|
1
|
Gherghel R, Macovei LA, Burlui MA, Cardoneanu A, Rezus II, Mihai IR, Rezus E. Osteoarthritis—The Role of Mesenchymal Stem Cells in Cartilage Regeneration. APPLIED SCIENCES 2023; 13:10617. [DOI: 10.3390/app131910617] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Osteoarthritis (OA) is a condition that can cause substantial pain, loss of joint function, and a decline in quality of life in patients. Numerous risk factors, including aging, genetics, and injury, have a role in the onset of OA, characterized by structural changes within the joints. Most therapeutic approaches focus on the symptoms and try to change or improve the structure of the joint tissues. Even so, no treatments have been able to stop or slow the progression of OA or give effective and long-lasting relief of symptoms. In the absence of disease-modifying drugs, regenerative medicine is being investigated as a possible treatment that can change the course of OA by changing the structure of damaged articular cartilage. In regenerative therapy for OA, mesenchymal stem cells (MSCs) have been the mainstay of translational investigations and clinical applications. In recent years, MSCs have been discovered to be an appropriate cell source for treating OA due to their ability to expand rapidly in culture, their nontumorigenic nature, and their ease of collection. MSCs’ anti-inflammatory and immunomodulatory capabilities may provide a more favorable local environment for the regeneration of injured articular cartilage, which was thought to be one of the reasons why they were seen as more suited for OA. In addition to bone marrow, MSCs have also been isolated from adipose tissue, synovium, umbilical cord, cord blood, dental pulp, placenta, periosteum, and skeletal muscle. Adipose tissue and bone marrow are two of the most essential tissues for therapeutic MSCs. Positive preclinical and clinical trial results have shown that, despite current limitations and risks, MSC-based therapy is becoming a promising approach to regenerative medicine in treating OA.
Collapse
Affiliation(s)
- Robert Gherghel
- Department of Orthopedics and Trauma Surgery, Piatra Neamt Emergency Hospital, 700115 Piatra Neamt, Romania
| | - Luana Andreea Macovei
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Maria-Alexandra Burlui
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Anca Cardoneanu
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Ioana-Irina Rezus
- Department of Dermatology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Ioana Ruxandra Mihai
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Elena Rezus
- Department of Rheumatology and Rehabilitation, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| |
Collapse
|
|
2
|
Fan L, Wei A, Gao Z, Mu X. Current progress of mesenchymal stem cell membrane-camouflaged nanoparticles for targeted therapy. Biomed Pharmacother 2023; 161:114451. [PMID: 36870279 DOI: 10.1016/j.biopha.2023.114451] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 02/17/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023] Open
Abstract
Nanodrug delivery systems have been widely used in disease treatment. However, weak drug targeting, easy to be cleared by the immune system, and low biocompatibility are great obstacles for drug delivery. As an important part of cell information transmission and behavior regulation, cell membrane can be used as drug coating material which represents a promising strategy and can overcome these limitations. Mesenchymal stem cell (MSC) membrane, as a new carrier, has the characteristics of active targeting and immune escape of MSC, and has broad application potential in tumor treatment, inflammatory disease, tissue regeneration and other fields. Here, we review recent progress on the use of MSC membrane-coated nanoparticles for therapy and drug delivery, aiming to provide guidance for the design and clinical application of membrane carrier in the future.
Collapse
Affiliation(s)
- Lianlian Fan
- Department of Pharmacy, China-Japan Union Hospital, Jilin University, Changchun130033, China
| | - Anhui Wei
- Department of Regenerative Medicine, College of Pharmacy, Jilin University, Changchun130021, China
| | - Zihui Gao
- Changchun City Experimental High School, Changchun130117, China
| | - Xupeng Mu
- Scientific Research Center, China-Japan Union Hospital, Jilin University, Changchun130033, China.
| |
Collapse
|
|
3
|
Hoseinzadeh A, Rezaieyazdi Z, Afshari JT, Mahmoudi A, Heydari S, Moradi R, Esmaeili SA, Mahmoudi M. Modulation of Mesenchymal Stem Cells-Mediated Adaptive Immune Effectors' Repertoire in the Recovery of Systemic Lupus Erythematosus. Stem Cell Rev Rep 2023; 19:322-344. [PMID: 36272020 DOI: 10.1007/s12015-022-10452-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2022] [Indexed: 02/07/2023]
Abstract
The breakdown of self-tolerance of the immune response can lead to autoimmune conditions in which chronic inflammation induces tissue damage. Systemic lupus erythematosus (SLE) is a debilitating multisystemic autoimmune disorder with a high prevalence in women of childbearing age; however, SLE incidence, prevalence, and severity are strongly influenced by ethnicity. Although the mystery of autoimmune diseases remains unsolved, disturbance in the proportion and function of B cell subsets has a major role in SLE's pathogenesis. Additionally, colocalizing hyperactive T helper cell subgroups within inflammatory niches are indispensable. Despite significant advances in standard treatments, nonspecific immunosuppression, the risk of serious infections, and resistance to conventional therapies in some cases have raised the urgent need for new treatment strategies. Without the need to suppress the immune system, mesenchymal stem cells (MSCs), as ''smart" immune modulators, are able to control cellular and humoral auto-aggression responses by participating in precursor cell development. In lupus, due to autologous MSCs disorder, the ability of allogenic engrafted MSCs in tissue regeneration and resetting immune homeostasis with the provision of a new immunocyte repertoire has been considered simultaneously. In Brief The bone marrow mesenchymal stem cells (BM-MSCs) lineage plays a critical role in maintaining the hematopoietic stem-cell microstructure and modulating immunocytes. The impairment of BM-MSCs and their niche partially contribute to the pathogenesis of SLE-like diseases. Allogenic MSC transplantation can reconstruct BM microstructure, possibly contributing to the recovery of immunocyte phenotype restoration of immune homeostasis. In terms of future prospects of MSCs, artificially gained by ex vivo isolation and culture adaptation, the wide variety of potential mediators and mechanisms might be linked to the promotion of the immunomodulatory function of MSCs.
Collapse
Affiliation(s)
- Akram Hoseinzadeh
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Rezaieyazdi
- Department of Rheumatology, Ghaem Hospital, Mashhad University of Medical Science, Mashhad, Iran.,Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jalil Tavakol Afshari
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sahar Heydari
- Department of Physiology and Pharmacology, Faculty of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Reza Moradi
- Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Immunology, Mashhad University of Medical Sciences, Azadi Square, Kalantari Blvd, Pardi's campusMashhad, Iran.
| |
Collapse
|
|
4
|
Pang QM, Chen SY, Xu QJ, Fu SP, Yang YC, Zou WH, Zhang M, Liu J, Wan WH, Peng JC, Zhang T. Neuroinflammation and Scarring After Spinal Cord Injury: Therapeutic Roles of MSCs on Inflammation and Glial Scar. Front Immunol 2021; 12:751021. [PMID: 34925326 PMCID: PMC8674561 DOI: 10.3389/fimmu.2021.751021] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/15/2021] [Indexed: 12/27/2022] Open
Abstract
Transected axons are unable to regenerate after spinal cord injury (SCI). Glial scar is thought to be responsible for this failure. Regulating the formation of glial scar post-SCI may contribute to axonal regrow. Over the past few decades, studies have found that the interaction between immune cells at the damaged site results in a robust and persistent inflammatory response. Current therapy strategies focus primarily on the inhibition of subacute and chronic neuroinflammation after the acute inflammatory response was executed. Growing evidences have documented that mesenchymal stem cells (MSCs) engraftment can be served as a promising cell therapy for SCI. Numerous studies have shown that MSCs transplantation can inhibit the excessive glial scar formation as well as inflammatory response, thereby facilitating the anatomical and functional recovery. Here, we will review the effects of inflammatory response and glial scar formation in spinal cord injury and repair. The role of MSCs in regulating neuroinflammation and glial scar formation after SCI will be reviewed as well.
Collapse
Affiliation(s)
- Qi-Ming Pang
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Si-Yu Chen
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Qi-Jing Xu
- Department of Human Anatomy, Zunyi Medical University, Zunyi, China
| | - Sheng-Ping Fu
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yi-Chun Yang
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wang-Hui Zou
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Meng Zhang
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Juan Liu
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wei-Hong Wan
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jia-Chen Peng
- Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| |
Collapse
|
|
5
|
Luo Q, He F, Cao J. A stromal and immune cell infiltration-based score model predicts prognosis and chemotherapy effect in colorectal cancer. Int Immunopharmacol 2021; 99:107940. [PMID: 34242996 DOI: 10.1016/j.intimp.2021.107940] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/17/2021] [Accepted: 06/29/2021] [Indexed: 12/16/2022]
Abstract
The stromal and immune cells crosstalk with cancer cells in tumor microenvironment, but few studies have fully considered the overall landscape of the infiltrating stromal and immune cells in colorectal cancer. We enrolled 1836 colorectal cancer patients and divided them into the training, validation and test cohorts. 64 stromal and immune cells were quantified in each primary colorectal cancer tissue by estimating gene expression data using xCell algorithm. Univariate, LASSO and multivariate Cox regression analyses were subsequently employed to establish a stromal and immune score prognostic model based on 13 potential cell biomarkers. Patients of the three cohorts were divided into the high- and low-risk groups according to the cutoff value. Compared with the low-risk group, high-risk group showed significant shorter survival, worse clinicopathologic outcomings, higher cancer-related expressions and more active epithelial-mesenchymal transformation. 5-Fu and FUFOL chemotherapy regimens made the low-risk patients gain significant survival advantage, while none chemotherapy regimens benefited the high-risk group, which may benefit from immune checkpoint inhibitors. The nomogram combining the stromal and immune score with standard TNM staging system showed better predictive accuracy than TNM stage alone. The stromal and immune cell infiltration-based score model can effectively and efficiently predict the prognosis and chemotherapy effect in colorectal cancer.
Collapse
Affiliation(s)
- Qingqing Luo
- Guangzhou Digestive Disease Center, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China; Guangzhou First People's Hospital, the Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong 510006, China
| | - Feng He
- Guangzhou Digestive Disease Center, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China; Guangzhou First People's Hospital, the Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong 510006, China.
| | - Jie Cao
- Guangzhou Digestive Disease Center, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510006, China; Guangzhou First People's Hospital, the Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong 510006, China.
| |
Collapse
|
|
6
|
Nowak B, Rogujski P, Janowski M, Lukomska B, Andrzejewska A. Mesenchymal stem cells in glioblastoma therapy and progression: How one cell does it all. Biochim Biophys Acta Rev Cancer 2021; 1876:188582. [PMID: 34144129 DOI: 10.1016/j.bbcan.2021.188582] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/11/2021] [Accepted: 06/13/2021] [Indexed: 12/15/2022]
Abstract
Mesenchymal stem cells (MSCs) are among the most investigated and applied somatic stem cells in experimental therapies for the regeneration of damaged tissues. Moreover, as it was recently postulated, MSCs may demonstrate anti-tumor properties. Glioblastoma (GBM) is a grade IV central nervous system tumor with no available effective therapy and an inevitably fatal prognosis. Experimental studies utilizing MSCs in GBM treatment resulted in numerous controversies. Native MSCs were shown to exert anti-GBM activity by controlling angiogenesis, regulating cell cycle, and inducing apoptosis. They also were used as sensitizing factors and vehicles delivering various anti-cancer compounds. On the other hand, some experiments revealed significant risks related to MSC-based therapies for GBM, such as enhancement of tumor cell proliferation, invasion, and aggressiveness. The following review elaborates on all mentioned contradictory data and provides a realistic, current clinical perspective on MSCs' potential in GBM treatment.
Collapse
Affiliation(s)
- Blazej Nowak
- Department of Neurosurgery, Central Clinical Hospital of Ministry of the Interior and Administration, Warsaw, Poland; Neurosurgery Department, John Paul II Western Hospital, Grodzisk Mazowiecki, Poland
| | - Piotr Rogujski
- NeuroRepair Department, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Miroslaw Janowski
- Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA; Tumor Immunology and Immunotherapy Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
| |
Collapse
|
|
7
|
Wang Q, Li J, Wang S, Deng Q, Wang K, Dai X, An Y, Dong G, Ke W, Chen F, Liu L, Yang H, Du Y, Zhao W, Shang Z. Single-cell transcriptome profiling reveals molecular heterogeneity in human umbilical cord tissue and culture-expanded mesenchymal stem cells. FEBS J 2021; 288:5311-5330. [PMID: 33763993 DOI: 10.1111/febs.15834] [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: 01/05/2021] [Revised: 02/24/2021] [Accepted: 03/22/2021] [Indexed: 01/08/2023]
Abstract
Human umbilical cord-derived mesenchymal stem/stromal cells (UMSCs) demonstrate great therapeutic potential in regenerative medicine. The use of UMSCs for clinical applications requires high quantity and good quality of cells usually by in vitro expansion. However, the heterogeneity and the characteristics of cultured UMSCs and the cognate human umbilical cord tissue at single-cell resolution remain poorly defined. In this study, we created a single-cell transcriptome profile of human umbilical cord tissue and the cognate culture-expanded UMSCs. Based on the inferred characteristics of cell clusters and trajectory analysis, we identified three subgroups in culture-expanded UMSCs and putative novel transcription factors (TFs) in regulating UMSC state transition. Further, putative ligand-receptor interaction analysis demonstrated that cellular interactions most frequently occurred in epithelial-like cells with other cell groups in umbilical cord tissue. Moreover, we dissected the transcriptomic differences of in vitro and in vivo subgroups and inferred the telomere-related molecules and pathways that might be activated in UMSCs for cell expansion in vitro. Our study provides a comprehensive and integrative study of the transcriptomics of human umbilical cord tissue and their cognate-cultured counterparts, which paves the way for a deeper understanding of cellular heterogeneity and offers fundamental biological insight of UMSCs-based cell therapy.
Collapse
Affiliation(s)
- Quanlei Wang
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.,BGI-Shenzhen, China.,Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics, BGI-Shenzhen, China
| | - Jinlu Li
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.,BGI-Shenzhen, China
| | - Shengpeng Wang
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.,BGI-Shenzhen, China
| | - Qiuting Deng
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.,BGI-Shenzhen, China
| | - Kuixing Wang
- BGI-Shenzhen, China.,Shenzhen BGI Cell Technology Co., Ltd, China
| | - Xi Dai
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.,BGI-Shenzhen, China
| | | | - Guoyi Dong
- BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.,BGI-Shenzhen, China
| | - Weilin Ke
- Department of Obstetrics, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, China
| | - Fang Chen
- BGI-Shenzhen, China.,MGI, BGI-Shenzhen, China
| | | | - Huanming Yang
- BGI-Shenzhen, China.,James D. Watson Institute of Genome Sciences, Hangzhou, China
| | | | - Weihua Zhao
- Department of Obstetrics, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, China
| | - Zhouchun Shang
- BGI-Shenzhen, China.,Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics, BGI-Shenzhen, China.,MGI, BGI-Shenzhen, China.,BGI College, Northwest University, Xi'an, China
| |
Collapse
|
|
8
|
Henao JC, Grismaldo A, Barreto A, Rodríguez-Pardo VM, Mejía-Cruz CC, Leal-Garcia E, Pérez-Núñez R, Rojas P, Latorre R, Carvacho I, Torres YP. TRPM8 Channel Promotes the Osteogenic Differentiation in Human Bone Marrow Mesenchymal Stem Cells. Front Cell Dev Biol 2021; 9:592946. [PMID: 33614639 PMCID: PMC7890257 DOI: 10.3389/fcell.2021.592946] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 01/05/2021] [Indexed: 11/29/2022] Open
Abstract
Various families of ion channels have been characterized in mesenchymal stem cells (MSCs), including some members of transient receptor potential (TRP) channels family. TRP channels are involved in critical cellular processes as differentiation and cell proliferation. Here, we analyzed the expression of TRPM8 channel in human bone marrow MSCs (hBM-MSCs), and its relation with osteogenic differentiation. Patch-clamp recordings showed that hBM-MSCs expressed outwardly rectifying currents which were increased by exposure to 500 μM menthol and were partially inhibited by 10 μM of BCTC, a TRPM8 channels antagonist. Additionally, we have found the expression of TRPM8 by RT-PCR and western blot. We also explored the TRPM8 localization in hBM-MSCs by immunofluorescence using confocal microscopy. Remarkably, hBM-MSCs treatment with 100 μM of menthol or 10 μM of icilin, TRPM8 agonists, increases osteogenic differentiation. Conversely, 20 μM of BCTC, induced a decrease of osteogenic differentiation. These results suggest that TRPM8 channels are functionally active in hBM-MSCs and have a role in cell differentiation.
Collapse
Affiliation(s)
- Juan C Henao
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Adriana Grismaldo
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Alfonso Barreto
- Grupo de Inmunobiología y Biología Celular, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Viviana M Rodríguez-Pardo
- Grupo de Inmunobiología y Biología Celular, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Claudia Camila Mejía-Cruz
- Grupo de Inmunobiología y Biología Celular, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Efrain Leal-Garcia
- Departamento de Ortopedia y Traumatología, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia
| | | | - Patricio Rojas
- Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Ramón Latorre
- Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile
| | - Ingrid Carvacho
- Department of Biology and Chemistry, Faculty of Basic Sciences, Universidad Católica del Maule, Talca, Chile
| | - Yolima P Torres
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| |
Collapse
|
|
9
|
Lyons JG, Plantz MA, Hsu WK, Hsu EL, Minardi S. Nanostructured Biomaterials for Bone Regeneration. Front Bioeng Biotechnol 2020; 8:922. [PMID: 32974298 PMCID: PMC7471872 DOI: 10.3389/fbioe.2020.00922] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/17/2020] [Indexed: 12/13/2022] Open
Abstract
This review article addresses the various aspects of nano-biomaterials used in or being pursued for the purpose of promoting bone regeneration. In the last decade, significant growth in the fields of polymer sciences, nanotechnology, and biotechnology has resulted in the development of new nano-biomaterials. These are extensively explored as drug delivery carriers and as implantable devices. At the interface of nanomaterials and biological systems, the organic and synthetic worlds have merged over the past two decades, forming a new scientific field incorporating nano-material design for biological applications. For this field to evolve, there is a need to understand the dynamic forces and molecular components that shape these interactions and influence function, while also considering safety. While there is still much to learn about the bio-physicochemical interactions at the interface, we are at a point where pockets of accumulated knowledge can provide a conceptual framework to guide further exploration and inform future product development. This review is intended as a resource for academics, scientists, and physicians working in the field of orthopedics and bone repair.
Collapse
Affiliation(s)
- Joseph G. Lyons
- Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Simpson Querrey Institute, Northwestern University, Chicago, IL, United States
| | - Mark A. Plantz
- Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Simpson Querrey Institute, Northwestern University, Chicago, IL, United States
| | - Wellington K. Hsu
- Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Simpson Querrey Institute, Northwestern University, Chicago, IL, United States
| | - Erin L. Hsu
- Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Simpson Querrey Institute, Northwestern University, Chicago, IL, United States
| | - Silvia Minardi
- Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Simpson Querrey Institute, Northwestern University, Chicago, IL, United States
| |
Collapse
|
|
10
|
Echeverry S, Grismaldo A, Sánchez C, Sierra C, Henao JC, Granados ST, Sutachán JJ, Torres YP. Activation of BK Channel Contributes to PL-Induced Mesenchymal Stem Cell Migration. Front Physiol 2020; 11:210. [PMID: 32265729 PMCID: PMC7105713 DOI: 10.3389/fphys.2020.00210] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 02/24/2020] [Indexed: 01/16/2023] Open
Abstract
Due to their capacity to proliferate, migrate, and differentiate, mesenchymal stem cells (MSCs) are considered to be good candidates for regenerative medicine applications. The mechanisms underlying proliferation and differentiation of MSCs have been studied. However, much less is known about the mechanisms regulating the migration of MSCs. Platelet lysate (PL), a supplement used to promote cell expansion, has been shown to promote MSCs migration; however, the underlying mechanism are unknown. Here, by using adipose-derived rat MSCs (rMSCs) and the scratch assay in the absence and presence of various BK channels modulators, we evaluated the role of BK channels in mediating the PL-stimulated migration of rMSCs. We found that 5% PL increased rMSCs migration, and this effect was blocked by the addition of the BK channel selective antagonist Iberiotoxin (IBTX). In the absence of PL, the BK channel agonist NS1619, stimulated rMSCs migration to similar level as 5% PL. Addition of both NS1619 and 5% PL resulted in an increase in rMSCs migration, that was higher than when either one was added individually. From whole-cell recordings, it was found that the addition of 5% PL increased the magnitude of BK current density. By using Western blot and flow cytometry, it was found that PL did not affect the expression of BK channels. Together, our results indicate that as shown in other cell types, activation of BK channels by themselves also promote rMSC migration, and show that activation of BK channels contribute to the observed PL-induced increase in migration of rMSC.
Collapse
|
|
11
|
c-Jun Overexpression Accelerates Wound Healing in Diabetic Rats by Human Umbilical Cord-Derived Mesenchymal Stem Cells. Stem Cells Int 2020; 2020:7430968. [PMID: 32399050 PMCID: PMC7201444 DOI: 10.1155/2020/7430968] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/18/2019] [Accepted: 12/20/2019] [Indexed: 12/19/2022] Open
Abstract
Objective Mesenchymal stem cells (MSCs) are considered a promising therapy for wound healing. Here, we explored the role of c-Jun in diabetic wound healing using human umbilical cord-derived MSCs (hUC-MSCs). Methods Freshly isolated hUC-MSCs were subjected to extensive in vitro subcultivation. The cell proliferative and migratory capacities were assessed by the Cell Counting Kit-8 and scratch assays, respectively. c-Jun expression was evaluated by RT-PCR and western blot analysis. The function of c-Jun was investigated with lentivirus transduction-based gene silencing and overexpression. Diabetes mellitus was induced in SD rats on a high-glucose/fat diet by streptozocin administration. Wounds were created on the dorsal skin. The effects of c-Jun silencing and overexpression on wound closure by hUC-MSCs were examined. Reepithelialization and angiogenesis were assessed by histological and immunohistochemical analysis, respectively. Platelet-derived growth factor A (PDGFA), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) levels were determined by western blot analysis. Results hUC-MSCs showed gradually decreased cell proliferation, migration, and c-Jun expression during subcultivation. c-Jun silencing inhibited cell proliferation and migration, while c-Jun overexpression enhanced proliferation but not migration. Compared with untransduced hUC-MSCs, local subcutaneous injection of c-Jun-overexpressing hUC-MSCs accelerated wound closure, enhanced angiogenesis and reepithelialization at the wound bed, and increased PDGFA and HGF levels in wound tissues. Conclusion c-Jun overexpression promoted hUC-MSC proliferation and migration in vitro and accelerated diabetic wound closure, reepithelization, and angiogenesis by hUC-MSCs in vivo. These beneficial effects of c-Jun overexpression in diabetic wound healing by hUC-MSCs were at least partially mediated by increased PDGFA and HGF levels in wound tissues.
Collapse
|
|
12
|
Chen J, Wu Z, Ding W, Xiao C, Zhang Y, Gao S, Gao Y, Cai W. SREBP1 siRNA enhance the docetaxel effect based on a bone-cancer dual-targeting biomimetic nanosystem against bone metastatic castration-resistant prostate cancer. Theranostics 2020; 10:1619-1632. [PMID: 32042326 PMCID: PMC6993241 DOI: 10.7150/thno.40489] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/19/2019] [Indexed: 12/13/2022] Open
Abstract
Until recently, there have been limited options for patients with bone metastatic castration-resistant prostate cancer (BmCRPC) following the failure of or development of resistance to docetaxel (DTX), which is one of the frontline treatments. Sterol regulatory element-binding protein 1 (SREBP1) is reported to regulate abnormal lipid metabolism and to promote the progression and metastasis of prostate cancer (PCa). The siRNA interferes SREBP1 may provide an efficient treatment when combined with DTX. Methods: In this study, lipoic acid (LA) and cross-linked peptide-lipoic acid micelles were cross-linked (LC) for DTX and siSREBP1 delivery (LC/D/siR). Then, cell membrane of PCa cells (Pm) and bone marrow mesenchymal stem cells (Bm) were fused for cloaking LC/D/siR (PB@LC/D/siR). Finally, the synthesized PB@LC/D/siR was evaluated in vitro and in vivo. Results: PB@LC/D/siR is internalized in PCa cells by a mechanism of lysosome escape. Tumor targeting and bone homing studies are evaluated using bone metastatic CRPC (BmCRPC) models, both in vitro and in vivo. Moreover, the enhanced anti-proliferation, anti-migration and anti-invasion capacities of DTX- and siSREBP1- loaded PB@LC (PB@LC/D/siR) were observed in vitro. Furthermore, PB@LC/D/siR was able to suppress the growth of the tumor effectively with deep tumor penetration, high safety and good protection of the bone at the tumor site. Additionally, the mRNA levels and protein levels of SREBP1 and SCD1 were able to be significantly downregulated by PB@LC/D/siR. Conclusion: This study presented a bone-cancer dual-targeting biomimetic nanodelivery system for bone metastatic CRPC.
Collapse
Affiliation(s)
- Jiyuan Chen
- Department of Clinical Pharmacy and Drug Administration, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Zhenjie Wu
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Weihong Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Chengwu Xiao
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Yu Zhang
- Department of Clinical Pharmacy and Drug Administration, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Shen Gao
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Yuan Gao
- Department of Clinical Pharmacy and Drug Administration, School of Pharmacy, Fudan University, Shanghai 201203, China
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Weimin Cai
- Department of Clinical Pharmacy and Drug Administration, School of Pharmacy, Fudan University, Shanghai 201203, China
| |
Collapse
|
|
13
|
Meng MY, Li L, Wang WJ, Liu FF, Song J, Yang SL, Tan J, Gao H, Zhao YY, Tang WW, Han R, Zhu K, Liao LW, Hou ZL. Assessment of tumor promoting effects of amniotic and umbilical cord mesenchymal stem cells in vitro and in vivo. J Cancer Res Clin Oncol 2019; 145:1133-1146. [PMID: 30805774 PMCID: PMC6482126 DOI: 10.1007/s00432-019-02859-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 02/07/2019] [Indexed: 12/30/2022]
Abstract
Purpose Human mesenchymal stem cells (hMSCs) have been applied in a variety of therapies recently. However, the role of MSCs in tumor progression remains largely elusive. Some studies demonstrated that MSCs can promote tumor growth, while others had opposite results. Therefore, the lack of evidence about the effect of MSCs on tumor cells impedes its further use. Methods In the current study, hMSCs from amniotic membrane (hAMSCs) and umbilical cord (hUCMSCs) were used to evaluate the effects of MSCs on tumor development in vitro and in vivo. Two different animal models based on subcutaneous xenograft bearing nude mice and a murine experimental metastatic model were established for in vivo study. Moreover, cytokines regulated by MSCs co-cultured with cancer cells SPC-A-1 were also analyzed by cytokine array. Results Our results indicated that hUCMSCs not only did not promote proliferation in cancer cells, but also inhibited migration. In addition, they inhibited tube formation in human umbilical vein endothelial cells (HUVECs). Although hAMSCs also showed inhibitory effects on cancer cell motility, the proliferation of cancer cells was indeed enhanced. The in vivo data revealed that hUCMSCs did not promote tumor progression in lung adenocarcinoma and gastric carcinoma xenografts. Nevertheless, hAMSCs could do. The results from murine experimental metastatic model also demonstrated that neither hUCMSCs nor hAMSCs significantly enhanced the lung metastasis. The data from cytokine array showed that 11 inflammatory factors, 8 growth factors and 11 chemokines were remarkably secreted and changed. Conclusions In view of the data from in vitro and in vivo studies, the exploitation of hUCMSCs in new therapeutic strategies should be safe compared to hAMSCs under malignant conditions. Moreover, this is the first report to systematically elucidate the possible molecular mechanisms involved in UCMSC- and AMSC-affected tumor growth and metastasis. Electronic supplementary material The online version of this article (10.1007/s00432-019-02859-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Ming-Yao Meng
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, Yunnan, People's Republic of China
| | - Lin Li
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, Yunnan, People's Republic of China
| | - Wen-Ju Wang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China.,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, Yunnan, People's Republic of China
| | - Fei-Fei Liu
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China.,Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Jian Song
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China.,Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Song-Lin Yang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China.,Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Jing Tan
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China
| | - Hui Gao
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China
| | - Yi-Yi Zhao
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China
| | - Wei-Wei Tang
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China
| | - Rui Han
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China.,Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Kai Zhu
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China.,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China.,Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Li-Wei Liao
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China. .,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China. .,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, Yunnan, People's Republic of China.
| | - Zong-Liu Hou
- Central Laboratory of Yan'an Hospital Affiliated to Kunming Medical University, No. 245 East of Renmin Road, Kunming, 650051, Yunnan, People's Republic of China. .,Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China. .,Yunnan Cell Biology and Clinical Translation Research Center, Kunming, Yunnan, People's Republic of China.
| |
Collapse
|
|
14
|
Ma Z, Cui X, Lu L, Chen G, Yang Y, Hu Y, Lu Y, Cao Z, Wang Y, Wang X. Exosomes from glioma cells induce a tumor-like phenotype in mesenchymal stem cells by activating glycolysis. Stem Cell Res Ther 2019; 10:60. [PMID: 30770778 PMCID: PMC6377719 DOI: 10.1186/s13287-019-1149-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 12/23/2018] [Accepted: 01/21/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Exosomes are nanoscale membrane vesicles secreted by both normal and cancer cells, and cancer cell-derived exosomes play an important role in the cross-talk between cancer cells and other cellular components in the tumor microenvironment. Mesenchymal stem cells (MSCs) have tropism for tumors and have been used as tumor-tropic vectors for tumor therapy; however, the safety of such therapeutic use of MSCs is unknown. In this study, we investigated the role of glioma cell-derived exosomes in the tumor-like phenotype transformation of human bone marrow mesenchymal stem cells (hBMSCs) and explored the underlying molecular mechanisms. METHODS The effect of exosomes from U251 glioma cells on the growth of hBMSCs was evaluated with the CCK-8 assay, KI67 staining, and a cell cycle distribution assessment. The migration and invasion of hBMSCs were evaluated with a Transwell assay. A proteomics and bioinformatics approach, together with Western blotting and reverse transcriptase-polymerase chain reaction, was used to investigate the effect of U251 cell-derived exosomes on the proteome of hBMSCs. RESULTS U251 cell-derived exosomes induced a tumor-like phenotype in hBMSCs by enhancing their proliferation, migration, and invasion and altering the production of proteins involved in the regulation of the cell cycle. Moreover, U251 cell-derived exosomes promoted the production of the metastasis-related proteins MMP-2 and MMP-9, glioma marker GFAP, and CSC markers (CD133 and Nestin). The ten differentially expressed proteins identified participated in several biological processes and exhibited various molecular functions, mainly related to the inactivation of glycolysis. Western blotting showed that U251 cell-derived exosomes upregulated the levels of Glut-1, HK-2, and PKM-2, leading to the induction of glucose consumption and generation of lactate and ATP. Treatment with 2-deoxy-D-glucose significantly reversed these effects of U251 cell-derived exosomes on hBMSCs. CONCLUSIONS Our data demonstrate that glioma cell-derived exosomes activate glycolysis in hBMSCs, resulting in their tumor-like phenotype transformation. This suggests that interfering with the interaction between exosomes and hBMSCs in the tumor microenvironment has potential as a therapeutic approach for glioma. ᅟ.
Collapse
Affiliation(s)
- Zhanjun Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu China
| | - Xue Cui
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu China
| | - Li Lu
- Institute of Pharmacology, School of Basic Medical Science, Lanzhou University, Lanzhou, 730000 Gansu China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, 730000 Gansu China
- School of Basic Medical Sciences of Lanzhou University, School of Medicine, 205 Tianshui Rd South, Lanzhou, 730000 Gansu China
| | - Guohu Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu China
| | - Yang Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu China
| | - Yan Hu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000 Gansu China
| | - Yubao Lu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000 Gansu China
| | - Zhangqi Cao
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000 Gansu China
| | - Yan Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000 Gansu China
| | - Xuexi Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000 Gansu China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, 730000 Gansu China
- School of Basic Medical Sciences of Lanzhou University, School of Medicine, 205 Tianshui Rd South, Lanzhou, 730000 Gansu China
| |
Collapse
|
|
15
|
Spano C, Grisendi G, Golinelli G, Rossignoli F, Prapa M, Bestagno M, Candini O, Petrachi T, Recchia A, Miselli F, Rovesti G, Orsi G, Maiorana A, Manni P, Veronesi E, Piccinno MS, Murgia A, Pinelli M, Horwitz EM, Cascinu S, Conte P, Dominici M. Soluble TRAIL Armed Human MSC As Gene Therapy For Pancreatic Cancer. Sci Rep 2019; 9:1788. [PMID: 30742129 PMCID: PMC6370785 DOI: 10.1038/s41598-018-37433-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 12/06/2018] [Indexed: 12/22/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive adult cancers with an unacceptable prognosis. For this reason novel therapies accounting for PDAC peculiarities, such as the relevant stromal reaction, are urgently needed. Here adipose mesenchymal stromal/stem cells (AD-MSC) have been armed to constantly release a soluble trimeric and multimeric variant of the known anti-cancer TNF-related apoptosis-inducing ligand (sTRAIL). This cancer gene therapy strategy was in vitro challenged demonstrating that sTRAIL was thermally stable and able to induce apoptosis in the PDAC lines BxPC-3, MIA PaCa-2 and against primary PDAC cells. sTRAIL released by AD-MSC relocated into the tumor stroma was able to significantly counteract tumor growth in vivo with a significant reduction in tumor size, in cytokeratin-7+ cells and by an anti-angiogenic effect. In parallel, histology on PDAC specimens form patients (n = 19) was performed to investigate the levels of TRAIL DR4, DR5 and OPG receptors generating promising insights on the possible clinical translation of our approach. These results indicate that adipose MSC can very efficiently vehicle a novel TRAIL variant opening unexplored opportunities for PDAC treatment.
Collapse
Affiliation(s)
- Carlotta Spano
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Rigenerand srl, Medolla, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Rigenerand srl, Medolla, Modena, Italy
| | - Giulia Golinelli
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Filippo Rossignoli
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Malvina Prapa
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Marco Bestagno
- International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
| | - Olivia Candini
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Rigenerand srl, Medolla, Modena, Italy
| | | | - Alessandra Recchia
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Francesca Miselli
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Rovesti
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Orsi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Department of Diagnostic and Clinical Medicine and of Public Health, Institute of Pathology, University of Modena and Reggio Emilia, Modena, Italy
| | - Paola Manni
- Department of Diagnostic and Clinical Medicine and of Public Health, Institute of Pathology, University of Modena and Reggio Emilia, Modena, Italy
| | - Elena Veronesi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Technopole of Mirandola TPM, Mirandola, Modena, Italy
| | | | - Alba Murgia
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Pinelli
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Edwin M Horwitz
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, GA, USA
| | - Stefano Cascinu
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Pierfranco Conte
- Department of Surgery, Oncology and Gastroenerology University of Padova, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy. .,Rigenerand srl, Medolla, Modena, Italy. .,Technopole of Mirandola TPM, Mirandola, Modena, Italy.
| |
Collapse
|
|
16
|
Zhou YL, Li YM, He WT. Oxygen-laden mesenchymal stem cells enhance the effect of gastric cancer chemotherapy in vitro. Oncol Lett 2018; 17:1245-1252. [PMID: 30655891 DOI: 10.3892/ol.2018.9670] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 08/07/2018] [Indexed: 12/12/2022] Open
Abstract
Hypoxia is an important factor that results in failure of chemotherapy for the majority of solid tumor types, particularly for gastric cancer. In the present study, mesenchymal stem cells (MSCs), which have the ability to migrate to cancer tissues were used as a vehicle to supply oxygen to gastric cancer. The hemoglobin genes were transfected into MSCs as MSC-hemo groups. Subsequently, MSC-hemo groups were induced by isopropyl-b-D-thiogalactopyranoside and hemin to express hemoglobin. The hemoglobin was detected by western blotting method. Following this, the MSC-hemo groups were placed in an atmosphere containing 100% oxygen and were used to investigate the effect of the function of the oxygen-laden MSC-hemo group on gastric cancer chemotherapy with an MTT assay. As a first approach to investigate the possibility of MSCs as a vehicle to supply oxygen to anoxic cancer types, including gastric, liver, breast cancer, the results indicated that the oxygen-laden MSC-hemo group significantly enhanced the effect of chemotherapeutic treatments on gastric cancer cells. Utilizing MSCs as a svehicle to supply oxygen to the solid tumor may be a novel method to improve the hypoxia conditions of tumor tissues and improve the effect of chemotherapy on tumor cells.
Collapse
Affiliation(s)
- Ya-Li Zhou
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Yu-Min Li
- Key Laboratory of Digestive System Tumors, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Wen-Ting He
- Key Laboratory of Digestive System Tumors, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| |
Collapse
|
|
17
|
Kerans FFA, Lungaro L, Azfer A, Salter DM. The Potential of Intrinsically Magnetic Mesenchymal Stem Cells for Tissue Engineering. Int J Mol Sci 2018; 19:E3159. [PMID: 30322202 PMCID: PMC6214112 DOI: 10.3390/ijms19103159] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/04/2018] [Accepted: 10/09/2018] [Indexed: 12/16/2022] Open
Abstract
The magnetization of mesenchymal stem cells (MSC) has the potential to aid tissue engineering approaches by allowing tracking, targeting, and local retention of cells at the site of tissue damage. Commonly used methods for magnetizing cells include optimizing uptake and retention of superparamagnetic iron oxide nanoparticles (SPIONs). These appear to have minimal detrimental effects on the use of MSC function as assessed by in vitro assays. The cellular content of magnetic nanoparticles (MNPs) will, however, decrease with cell proliferation and the longer-term effects on MSC function are not entirely clear. An alternative approach to magnetizing MSCs involves genetic modification by transfection with one or more genes derived from Magnetospirillum magneticum AMB-1, a magnetotactic bacterium that synthesizes single-magnetic domain crystals which are incorporated into magnetosomes. MSCs with either or mms6 and mmsF genes are followed by bio-assimilated synthesis of intracytoplasmic magnetic nanoparticles which can be imaged by magnetic resonance (MR) and which have no deleterious effects on MSC proliferation, migration, or differentiation. The stable transfection of magnetosome-associated genes in MSCs promotes assimilation of magnetic nanoparticle synthesis into mammalian cells with the potential to allow MR-based cell tracking and, through external or internal magnetic targeting approaches, enhanced site-specific retention of cells for tissue engineering.
Collapse
Affiliation(s)
- Fransiscus F A Kerans
- Centre for Genomics and Experimental Medicine, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
| | - Lisa Lungaro
- Centre for Genomics and Experimental Medicine, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
| | - Asim Azfer
- Centre for Genomics and Experimental Medicine, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
| | - Donald M Salter
- Centre for Genomics and Experimental Medicine, MRC IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
| |
Collapse
|
|
18
|
SiNWs Biophysically Regulate the Fates of Human Mesenchymal Stem Cells. Sci Rep 2018; 8:12913. [PMID: 30150652 PMCID: PMC6110734 DOI: 10.1038/s41598-018-30854-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 08/06/2018] [Indexed: 01/17/2023] Open
Abstract
While biophysical stimuli from polymeric matrices are known to significantly affect the fates of human mesenchymal stem cells (hMSCs), the stimulatory effects of nano-sized silicon-based matrices on hMSCs have not been thoroughly investigated. We previously demonstrated that vertically aligned, single-crystalline silicon nanowires (SiNWs) can control the osteogenicity of hMSCs via controllable spring constants from SiNWs matrix. However, other possible differentiation fates of hMSCs on SiNWs have not been explored. We hypothesize that tunable spring constant from artificial SiNWs matrices can direct different types of hMSC differentiations. The spring constants of tunable SiNW matrices can be consistently controlled by tuning the SiNW length. The results of gene expression and cell stiffness suggest that hMSCs differentiations are sensitive to our distinguishable spring constants from the SiNWs groups, and simultaneously conduct osteogenicity and adipogenicity. These findings suggest that SiNW matrices can regulate the fates of hMSCs when the SiNW characteristics are carefully tuned.
Collapse
|
|
19
|
Wang W, Guo H, Li H, Yan Y, Wu C, Wang X, He X, Zhao N. Interleukin-35 Gene-Modified Mesenchymal Stem Cells Protect Concanavalin A-Induced Fulminant Hepatitis by Decreasing the Interferon Gamma Level. Hum Gene Ther 2018; 29:234-241. [PMID: 29054137 DOI: 10.1089/hum.2017.171] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Interleukin 35 (IL-35) is a relatively newly identified cytokine required for the regulatory and suppressive functions of regulatory T cells (Treg), playing an important role in the prevention of autoimmune diseases. This study used mesenchymal stem cells (MSCs) as the gene-delivery vehicles for IL-35 gene therapy and investigated their protective effects in Concanavalin A (Con A)-induced autoimmune hepatitis. Results showed that IL-35 gene modified MSCs (IL-35-MSCs) can specifically migrate to the injured liver tissues and significantly narrow the necrosis areas of injured livers. IL-35-MSCs prevented hepatocyte apoptosis by reducing the FASL expression by mononuclear cells. Although MSC treatment can alleviate liver injury to some extent, IL-35-MSCs showed a stronger protective effect, which means some novel mechanisms exist. The results show that IL-35-MSCs could decrease the level of interferon gamma secreted by liver mononuclear cells through the JAK1-STAT1/STAT4 signal pathway. In summary, this study thus demonstrates a novel and efficient treatment for Con A-induced fulminant hepatitis through negatively regulating the secretion of interferon gamma, thus providing a novel therapeutic approach for this devastating liver disease.
Collapse
Affiliation(s)
- Wei Wang
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin, China
| | - Hao Guo
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin, China
| | - Hongyue Li
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin, China
| | - Yongjia Yan
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin, China
| | - Chao Wu
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin, China
| | - Xiaodong Wang
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin, China
| | - Xianghui He
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin, China
| | - Na Zhao
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin, China
| |
Collapse
|
|
20
|
Ferreira LP, Gaspar VM, Henrique R, Jerónimo C, Mano JF. Mesenchymal Stem Cells Relevance in Multicellular Bioengineered 3D In Vitro Tumor Models. Biotechnol J 2017; 12:10.1002/biot.201700079. [PMID: 28834355 PMCID: PMC7617208 DOI: 10.1002/biot.201700079] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 07/19/2017] [Indexed: 12/14/2022]
Abstract
In vitro 3D tumor microenvironment mimicking models are gathering momentum as alternatives to traditional 2D flat monolayer cultures due to their potential for recapitulating major cancer hallmarks. To fulfill such potential, it is crucial that 3D tumor testing platforms completely emulate in vitro the complex in vivo tumor niche and its cellular constituents. Mesenchymal stem cells (MSCs) are recognized to play a pivotal multi-modulatory role in cancer, generating interest as biological targets and as key tumor suppressing, or tumor promoting effectors. This review discusses the biological influence of different types of MSCs in the tumor microenvironment and showcases recent studies that engineer 3D MSCs-cancer cells co-cultures as advanced in vitro therapy testing platforms. A special focus is given to MSCs-cancer 3D co-culture set-up parameters, challenges, and future opportunities. Understanding cancer-MSCs crosstalk and their underlying effects is envisioned to support the development of advanced 3D in vitro disease models for discovery of forefront cancer treatments.
Collapse
Affiliation(s)
- Luís P. Ferreira
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal
| | - Vítor M. Gaspar
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)
- Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)
| | - João F. Mano
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal
| |
Collapse
|
|
21
|
Oloyo AK, Ambele MA, Pepper MS. Contrasting Views on the Role of Mesenchymal Stromal/Stem Cells in Tumour Growth: A Systematic Review of Experimental Design. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1083:103-124. [DOI: 10.1007/5584_2017_118] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
22
|
Tan B, Shen L, Yang K, Huang D, Li X, Li Y, Zhao L, Chen J, Yi Q, Xu H, Tian J, Zhu J. C6 glioma-conditioned medium induces malignant transformation of mesenchymal stem cells: Possible role of S100B/RAGE pathway. Biochem Biophys Res Commun 2017; 495:78-85. [PMID: 29050939 DOI: 10.1016/j.bbrc.2017.10.071] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 10/15/2017] [Indexed: 01/03/2023]
Abstract
Mesenchymal stem cells (MSCs) have been widely studied as an attractive therapeutic agent for the treatment of tumors. However, the adverse effects of the tumor paracrine factors who affect MSCs are still unclear. In this study, we report for the first time that C6 glioma-conditioned medium (GCM) induces malignant transformation of MSCs. In contrast to MSCs, the transformed mesenchymal stem cells (TMCs) exhibited tumor cell characterizations in vitro and highly tumorigenic in vivo. Furthermore, GCM and recombinant S100B increased receptor for advanced glycation end products (RAGE) and its downstream Akt1, STAT3 genes expression as well as phosphorylation and transcriptional activation. Finally, blockage of S100B-RAGE interaction by RAGE inhibitor FPS-ZM1 attenuated GCM and S100B-induced Akt1, STAT3 activation, abolished its cell proliferation, migration and invasion actions. Together, these results suggest that the RAGE pathway may play a possible role in malignant transformation procedure of MSCs, and that this process may be mediated through S100B.
Collapse
Affiliation(s)
- Bin Tan
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Lianju Shen
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, 400014, China
| | - Ke Yang
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing, 400014, China
| | - Daochao Huang
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Xin Li
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Yasha Li
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Li Zhao
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Jie Chen
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Qing Yi
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Hao Xu
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Jie Tian
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China
| | - Jing Zhu
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China.
| |
Collapse
|
|
23
|
Role of Mesenchymal Stem Cells in Cancer Development and Their Use in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1083:45-62. [DOI: 10.1007/5584_2017_64] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
24
|
Devarasetty M, Wang E, Soker S, Skardal A. Mesenchymal stem cells support growth and organization of host-liver colorectal-tumor organoids and possibly resistance to chemotherapy. Biofabrication 2017; 9:021002. [PMID: 28589925 DOI: 10.1088/1758-5090/aa7484] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Despite having yielded extensive breakthroughs in cancer research, traditional 2D cell cultures have limitations in studying cancer progression and metastasis and screening therapeutic candidates. 3D systems can allow cells to grow, migrate, and interact with each other and the surrounding matrix, resulting in more realistic constructs. Furthermore, interactions between host tissue and developing tumors influence the susceptibility of tumors to drug treatments. Host-liver colorectal-tumor spheroids composed of primary human hepatocytes, mesenchymal stem cells (MSC) and colon carcinoma HCT116 cells were created in simulated microgravity rotating wall vessel (RWV) bioreactors. The cells were seeded on hyaluronic acid-based microcarriers, loaded with liver-specific growth factors and ECM components. Only in the presence of MSC, large tumor foci rapidly formed inside the spheroids and increased in size steadily over time, while not greatly impacting albumin secretion from hepatocytes. The presence of MSC appeared to drive self-organization and formation of a stroma-like tissue surrounding the tumor foci and hepatocytes. Exposure to a commonly used chemotherapeutic 5-FU showed a dose-dependent cytotoxicity. However, if tumor organoids were allowed to mature in the RWV, they were less sensitive to the drug treatment. These data demonstrate the potential utility of liver tumor organoids for cancer progression and drug response modeling.
Collapse
Affiliation(s)
- Mahesh Devarasetty
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States of America. Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem, NC, United States of America
| | | | | | | |
Collapse
|
|
25
|
Lerrer S, Liubomirski Y, Bott A, Abnaof K, Oren N, Yousaf A, Körner C, Meshel T, Wiemann S, Ben-Baruch A. Co-Inflammatory Roles of TGFβ1 in the Presence of TNFα Drive a Pro-inflammatory Fate in Mesenchymal Stem Cells. Front Immunol 2017; 8:479. [PMID: 28553282 PMCID: PMC5425596 DOI: 10.3389/fimmu.2017.00479] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 04/05/2017] [Indexed: 12/19/2022] Open
Abstract
High plasticity is a hallmark of mesenchymal stem cells (MSCs), and as such, their differentiation and activities may be shaped by factors of their microenvironment. Bones, tumors, and cardiomyopathy are examples of niches and conditions that contain MSCs and are enriched with tumor necrosis factor α (TNFα) and transforming growth factor β1 (TGFβ1). These two cytokines are generally considered as having opposing roles in regulating immunity and inflammation (pro- and anti-inflammatory, respectively). Here, we performed global gene expression analysis of human bone marrow-derived MSCs and identified overlap in half of the transcriptional programs that were modified by TNFα and TGFβ1. The two cytokines elevated the mRNA expression of soluble factors, including mRNAs of pro-inflammatory mediators. Accordingly, the typical pro-inflammatory factor TNFα prominently induced the protein expression levels of the pro-inflammatory mediators CCL2, CXCL8 (IL-8), and cyclooxygenase-2 (Cox-2) in MSCs, through the NF-κB/p65 pathway. In parallel, TGFβ1 did not elevate CXCL8 protein levels and induced the protein expression of CCL2 at much lower levels than TNFα; yet, TGFβ1 readily induced Cox-2 and acted predominantly via the Smad3 pathway. Interestingly, combined stimulation of MSCs by TNFα + TGFβ1 led to a cooperative induction of all three inflammatory mediators, indicating that TGFβ1 functioned as a co-inflammatory cytokine in the presence of TNFα. The cooperative activities of TNFα + TGFβ1 that have led to CCL2 and CXCL8 induction were almost exclusively dependent on p65 activation and were not regulated by Smad3 or by the upstream regulator TGFβ-activated kinase 1 (TAK1). In contrast, the TNFα + TGFβ1-induced cooperative elevation in Cox-2 was mostly dependent on Smad3 (demonstrating cooperativity with activated NF-κB) and was partly regulated by TAK1. Studies with MSCs activated by TNFα + TGFβ1 revealed that they release factors that can affect other cells in their microenvironment and induce breast tumor cell elongation, migration, and scattering out of spheroid tumor masses. Thus, our findings demonstrate a TNFα + TGFβ1-driven pro-inflammatory fate in MSCs, identify specific molecular mechanisms involved, and propose that TNFα + TGFβ1-stimulated MSCs influence the tumor niche. These observations suggest key roles for the microenvironment in regulating MSC functions, which in turn may affect different health-related conditions.
Collapse
Affiliation(s)
- Shalom Lerrer
- Faculty of Life Sciences, Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel
| | - Yulia Liubomirski
- Faculty of Life Sciences, Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel
| | - Alexander Bott
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Khalid Abnaof
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nino Oren
- Faculty of Life Sciences, Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel
| | - Afsheen Yousaf
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Cindy Körner
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tsipi Meshel
- Faculty of Life Sciences, Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel
| | - Stefan Wiemann
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Adit Ben-Baruch
- Faculty of Life Sciences, Department of Cell Research and Immunology, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
26
|
Mesenchymal stem cells induce epithelial mesenchymal transition in melanoma by paracrine secretion of transforming growth factor-β. Melanoma Res 2017; 27:74-84. [DOI: 10.1097/cmr.0000000000000325] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
|
|
27
|
|
|
28
|
Almela T, Brook IM, Moharamzadeh K. The significance of cell-related challenges in the clinical application of tissue engineering. J Biomed Mater Res A 2016; 104:3157-3163. [DOI: 10.1002/jbm.a.35856] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 06/24/2016] [Accepted: 08/04/2016] [Indexed: 12/31/2022]
Affiliation(s)
- Thafar Almela
- School of Clinical Dentistry; University of Sheffield, Claremont Crescent; Sheffield S10 2TA United Kingdom
| | - Ian M. Brook
- School of Clinical Dentistry; University of Sheffield, Claremont Crescent; Sheffield S10 2TA United Kingdom
| | - Keyvan Moharamzadeh
- School of Clinical Dentistry; University of Sheffield, Claremont Crescent; Sheffield S10 2TA United Kingdom
| |
Collapse
|
|
29
|
Cai Y, Xi Y, Cao Z, Xiang G, Ni Q, Zhang R, Chang J, Du X, Yang A, Yan B, Zhao J. Dual targeting and enhanced cytotoxicity to HER2-overexpressing tumors by immunoapoptotin-armored mesenchymal stem cells. Cancer Lett 2016; 381:104-12. [PMID: 27473824 DOI: 10.1016/j.canlet.2016.07.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 07/13/2016] [Accepted: 07/24/2016] [Indexed: 12/20/2022]
Abstract
Mesenchymal stem cells (MSCs) are promising vehicles for the delivery of anticancer agents in cancer therapy. However, the tumor targeting of loaded therapeutics is essential. Here, we explored a dual-targeting strategy to incorporate tumor-tropic MSC delivery with HER2-specific killing by the immunoapoptotin e23sFv-Fdt-tBid generated in our previous studies. The MSC engineering allowed simultaneous immunoapoptotin secretion and bioluminescence detection of the modified MSCs. Systemic administration of the immunoapoptotin-engineered MSCs was investigated in human HER2-reconstituted syngeneic mouse models of orthotopic and metastatic breast cancer, as well as in a xenograft nude mouse model of orthotopic gastric cancer. In vivo dual tumor targeting was confirmed by local accumulation of the bioluminescence-imaged MSCs and persistence of His-immunostained immunoapoptotins in tumor sites. The added tumor preference of MSC-secreted immunoapoptotins resulted in a significantly stronger antitumor effect compared with purified immunoapoptotins and Jurkat-delivered immunoapoptotins. This immunoapoptotin-armored MSC strategy provides a rationale for its use in extended malignancies by combining MSC mobility with redirected immunoapoptotins against a given tumor antigen.
Collapse
Affiliation(s)
- Yanhui Cai
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Yujing Xi
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; School of Pharmacy, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Zhongyuan Cao
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Geng Xiang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Qingrong Ni
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Rui Zhang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jing Chang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xiao Du
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Angang Yang
- The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Bo Yan
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
| | - Jing Zhao
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
| |
Collapse
|
|
30
|
Abstract
Compared with traditional 2D adherent cell culture, 3D spheroidal cell aggregates, or spheroids, are regarded as more physiological, and this technique has been exploited in the field of oncology, stem cell biology, and tissue engineering. Mesenchymal stem cells (MSCs) cultured in spheroids have enhanced anti-inflammatory, angiogenic, and tissue reparative/regenerative effects with improved cell survival after transplantation. Cytoskeletal reorganization and drastic changes in cell morphology in MSC spheroids indicate a major difference in mechanophysical properties compared with 2D culture. Enhanced multidifferentiation potential, upregulated expression of pluripotency marker genes, and delayed replicative senescence indicate enhanced stemness in MSC spheroids. Furthermore, spheroid formation causes drastic changes in the gene expression profile of MSC in microarray analyses. In spite of these significant changes, underlying molecular mechanisms and signaling pathways triggering and sustaining these changes are largely unknown.
Collapse
|
|
31
|
Nowakowski A, Walczak P, Janowski M, Lukomska B. Genetic Engineering of Mesenchymal Stem Cells for Regenerative Medicine. Stem Cells Dev 2015; 24:2219-42. [PMID: 26140302 DOI: 10.1089/scd.2015.0062] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs), which can be obtained from various organs and easily propagated in vitro, are one of the most extensively used types of stem cells and have been shown to be efficacious in a broad set of diseases. The unique and highly desirable properties of MSCs include high migratory capacities toward injured areas, immunomodulatory features, and the natural ability to differentiate into connective tissue phenotypes. These phenotypes include bone and cartilage, and these properties predispose MSCs to be therapeutically useful. In addition, MSCs elicit their therapeutic effects by paracrine actions, in which the metabolism of target tissues is modulated. Genetic engineering methods can greatly amplify these properties and broaden the therapeutic capabilities of MSCs, including transdifferentiation toward diverse cell lineages. However, cell engineering can also affect safety and increase the cost of therapy based on MSCs; thus, the advantages and disadvantages of these procedures should be discussed. In this review, the latest applications of genetic engineering methods for MSCs with regenerative medicine purposes are presented.
Collapse
Affiliation(s)
- Adam Nowakowski
- 1 NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland
| | - Piotr Walczak
- 2 Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland.,3 Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland.,4 Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury , Olsztyn, Poland
| | - Miroslaw Janowski
- 1 NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland .,2 Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland.,3 Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland
| | - Barbara Lukomska
- 1 NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences , Warsaw, Poland
| |
Collapse
|
|
32
|
Luan C, Chen R, Chen B, Ding J, Ni M. Umbilical cord blood transplantation supplemented with the infusion of mesenchymal stem cell for an adolescent patient with severe aplastic anemia: a case report and review of literature. Patient Prefer Adherence 2015; 9:759-765. [PMID: 26089653 PMCID: PMC4468992 DOI: 10.2147/ppa.s81509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Delayed hematopoietic recovery and increased rate of engraftment failure limit the use of umbilical cord blood transplantation (UCBT). We describe a case of severe aplastic anemia treated by UCBT combined with mesenchymal stem cells. Our case reveals that infusing mesenchymal stem cells early (about 40 days) after UCBT may promote hematopoietic recovery. This experience will guide clinical scientists, especially hematologists, to deal with similar situations and encourage them to widen this strategy.
Collapse
Affiliation(s)
- Chengxin Luan
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Runzhe Chen
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Baoan Chen
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Jiahua Ding
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China
| | - Ming Ni
- Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China
| |
Collapse
|
|
33
|
Salmasi S, Kalaskar DM, Yoon WW, Blunn GW, Seifalian AM. Role of nanotopography in the development of tissue engineered 3D organs and tissues using mesenchymal stem cells. World J Stem Cells 2015; 7:266-80. [PMID: 25815114 PMCID: PMC4369486 DOI: 10.4252/wjsc.v7.i2.266] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 11/07/2014] [Accepted: 12/03/2014] [Indexed: 02/06/2023] Open
Abstract
Recent regenerative medicine and tissue engineering strategies (using cells, scaffolds, medical devices and gene therapy) have led to fascinating progress of translation of basic research towards clinical applications. In the past decade, great deal of research has focused on developing various three dimensional (3D) organs, such as bone, skin, liver, kidney and ear, using such strategies in order to replace or regenerate damaged organs for the purpose of maintaining or restoring organs' functions that may have been lost due to aging, accident or disease. The surface properties of a material or a device are key aspects in determining the success of the implant in biomedicine, as the majority of biological reactions in human body occur on surfaces or interfaces. Furthermore, it has been established in the literature that cell adhesion and proliferation are, to a great extent, influenced by the micro- and nano-surface characteristics of biomaterials and devices. In addition, it has been shown that the functions of stem cells, mesenchymal stem cells in particular, could be regulated through physical interaction with specific nanotopographical cues. Therefore, guided stem cell proliferation, differentiation and function are of great importance in the regeneration of 3D tissues and organs using tissue engineering strategies. This review will provide an update on the impact of nanotopography on mesenchymal stem cells for the purpose of developing laboratory-based 3D organs and tissues, as well as the most recent research and case studies on this topic.
Collapse
Affiliation(s)
- Shima Salmasi
- Shima Salmasi, Deepak M Kalaskar, Alexander M Seifalian, UCL Division of Surgery and Interventional Science, Centre for Nanotechnology and Regenerative Medicine, University College London, NW3 2PF London, United Kingdom
| | - Deepak M Kalaskar
- Shima Salmasi, Deepak M Kalaskar, Alexander M Seifalian, UCL Division of Surgery and Interventional Science, Centre for Nanotechnology and Regenerative Medicine, University College London, NW3 2PF London, United Kingdom
| | - Wai-Weng Yoon
- Shima Salmasi, Deepak M Kalaskar, Alexander M Seifalian, UCL Division of Surgery and Interventional Science, Centre for Nanotechnology and Regenerative Medicine, University College London, NW3 2PF London, United Kingdom
| | - Gordon W Blunn
- Shima Salmasi, Deepak M Kalaskar, Alexander M Seifalian, UCL Division of Surgery and Interventional Science, Centre for Nanotechnology and Regenerative Medicine, University College London, NW3 2PF London, United Kingdom
| | - Alexander M Seifalian
- Shima Salmasi, Deepak M Kalaskar, Alexander M Seifalian, UCL Division of Surgery and Interventional Science, Centre for Nanotechnology and Regenerative Medicine, University College London, NW3 2PF London, United Kingdom
| |
Collapse
|
|
34
|
Zhang L, Su XS, Ye JS, Wang YY, Guan Z, Yin YF. Bone marrow mesenchymal stem cells suppress metastatic tumor development in mouse by modulating immune system. Stem Cell Res Ther 2015; 6:45. [PMID: 25889932 PMCID: PMC4425902 DOI: 10.1186/s13287-015-0039-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 01/21/2015] [Accepted: 03/05/2015] [Indexed: 12/14/2022] Open
Abstract
Introduction Bone marrow mesenchymal stem cells (BMSCs) have been studied extensively because of their potential use in clinical therapy, regenerative medicine, and tissue engineering. However, their application in tumor therapy remains yet in preclinical stage because of the distinct results from different researches and vagueness of their functional mechanism. In this study, the influence of BMSCs on tumor growth was observed and the potential mechanism was investigated. Method Two animal models, H22 ascitogenous hepatoma in BALb/c mouse and B16-F10 pulmonary metastatic melanoma in C57 mouse, were adopted in experience in vivo and treated with BMSCs by intravenous injection. The percentage of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) and IFN-γ+ T cells were observed in peripheral blood (PB) and bone marrow (BM) by Flow Cytometry. BMSCs were co-cultured in vitro with tumor cells and MDSCs in a tumor conditioned medium separately in order to illustrate the mechanism. Results Our results demonstrated that BMSCs treatment caused a delayed tumor growth and a prolonged survival in both tumor models, the homing fraction of BMSCs in BM was 2% - 5% in 24–72 hours after transfusion and the percentage of Gr-1+CD11b+ MDSCs was downregulated in peripheral blood and BM. Meanwhile, IFN-γ+ T lymphocytes in PB increased. In vitro co-culture showed that BMSCs inhibited the induction and proliferation of MDSCs in tumor conditioned medium, whereas they didn’t affect the proliferation of B16-F10 and H22 cells by in vitro co-culture. Both in vivo and in vitro results showed that BMSCs have a systemic suppressive effect on MDSCs. Conclusion Our data suggest that BMSCs has suppressive effect on tumor and is feasible to be applied in cancer treatment. BMSCs inhibiting MDSCs induction and proliferation is likely one of the mechanism.
Collapse
Affiliation(s)
- Lei Zhang
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Xiao San Su
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Jun Song Ye
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Yi Yin Wang
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Zheng Guan
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Yan Feng Yin
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| |
Collapse
|
|
35
|
MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep 2015; 5:9073. [PMID: 25766410 PMCID: PMC4358056 DOI: 10.1038/srep09073] [Citation(s) in RCA: 232] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 01/28/2015] [Indexed: 12/21/2022] Open
Abstract
Mitochondrial activity is central to tissue homeostasis. Mitochondria dysfunction constitutes a hallmark of many genetic diseases and plays a key role in tumor progression. The essential role of mitochondria, added to their recently documented capacity to transfer from cell to cell, obviously contributes to their current interest. However, determining the proper role of mitochondria in defined biological contexts was hampered by the lack of suitable experimental tools. We designed a protocol (MitoCeption) to directly and quantitatively transfer mitochondria, isolated from cell type A, to recipient cell type B. We validated and quantified the effective mitochondria transfer by imaging, fluorescence-activated cell sorting (FACS) and mitochondrial DNA analysis. We show that the transfer of minute amounts of mesenchymal stem/stromal cell (MSC) mitochondria to cancer cells, a process otherwise occurring naturally in coculture, results in cancer cell enhanced oxidative phosphorylation (OXPHOS) activity and favors cancer cell proliferation and invasion. The MitoCeption technique, which can be applied to different cell systems, will therefore be a method of choice to analyze the metabolic modifications induced by exogenous mitochondria in host cells.
Collapse
|
|
36
|
Leder A, Raschzok N, Schmidt C, Arabacioglu D, Butter A, Kolano S, de Sousa Lisboa LS, Werner W, Polenz D, Reutzel-Selke A, Pratschke J, Sauer IM. Micron-sized iron oxide-containing particles for microRNA-targeted manipulation and MRI-based tracking of transplanted cells. Biomaterials 2015. [PMID: 25771004 DOI: 10.1016/j.biomaterials.2015.01.065] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Particle-based delivery systems for therapeutic manipulation and tracking of transplanted cells by magnetic resonance imaging (MRI) are commonly based on nanometer-sized superparamagnetic iron oxide particles (SPIOs). Here, we present a proof of concept for multifunctional, silica based micron-sized iron oxide-containing particles (sMPIO) that combine fluorescence imaging, MRI tracking, and on-the-spot targeting of specific microRNAs on a particle surface for therapeutic manipulation by RNA interference. Antisense locked nucleic acids (α-LNA) were covalently bound to the surface of silica-based, DAPI-integrated, micron-sized iron oxide particles (sMPIO-α-LNA). In vitro studies using primary human hepatocytes showed rapid particle uptake (4 h) that was accompanied by significant depletion of the targeted microRNA Let7g (80%), up-regulation of the target proteins Cyclin D1 and c-Myc, and specific proteome changes. sMPIO-α-LNA-labeled cells were successfully detected by fluorescence imaging and could be visualized by MRI after intrasplenic transplantation in rats. This new theranostic particle provides a promising tool for cell transplantation where cellular imaging and microRNA-based manipulation is needed. [165].
Collapse
Affiliation(s)
- Annekatrin Leder
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
| | - Nathanael Raschzok
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | | | - Duygu Arabacioglu
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Antje Butter
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Susanne Kolano
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Luisa S de Sousa Lisboa
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Wiebke Werner
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Dietrich Polenz
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Anja Reutzel-Selke
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Johann Pratschke
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Igor M Sauer
- General, Visceral, and Transplantation Surgery, Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany
| |
Collapse
|
|
37
|
Lee SW, Jeon TJ, Biswal S. Effect of local treatment with adipose tissue-derived mesenchymal stem cells in the early tumorigenesis of osteosarcoma. Oncol Rep 2015; 33:1381-7. [PMID: 25572125 DOI: 10.3892/or.2015.3711] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 12/12/2014] [Indexed: 11/05/2022] Open
Abstract
There are conflicting data describing the effect of mesenchymal stem cells (MSCs) on tumorigenesis. The present study aimed to determine the survival rate and effect of adipose tissue-derived MSCs (ADMSCs) in tumor growth using bioluminescence imaging (BLI) and ultrasound (US) in an osteosarcoma xenograft model. Firefly luciferase-expressing ADMSCs combined with the osteosarcoma cell line UMR-106 in 4 different proportions (5, 10, 15 and 25%, named G1-G4, respectively) were xenografted into the right flanks of nude mice. The same number of UMR-106 cells was inoculated into the contralateral side of each mouse. Serial bioluminescence images were captured over 16 days to monitor the presence of ADMSCs in each group of 5 animals. The tumor volume was measured by ultra-high resolution US, and the tumor volume ratio (AMDSC mixed xenograft/control xenograft) was obtained to evaluate the effect of AMDSCs on tumor growth. Immunohistochemistry was performed to confirm the distribution of residual AMDSCs in the tumor. In G1, G2 and G3, the suppression of tumor growth by AMDSCs was noted in 2/5, 4/5 and 4/5 mice, respectively. However, accelerated tumor growth was noted in G4, which had the highest proportion of ADMSCs. The tumor volume ratio was significantly lower in G2 and G3 compared to G4, by Mann-Whitney U test (P=0.0159). Bioluminescence images demonstrated a serial decrement of the reporter gene for ADMSCs in the tumor mass without evidence of proliferation. Immunohistochemistry staining revealed minimal residual ADMSCs in the tumor periphery. Taken together, our data revealed that direct inoculation of ADMSCs into a tumor xenograft caused the death of the majority of ADMSCs in the tumor mass. Furthermore, relatively low proportions of ADMSCs suppressed the growth of osteosarcoma, while higher proportions showed a tumor-promoting effect.
Collapse
Affiliation(s)
- Sheen-Woo Lee
- Department of Radiology, Gil Hospital, Gachon University School of Medicine and Science, Incheon 406‑799, Republic of Korea
| | - Tae Joo Jeon
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Republic of Korea
| | - Sandip Biswal
- Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305-5105, USA
| |
Collapse
|
|
38
|
Machado AK, Cadoná FC, Azzolin VF, Dornelles EB, Barbisan F, Ribeiro EE, Mânica-Cattani MF, Duarte MMMF, Saldanha JRP, da Cruz IBM. Guaraná (Paullinia cupana) improves the proliferation and oxidative metabolism of senescent adipocyte stem cells derived from human lipoaspirates. Food Res Int 2015. [DOI: 10.1016/j.foodres.2014.11.056] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
|
|
39
|
Zhu Y, Cheng M, Yang Z, Zeng CY, Chen J, Xie Y, Luo SW, Zhang KH, Zhou SF, Lu NH. Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts. Drug Des Devel Ther 2014; 8:2449-62. [PMID: 25525335 PMCID: PMC4267519 DOI: 10.2147/dddt.s71466] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met) which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP). Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS), MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor tissues after systemic injection. The microvessel density of tumor xenografts was decreased, and tumor cellular apoptosis was significantly induced in the mice treated with MSCs-NK4 compared to control mice. These findings demonstrate that MSC-based NK4 gene therapy can obviously inhibit the growth of gastric cancer xenografts, and MSCs are a better vehicle for NK4 gene therapy than lentiviral vectors. Further studies are warranted to explore the efficacy and safety of the MSC-based NK4 gene therapy in animals and cancer patients.
Collapse
Affiliation(s)
- Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| | - Ming Cheng
- Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| | - Zhen Yang
- Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| | - Chun-Yan Zeng
- Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| | - Jiang Chen
- Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| | - Yong Xie
- Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| | - Shi-Wen Luo
- Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| | - Kun-He Zhang
- Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
- Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China
| |
Collapse
|
|
40
|
Basu J, Assaf BT, Bertram TA, Rao M. Preclinical biosafety evaluation of cell-based therapies: emerging global paradigms. Toxicol Pathol 2014; 43:115-25. [PMID: 25476796 DOI: 10.1177/0192623314559104] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cell-based therapies have the potential to treat a diversity of disease conditions, many representing significant and long-standing unmet medical needs. Certain properties of cell-based therapies, such as differentiation potential and proliferative potential, present safety concerns uniquely distinct from those of small molecule drugs and other macromolecule biologics. These cellular products carry risks associated with localized host tissue response, long-term persistence, ectopic tissue formation, differentiation to undesirable cell and tissue types, uncontrollable biodistribution, tumorigenicity, and immunogenicity. Such risks are generally evaluated in preclinical animal model studies as part of a comprehensive safety program prior to administration in humans. However, safety assessment for these products can be challenging because of inconsistent approaches to product characterization, inadequately defined product parameters that anticipate adverse events, and the lack of standardized approaches in evaluating in vivo host responses. In this symposium, we introduced cell-based therapies as an emerging product class to the Society of Toxicologic Pathology (STP) and highlighted key challenges for consideration during product biosafety evaluation.
Collapse
Affiliation(s)
- Joydeep Basu
- Tengion, Inc., Winston-Salem, North Carolina, USA
| | - Basel T Assaf
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA
| | | | - Mahendra Rao
- New York Stem Cell Foundation, New York, New York, USA
| |
Collapse
|
|
41
|
Stem cell-based approaches to improve nerve regeneration: potential implications for reconstructive transplantation? Arch Immunol Ther Exp (Warsz) 2014; 63:15-30. [PMID: 25428664 DOI: 10.1007/s00005-014-0323-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 10/07/2014] [Indexed: 12/17/2022]
Abstract
Reconstructive transplantation has become a viable option to restore form and function after devastating tissue loss. Functional recovery is a key determinant of overall success and critically depends on the quality and pace of nerve regeneration. Several molecular and cell-based therapies have been postulated and tested in pre-clinical animal models to enhance nerve regeneration. Schwann cells remain the mainstay of research focus providing neurotrophic support and signaling cues for regenerating axons. Alternative cell sources such as mesenchymal stem cells and adipose-derived stromal cells have also been tested in pre-clinical animal models and in clinical trials due to their relative ease of harvest, rapid expansion in vitro, minimal immunogenicity, and capacity to integrate and survive within host tissues, thereby overcoming many of the challenges faced by culturing of human Schwann cells and nerve allografting. Induced pluripotent stem cell-derived Schwann cells are of particular interest since they can provide abundant, patient-specific autologous Schwann cells. The majority of experimental evidence on cell-based therapies, however, has been generated using stem cell-seeded nerve guides that were developed to enhance nerve regeneration across "gaps" in neural repair. Although primary end-to-end repair is the preferred method of neurorrhaphy in reconstructive transplantation, mechanistic studies elucidating the principles of cell-based therapies from nerve guidance conduits will form the foundation of further research employing stem cells in end-to-end repair of donor and recipient nerves. This review presents key components of nerve regeneration in reconstructive transplantation and highlights the pre-clinical studies that utilize stem cells to enhance nerve regeneration.
Collapse
|
|
42
|
Microenvironment, oncoantigens, and antitumor vaccination: lessons learned from BALB-neuT mice. BIOMED RESEARCH INTERNATIONAL 2014; 2014:534969. [PMID: 25136593 PMCID: PMC4065702 DOI: 10.1155/2014/534969] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 05/12/2014] [Indexed: 12/20/2022]
Abstract
The tyrosine kinase human epidermal growth factor receptor 2 (HER2) gene is amplified in approximately 20% of human breast cancers and is associated with an aggressive clinical course and the early development of metastasis. Its crucial role in tumor growth and progression makes HER2 a prototypic oncoantigen, the targeting of which may be critical for the development of effective anticancer therapies. The setup of anti-HER2 targeting strategies has revolutionized the clinical outcome of HER2+ breast cancer. However, their initial success has been overshadowed by the onset of pharmacological resistance that renders them ineffective. Since the tumor microenvironment (TME) plays a crucial role in drug resistance, the design of more effective anticancer therapies should depend on the targeting of both cancer cells and their TME as a whole. In this review, starting from the successful know-how obtained with a HER2+ mouse model of mammary carcinogenesis, the BALB-neuT mice, we discuss the role of TME in mammary tumor development. Indeed, a deeper knowledge of antigens critical for cancer outbreak and progression and of the mechanisms that regulate the interplay between cancer and stromal cell populations could advise promising ways for the development of the best anticancer strategy.
Collapse
|