEMENT OF SIGNIFICANCE: In this article, we have presented the case for the application of biomaterials in developing personalized models of complex diseases such as cancers. TSM could bring about breakthroughs in the promise of precision medicine. The critical components of the diverse tumor microenvironments, that lead to treatment failures, include cellular- and extracellular matrix- heterogeneity, and biophysical signals to the cells. Therefore, we have described these dynamic components of the tumor microenvironments, and have highlighted how contemporary biomaterials can be utilized to create personalized in vitro models of cancers. We have also described the application of the TSM to predict the dynamic patterns of disease progression, and predict effective therapies that can produce durable responses, limit relapses, and treat any minimal residual disease.
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Affiliation(s)
- Eric N Horst
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Michael E Bregenzer
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Pooja Mehta
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Catherine S Snyder
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Taylor Repetto
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States
| | - Yang Yang-Hartwich
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, CT 06510, United States
| | - Geeta Mehta
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109, United States; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, United States; Precision Health, University of Michigan, Ann Arbor, MI 48109, United States.
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26
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Abstract
Mesenchymal stem cells (MSCs), a kind of multipotent stem cells with self-renewal ability and multi-differentiation ability, have become the “practical stem cells” for the treatment of diseases. MSCs have immunomodulatory properties and can be used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE) and Crohn’s disease. MSCs also can be used in cancer and aging. At present, many clinical experiments are using MSCs. MSCs can reduce the occurrence of inflammation and apoptosis of tissue cells, and promote the proliferation of endogenous tissue and organ cells, so as to achieve the effect of repairing tissue and organs. MSCs presumably also play an important role in Corona Virus Disease 2019 (COVID-19) infection.
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27
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Kostadinova M, Mourdjeva M. Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies. Curr Stem Cell Res Ther 2021; 15:482-491. [PMID: 32148199 DOI: 10.2174/1574888x15666200310171547] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/27/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.
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Affiliation(s)
- Milena Kostadinova
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction "Acad. Kiril Bratanov", Bulgarian Academy of Sciences, 73 Tsarigradsko Shose, 1113 Sofia, Bulgaria
| | - Milena Mourdjeva
- Department of Molecular Immunology, Institute of Biology and Immunology of Reproduction "Acad. Kiril Bratanov", Bulgarian Academy of Sciences, 73 Tsarigradsko Shose, 1113 Sofia, Bulgaria
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28
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Murray HE, Zafar A, Qureshi KM, Paget MB, Bailey CJ, Downing R. The potential role of multifunctional human amniotic epithelial cells in pancreatic islet transplantation. J Tissue Eng Regen Med 2021; 15:599-611. [PMID: 34216434 DOI: 10.1002/term.3214] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/23/2021] [Indexed: 11/08/2022]
Abstract
Pancreatic islet cell transplantation has proven efficacy as a treatment for type 1 diabetes mellitus, chiefly in individuals who are refractory to conventional insulin replacement therapy. At present its clinical use is restricted, firstly by the limited access to suitable donor organs but also due to factors associated with the current clinical transplant procedure which inadvertently impair the long-term functionality of the islet graft. Of note, the physical, biochemical, inflammatory, and immunological stresses to which islets are subjected, either during pretransplant processing or following implantation are detrimental to their sustained viability, necessitating repeated islet infusions to attain adequate glucose control. Progressive decline in functional beta (β)-cell mass leads to graft failure and the eventual re-instatement of exogenous insulin treatment. Strategies which protect and/or preserve optimal islet function in the peri-transplant period would improve clinical outcomes. Human amniotic epithelial cells (HAEC) exhibit both pluripotency and immune-privilege and are ideally suited for use in replacement and regenerative therapies. The HAEC secretome exhibits trophic, anti-inflammatory, and immunomodulatory properties of relevance to islet graft survival. Facilitated by β-cell supportive 3D cell culture systems, HAEC may be integrated with islets bringing them into close spatial arrangement where they may exert paracrine influences that support β-cell function, reduce hypoxia-induced islet injury, and alter islet alloreactivity. The present review details the potential of multifunctional HAEC in the context of islet transplantation, with a focus on the innate capabilities that may counter adverse events associated with the current clinical transplant protocol to achieve long-term islet graft function.
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Affiliation(s)
- Hilary E Murray
- The Islet Research Laboratory, Worcester Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | - Ali Zafar
- The Islet Research Laboratory, Worcester Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK.,Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Khalid M Qureshi
- The Islet Research Laboratory, Worcester Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK.,Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | - Michelle B Paget
- The Islet Research Laboratory, Worcester Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | - Clifford J Bailey
- Diabetes Research, School of Life and Health Sciences, Aston University, Birmingham, UK
| | - Richard Downing
- The Islet Research Laboratory, Worcester Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
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29
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Nieto-Nicolau N, Martínez-Conesa EM, Fuentes-Julián S, Arnalich-Montiel F, García-Tuñón I, De Miguel MP, Casaroli-Marano RP. Priming human adipose-derived mesenchymal stem cells for corneal surface regeneration. J Cell Mol Med 2021; 25:5124-5137. [PMID: 33951289 PMCID: PMC8178265 DOI: 10.1111/jcmm.16501] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 12/13/2022] Open
Abstract
Limbal stem cells (LSC) maintain the transparency of the corneal epithelium. Chemical burns lead the loss of LSC inducing an up-regulation of pro-inflammatory and pro-angiogenic factors, triggering corneal neovascularization and blindness. Adipose tissue-derived mesenchymal stem cells (AT-MSC) have shown promise in animal models to treat LSC deficiency (LSCD), but there are not studies showing their efficacy when primed with different media before transplantation. We cultured AT-MSC with standard medium and media used to culture LSC for clinical application. We demonstrated that different media changed the AT-MSC paracrine secretion showing different paracrine effector functions in an in vivo model of chemical burn and in response to a novel in vitro model of corneal inflammation by alkali induction. Treatment of LSCD with AT-MSC changed the angiogenic and inflammatory cytokine profile of mice corneas. AT-MSC cultured with the medium that improved their cytokine secretion, enhanced the anti-angiogenic and anti-inflammatory profile of the treated corneas. Those corneas also presented better outcome in terms of corneal transparency, neovascularization and histologic reconstruction. Priming human AT-MSC with LSC specific medium can potentiate their ability to improve corneal wound healing, decrease neovascularization and inflammation modulating paracrine effector functions in an in vivo optimized rat model of LSCD.
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Affiliation(s)
- Núria Nieto-Nicolau
- CellTec-UB, Department of Cell Biology, University of Barcelona, Barcelona, Spain.,Barcelona Tissue Bank (BTB), Banc de Sang I Teixits (BST), Barcelona, Spain.,Institute of Biomedical Research IIB-Sant Pau (SGR1113), Barcelona, Spain
| | - Eva M Martínez-Conesa
- Barcelona Tissue Bank (BTB), Banc de Sang I Teixits (BST), Barcelona, Spain.,Institute of Biomedical Research IIB-Sant Pau (SGR1113), Barcelona, Spain
| | | | | | - Ignacio García-Tuñón
- Cell Engineering Laboratory, La Paz Hospital Research Institute (IdiPAZ), Madrid, Spain
| | - María P De Miguel
- Cell Engineering Laboratory, La Paz Hospital Research Institute (IdiPAZ), Madrid, Spain
| | - Ricardo P Casaroli-Marano
- CellTec-UB, Department of Cell Biology, University of Barcelona, Barcelona, Spain.,Barcelona Tissue Bank (BTB), Banc de Sang I Teixits (BST), Barcelona, Spain.,Institute of Biomedical Research IIB-Sant Pau (SGR1113), Barcelona, Spain.,Department of Surgery & Hospital Clinic de Barcelona, School of Medicine, University of Barcelona, Barcelona, Spain
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30
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Lim EJ, Kim S, Oh Y, Suh Y, Kaushik N, Lee JH, Lee HJ, Kim MJ, Park MJ, Kim RK, Cha J, Kim SH, Shim JK, Choi J, Chang JH, Hong YK, Huh YM, Kim P, Kang SG, Lee SJ. Crosstalk between GBM cells and mesenchymal stemlike cells promotes the invasiveness of GBM through the C5a/p38/ZEB1 axis. Neuro Oncol 2021; 22:1452-1462. [PMID: 32179921 DOI: 10.1093/neuonc/noaa064] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors. METHODS To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system. RESULTS Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue. CONCLUSION Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression. KEY POINTS 1. MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment.2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.
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Affiliation(s)
- Eun-Jung Lim
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.,Memorial Sloan Kettering, Cancer Center, New York, New York, USA
| | - Seungmo Kim
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Yoonjee Oh
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea
| | - Yongjoon Suh
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Neha Kaushik
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Ji-Hyun Lee
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hae-June Lee
- Division of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul, Korea
| | - Min-Jung Kim
- Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Myung-Jin Park
- Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Rae-Kwon Kim
- Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Korea
| | - Junghwa Cha
- College of Pharmacy, Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon, Korea
| | - Se Hoon Kim
- Department of Pathology, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea
| | - Jin-Kyoung Shim
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Junjeong Choi
- College of Pharmacy, Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon, Korea.,KAIST Institute for Health Science and Technology, Daejeon, Korea
| | - Jong Hee Chang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Kil Hong
- Department of Neurosurgery, Seoul St Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Yong Min Huh
- Department of Radiology, Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea
| | - Pilnam Kim
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.,KAIST Institute for Health Science and Technology, Daejeon, Korea
| | - Seok-Gu Kang
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Su-Jae Lee
- Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
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31
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Borkar R, Wang X, Zheng D, Miao Z, Zhang Z, Li E, Wu Y, Xu RH. Human ESC-derived MSCs enhance fat engraftment by promoting adipocyte reaggregation, secreting CCL2 and mobilizing macrophages. Biomaterials 2021; 272:120756. [PMID: 33798959 DOI: 10.1016/j.biomaterials.2021.120756] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 02/10/2021] [Accepted: 02/25/2021] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) derived from somatic tissues have been used to promote lipotransfer, a common practice in cosmetic surgery. However, the effect of lipotransfer varies, and the mechanism of action remains vague. To address these questions, we differentiated human embryonic stem cells, a stable and unlimited source, into MSCs (EMSCs). Then we subcutaneously transplanted human fat aspirates together with EMSCs or PBS as a control into the back of nude mice. Within 24 h of transplantation, EMSCs promoted aggregation and encapsulation of injected fat tissues. Afterward, all grafts gradually shrank. However, EMSC-containing grafts were larger, heavier and had fewer dark areas on the surface than the control grafts. Histologically, more live adipocytes, vascular cells, and macrophages and less fibrosis were observed in EMSC-containing grafts than in the controls. Some EMSCs differentiated into vascular cells and adipocytes in the EMSC-containing grafts. RNA sequencing revealed that human RNA was shown to decline rapidly, while mouse RNA increased in the grafts; further, human genes related to extracellular matrix remodeling, adipogenesis, and chemokine (including CCL2) signaling were expressed at higher levels in the EMSC-containing grafts than they were in the controls. CCL2 knockout reduced macrophage migration towards EMSCs in vitro and early macrophage recruitment to the grafts and the pro-engraftment effect of EMSCs in vivo. Treating mice with a macrophage inhibitor abolished the EMSC effects and converted the grafts to heavy masses of cell debris. Together, these data demonstrate that EMSCs promote fat engraftment via enhanced tissue reconstitution and encapsulation of implanted tissues, which was followed by increased angiogenesis and adipocyte survival and reduced fibrosis, in which stimulated CCL2 signaling and mobilized macrophages play pivotal roles.
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Affiliation(s)
- Roma Borkar
- Center of Reproduction, Development & Aging, And Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Xiaoyan Wang
- Center of Reproduction, Development & Aging, And Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Dejin Zheng
- Center of Reproduction, Development & Aging, And Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Zhengqiang Miao
- Center of Reproduction, Development & Aging, And Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Zhenwu Zhang
- Center of Reproduction, Development & Aging, And Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Enqin Li
- Center of Reproduction, Development & Aging, And Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Yaojiong Wu
- The Shenzhen Key Laboratory of Health Sciences and Technology, International Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
| | - Ren-He Xu
- Center of Reproduction, Development & Aging, And Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
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Muscarella AM, Aguirre S, Hao X, Waldvogel SM, Zhang XHF. Exploiting bone niches: progression of disseminated tumor cells to metastasis. J Clin Invest 2021; 131:143764. [PMID: 33720051 PMCID: PMC7954594 DOI: 10.1172/jci143764] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Many solid cancers metastasize to the bone and bone marrow (BM). This process may occur even before the diagnosis of primary tumors, as evidenced by the discovery of disseminated tumor cells (DTCs) in patients without occult malignancies. The cellular fates and metastatic progression of DTCs are determined by complicated interactions between cancer cells and BM niches. Not surprisingly, these niches also play important roles in normal biology, including homeostasis and turnover of skeletal and hematopoiesis systems. In this Review, we summarize recent findings on functions of BM niches in bone metastasis (BoMet), particularly during the early stage of colonization. In light of the rich knowledge of hematopoiesis and osteogenesis, we highlight how DTCs may progress into overt BoMet by taking advantage of niche cells and their activities in tissue turnover, especially those related to immunomodulation and bone repair.
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Affiliation(s)
- Aaron M. Muscarella
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas, USA
| | - Sergio Aguirre
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas, USA
| | - Xiaoxin Hao
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Sarah M. Waldvogel
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA
| | - Xiang H.-F. Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- McNair Medical Institute, Baylor College of Medicine, Houston, Texas, USA
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Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature. Cancer Cell Int 2021; 21:158. [PMID: 33685452 PMCID: PMC7938588 DOI: 10.1186/s12935-021-01836-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/15/2021] [Indexed: 12/27/2022] Open
Abstract
A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.
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Chen B, Cai T, Huang C, Zang X, Sun L, Guo S, Wang Q, Chen Z, Zhao Y, Han Z, Xu R, Xu W, Wang M, Shen B, Zhu W. G6PD-NF-κB-HGF Signal in Gastric Cancer-Associated Mesenchymal Stem Cells Promotes the Proliferation and Metastasis of Gastric Cancer Cells by Upregulating the Expression of HK2. Front Oncol 2021; 11:648706. [PMID: 33718248 PMCID: PMC7952978 DOI: 10.3389/fonc.2021.648706] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 02/08/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Tumor-associated stromal cells have been widely recognized for their tumor-promoting capability involving paracrine signaling. However, the underlying mechanism and the effects of the molecules in the glycolysis pathway in gastric cancer-associated mesenchymal stem cells (GCMSCs) and gastric cancer cells on tumor progression remain unclear. Methods: The expression of hepatocyte growth factor (HGF) in GCMSCs and bone marrow mesenchymal stem cells (BMMSCs) was detected by enzyme-linked immunosorbent assay (ELISA). The effect of HGF derived from GCMSCs on the proliferation, metastasis, and HK2 expression of gastric cancer cells was evaluated in vitro and in vivo. The effects of G6PD on the production of HGF in mesenchymal stem cells (MSCs) were analyzed by immunoblotting. Results: HGF derived from GCMSCs promoted glycolysis, proliferation, and metastasis of gastric cancer by upregulating c-Myc-HK2 signal. The progression of the disease induced by GCMSCs decelerated in the absence of HK2. The expression of G6PD activated NF-κB signaling and stimulated the production of HGF in GCMSCs. Blocking HGF derived from GCMSCs decreased proliferation, metastasis, and angiogenesis of gastric cancer cells in vivo. Conclusions: GCMSCs highly expressed G6PD and facilitated the progression of gastric cancer through the G6PD-NF-κB-HGF axis coordinates. Blocking HGF derived from GCMSCs is a potential new therapeutic target for the treatment of gastric cancer.
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Affiliation(s)
- Bin Chen
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tuo Cai
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Chao Huang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xueyan Zang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Sun
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Shuwei Guo
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Qianqian Wang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhihong Chen
- Department of Surgery, Zhenjiang First People's Hospital, Zhenjiang, China
| | - Yuanyuan Zhao
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhiqiang Han
- Department of Orthopedics, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Rongman Xu
- Department of Clinical Laboratory, Haian People's Hospital, Haian, China
| | - Wenrong Xu
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Mei Wang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Bo Shen
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Wei Zhu
- School of Medicine, Jiangsu University, Zhenjiang, China
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McGuire JJ, Frieling JS, Lo CH, Li T, Muhammad A, Lawrence HR, Lawrence NJ, Cook LM, Lynch CC. Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer. Nat Commun 2021; 12:723. [PMID: 33526787 PMCID: PMC7851397 DOI: 10.1038/s41467-021-20962-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 01/06/2021] [Indexed: 01/12/2023] Open
Abstract
Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.
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Affiliation(s)
- Jeremy J McGuire
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jeremy S Frieling
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Chen Hao Lo
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Tao Li
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ayaz Muhammad
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Harshani R Lawrence
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Nicholas J Lawrence
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Leah M Cook
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Conor C Lynch
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
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Liang W, Chen X, Zhang S, Fang J, Chen M, Xu Y, Chen X. Mesenchymal stem cells as a double-edged sword in tumor growth: focusing on MSC-derived cytokines. Cell Mol Biol Lett 2021; 26:3. [PMID: 33472580 PMCID: PMC7818947 DOI: 10.1186/s11658-020-00246-5] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 12/27/2020] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) show homing capacity towards tumor sites. Numerous reports indicate that they are involved in multiple tumor-promoting processes through several mechanisms, including immunosuppression; stimulation of angiogenesis; transition to cancer-associated fibroblasts; inhibition of cancer cell apoptosis; induction of epithelial-mesenchymal transition (EMT); and increase metastasis and chemoresistance. However, other studies have shown that MSCs suppress tumor growth by suppressing angiogenesis, incrementing inflammatory infiltration, apoptosis and cell cycle arrest, and inhibiting the AKT and Wnt signaling pathways. In this review, we discuss the supportive and suppressive impacts of MSCs on tumor progression and metastasis. We also discuss MSC-based therapeutic strategies for cancer based on their potential for homing to tumor sites.
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Affiliation(s)
- Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, 355 Xinqiao Road, Dinghai District, Zhoushan, 316000, Zhejiang, People's Republic of China.
| | - Xiaozhen Chen
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Songou Zhang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Jian Fang
- College of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Meikai Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Yifan Xu
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
| | - Xuerong Chen
- Department of Orthopaedics, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing University, Shaoxing, 312000, Zhejiang, People's Republic of China
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Sun Y, Tao Q, Wu X, Zhang L, Liu Q, Wang L. The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications. Front Endocrinol (Lausanne) 2021; 12:756581. [PMID: 34764939 PMCID: PMC8576340 DOI: 10.3389/fendo.2021.756581] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus and the associated complications are metabolic diseases with high morbidity that result in poor quality of health and life. The lack of diagnostic methods for early detection results in patients losing the best treatment opportunity. Oral hypoglycemics and exogenous insulin replenishment are currently the most common therapeutic strategies, which only yield temporary glycemic control rather than curing the disease and its complications. Exosomes are nanoparticles containing bioactive molecules reflecting individual physiological status, regulating metabolism, and repairing damaged tissues. They function as biomarkers of diabetes mellitus and diabetic complications. Considering that exosomes are bioactive molecules, can be obtained from body fluid, and have cell-type specificity, in this review, we highlight the multifold effects of exosomes in the pathology and therapy of diabetes mellitus and diabetic complications.
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Affiliation(s)
- Yaoxiang Sun
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Qing Tao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Xueqin Wu
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Ling Zhang
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Qi Liu
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Lei Wang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
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Anwar I, Ashfaq UA, Shokat Z. Therapeutic Potential of Umbilical Cord Stem Cells for Liver Regeneration. Curr Stem Cell Res Ther 2020; 15:219-232. [PMID: 32077830 DOI: 10.2174/1568026620666200220122536] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 07/16/2019] [Accepted: 08/08/2019] [Indexed: 01/18/2023]
Abstract
The liver is a vital organ for life and the only internal organ that is capable of natural regeneration. Although the liver has high regeneration capacity, excessive hepatocyte death can lead to liver failure. Various factors can lead to liver damage including drug abuse, some natural products, alcohol, hepatitis, and autoimmunity. Some models for studying liver injury are APAP-based model, Fas ligand (FasL), D-galactosamine/endotoxin (Gal/ET), Concanavalin A, and carbon tetrachloride-based models. The regeneration of the liver can be carried out using umbilical cord blood stem cells which have various advantages over other stem cell types used in liver transplantation. UCB-derived stem cells lack tumorigenicity, have karyotype stability and high immunomodulatory, low risk of graft versus host disease (GVHD), low risk of transmitting somatic mutations or viral infections, and low immunogenicity. They are readily available and their collection is safe and painless. This review focuses on recent development and modern trends in the use of umbilical cord stem cells for the regeneration of liver fibrosis.
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Affiliation(s)
- Ifrah Anwar
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Usman A Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Zeeshan Shokat
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
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Xu R, Bai Y, Min S, Xu X, Tang T, Ju S. In vivo Monitoring and Assessment of Exogenous Mesenchymal Stem Cell-Derived Exosomes in Mice with Ischemic Stroke by Molecular Imaging. Int J Nanomedicine 2020; 15:9011-9023. [PMID: 33235449 PMCID: PMC7680167 DOI: 10.2147/ijn.s271519] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022] Open
Abstract
Purpose Mesenchymal stem cell-derived exosomes (MSC-exos) are considered an important restorative treatment for ischemic stroke. However, the migration ability and survival of exogenous MSC-exos remain unclear. Here, we investigated whether MSC-exos migrate into the ischemic brain and play a protective role against ischemic stroke. Methods MSC-exos labeled with DiR were injected intravenously into mice with ischemic stroke. Near-infrared fluorescence (NIRF) images were obtained on days 0, 1, 3, 5, 7, 10, and 14, and magnetic resonance (MR) images were obtained on days 1, 7 and 14. On day 14, the functional outcomes, angiogenesis, neurogenesis, and white matter remodeling were assessed, and Western blot assays were performed. Results Fluorescence signals from the MSC-exos appeared in the injured brain from day 1 and peaked on day 3. The immunofluorescence staining of the brain samples revealed that the MSC-exos were localized in neurons. The behavioral scores and T2-weighted imaging indicated that the MSC-exos improved neurological functional recovery after stroke. In addition, the in vivo MR-diffusion tensor imaging (DTI) indicated that the exogenous MSC-exos increased the fractional anisotropy (FA) value, fiber length, and fiber number ratio. Furthermore, in the mice with ischemic stroke treated with MSC-exos, angiogenesis and neurogenesis were significantly improved, and the expression of IL-1β was reduced. Conclusion MSC-exos can migrate into the brains of mice with ischemic stroke and exert therapeutic effects against ischemic stroke; therefore, MSC-exos may have broad clinical applications in the future.
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Affiliation(s)
- Rong Xu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Yingying Bai
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Shudan Min
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Xiaoxuan Xu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Tianyu Tang
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
| | - Shenghong Ju
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, People's Republic of China
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Le TM, Morimoto N, Ly NTM, Mitsui T, Notodihardjo SC, Ogino S, Arata J, Kakudo N, Kusumoto K. Ex vivo Induction of Apoptotic Mesenchymal Stem Cell by High Hydrostatic Pressure. Stem Cell Rev Rep 2020; 17:662-672. [PMID: 33128169 PMCID: PMC8036216 DOI: 10.1007/s12015-020-10071-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2020] [Indexed: 01/01/2023]
Abstract
Among promising solutions for tissue repair and wound healing, mesenchymal stem (or stromal) cells (MSCs) have been a focus of attention and have become the most clinically studied experimental cell therapy. Recent studies reported the importance of apoptosis in MSC-mediated immunomodulation, in which apoptotic MSCs (apoMSCs) were shown to be superior to living MSCs. Nowadays, high hydrostatic pressure (HHP), a physical technique that uses only fluid pressure, has been developed and applied in various bioscience fields, including biotechnology, biomaterials, and regenerative medicine, as its safe and simply operation. In the current study, we investigated the impact of HHP treatment on human bone marrow-MSC survival and proliferation. Based on the detection of executioner caspase activation, phosphatidylserine exposure, DNA fragmentation (TUNEL) and irrefutable ultrastructural morphological changes on transmission electron microscopy (TEM), our data revealed that HHP treatment induced complete apoptosis in MSCs. Notably, this technique might provide manipulated products for use in cell-based therapies as manufacturing capability expands. We hope that our findings will contribute to the improvement of MSCs or EVs in translational research development.
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