|
1
|
Jafar H, Alqudah D, Rahmeh R, Al-Hattab D, Ahmed K, Rayyan R, Abusneinah A, Rasheed M, Rayyan Y, Awidi A. Safety and Potential Efficacy of Expanded Umbilical Cord-Derived Mesenchymal Stromal Cells in Luminal Ulcerative Colitis Patients. Stem Cells Dev 2024; 33:645-651. [PMID: 39446772 DOI: 10.1089/scd.2024.0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by periods of flare-ups and remission. It is likely to be an autoimmune in origin, presenting persistent therapeutic challenges despite current therapies. This study aims to investigate the potential of umbilical cord mesenchymal stromal cells (UCMSCs) in treating ulcerative colitis (UC). This study is a prospective phase 1 pilot, open-label, single-arm, and single-center study. UCMSCs were cultured under current Good Manufacturing Practice (cGMP) conditions and intravenously administered to six patients with UC. Safety and efficacy were evaluated using the Mayo Score/Disease Activity Index. Among the six enrolled adult patients, five completed long-term follow-ups. All exhibited at diagnosis active UC confirmed through comprehensive assessment methods. Each patient received three injections intravenously 2 weeks apart with a dose of 100 million UCMSC each. No significant short-term or intermediate-term adverse events were detected post-UCMSC administration. Long-term follow-up at 12 and 24 months showed sustained safety and no adverse events. Notably, three out of five patients achieved a Mayo score of 0 for UC, maintained at both 12 and 24 months, indicating a highly significant response (P < 0.001). This study demonstrates the safety and potential efficacy of UCMSCs in active UC. However, larger trials are warranted to validate these preliminary findings and to establish the role of UCMSC therapy as an option for managing UC.
Collapse
Affiliation(s)
- Hanan Jafar
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Dana Alqudah
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Reem Rahmeh
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Dana Al-Hattab
- Cell Therapy Center, The University of Jordan, Amman, Jordan
- Electrical and Mathematical Sciences and Engineering Department, King Abdulla University of Science and Technology, Thuwal, ThuwalSaudi Arabia
| | - Khalid Ahmed
- School of Medicine, The University of Jordan, Amman, Jordan
| | - Rama Rayyan
- School of Medicine, The University of Jordan, Amman, Jordan
| | - Awni Abusneinah
- School of Medicine, The University of Jordan, Amman, Jordan
- Internal Medicine Department, Jordan University Hospital, Amman, Jordan
| | - Mohammad Rasheed
- School of Medicine, The University of Jordan, Amman, Jordan
- Internal Medicine Department, Jordan University Hospital, Amman, Jordan
| | - Yaser Rayyan
- School of Medicine, The University of Jordan, Amman, Jordan
- Internal Medicine Department, Jordan University Hospital, Amman, Jordan
| | - Abdalla Awidi
- Cell Therapy Center, The University of Jordan, Amman, Jordan
- School of Medicine, The University of Jordan, Amman, Jordan
- Internal Medicine Department, Jordan University Hospital, Amman, Jordan
| |
Collapse
|
|
2
|
Chen S, Liang B, Xu J. Unveiling heterogeneity in MSCs: exploring marker-based strategies for defining MSC subpopulations. J Transl Med 2024; 22:459. [PMID: 38750573 PMCID: PMC11094970 DOI: 10.1186/s12967-024-05294-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/11/2024] [Indexed: 05/19/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) represent a heterogeneous cell population distributed throughout various tissues, demonstrating remarkable adaptability to microenvironmental cues and holding immense promise for disease treatment. However, the inherent diversity within MSCs often leads to variability in therapeutic outcomes, posing challenges for clinical applications. To address this heterogeneity, purification of MSC subpopulations through marker-based isolation has emerged as a promising approach to ensure consistent therapeutic efficacy. In this review, we discussed the reported markers of MSCs, encompassing those developed through candidate marker strategies and high-throughput approaches, with the aim of explore viable strategies for addressing the heterogeneity of MSCs and illuminate prospective research directions in this field.
Collapse
Affiliation(s)
- Si Chen
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Bowei Liang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Jianyong Xu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Fuqiang Avenue 1001, Shenzhen, 518060, Guangdong, People's Republic of China.
- Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen, 518000, People's Republic of China.
| |
Collapse
|
|
3
|
Kolahi Azar H, Imanpour A, Rezaee H, Ezzatifar F, Zarei-Behjani Z, Rostami M, Azami M, Behestizadeh N, Rezaei N. Mesenchymal stromal cells and CAR-T cells in regenerative medicine: The homing procedure and their effective parameters. Eur J Haematol 2024; 112:153-173. [PMID: 37254607 DOI: 10.1111/ejh.14014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 06/01/2023]
Abstract
Mesenchymal stromal cells (MSCs) and chimeric antigen receptor (CAR)-T cells are two core elements in cell therapy procedures. MSCs have significant immunomodulatory effects that alleviate inflammation in the tissue regeneration process, while administration of specific chemokines and adhesive molecules would primarily facilitate CAR-T cell trafficking into solid tumors. Multiple parameters affect cell homing, including the recipient's age, the number of cell passages, proper cell culture, and the delivery method. In addition, several chemokines are involved in the tumor microenvironment, affecting the homing procedure. This review discusses parameters that improve the efficiency of cell homing and significant cell therapy challenges. Emerging comprehensive mechanistic strategies such as non-systemic and systemic homing that revealed a significant role in cell therapy remodeling were also reviewed. Finally, the primary implications for the development of combination therapies that incorporate both MSCs and CAR-T cells for cancer treatment were discussed.
Collapse
Affiliation(s)
- Hanieh Kolahi Azar
- Department of Pathology, Tabriz University of Medical Sciences, Tabriz, Iran
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Aylar Imanpour
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hanieh Rezaee
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ezzatifar
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Molecular and Cell Biology Research Center, Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Zeinab Zarei-Behjani
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, Advanced School of Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Rostami
- Division of Food Safety and Hygiene, Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Food Science and Nutrition Group (FSAN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahmoud Azami
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Behestizadeh
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| |
Collapse
|
|
4
|
Rasouli M, Naeimzadeh Y, Hashemi N, Hosseinzadeh S. Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging. Curr Stem Cell Res Ther 2024; 19:15-32. [PMID: 36642876 DOI: 10.2174/1574888x18666230113144016] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/28/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023]
Abstract
Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs.
Collapse
Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
5
|
Ichiseki T, Shimasaki M, Ueda S, Hirata H, Souma D, Kawahara N, Ueda Y. Efficacy of Rectal Systemic Administration of Mesenchymal Stem Cells to Injury Sites via the CXCL12/CXCR4 Axis to Promote Regeneration in a Rabbit Skeletal Muscle Injury Model. Cells 2023; 12:1729. [PMID: 37443763 PMCID: PMC10340610 DOI: 10.3390/cells12131729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/22/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been transplanted directly into lesions or injected intravenously. The administration of MSCs using these delivery methods requires specialized knowledge, techniques, and facilities. Here, we describe intrarectal systemic administration of MSCs, a simple, non-invasive route for homing to the injury sites to promote the regeneration of skeletal muscle injuries. Using a cardiotoxin (CTX)-induced rabbit skeletal muscle injury model, homing to the site of muscle injury was confirmed by intrarectal administration of MSCs; the time required for homing after intrarectal administration was approximately 5 days. In addition, the C-X-C chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor-4 (CXCR4) axis was found to be involved in the homing process. Histopathological examinations showed that skeletal muscle regeneration was promoted in the MSCs-administered group compared to the CTX-only group. Myosin heavy polypeptide 3 (Myh3) expression, an indicator of early muscle regeneration, was detected earlier in the intrarectal MSCs group compared to the CTX-only group. These findings indicate that intrarectal administration of MSCs is effective in homing to the injured area, where they promote injury repair. Since intrarectal administration is a simple and non-invasive delivery route, these findings may be valuable in future research on stem cell therapy.
Collapse
Affiliation(s)
- Toru Ichiseki
- Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada-machi, Kahoku 920-0293, Japan; (S.U.)
| | - Miyako Shimasaki
- Department of Pathology 2, Kanazawa Medical University, Daigaku 1-1, Uchinada-machi, Kahoku 920-0293, Japan;
| | - Shusuke Ueda
- Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada-machi, Kahoku 920-0293, Japan; (S.U.)
| | - Hiroaki Hirata
- Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada-machi, Kahoku 920-0293, Japan; (S.U.)
| | - Daisuke Souma
- Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada-machi, Kahoku 920-0293, Japan; (S.U.)
| | - Norio Kawahara
- Department of Orthopaedic Surgery, Kanazawa Medical University, Daigaku 1-1, Uchinada-machi, Kahoku 920-0293, Japan; (S.U.)
| | - Yoshimichi Ueda
- Department of Pathology, Keiju Medical Center, 94, Tomioka-machi, Nanao 926-0816, Japan
| |
Collapse
|
|
6
|
Luo M, Zhao Z, Yi J. Osteogenesis of bone marrow mesenchymal stem cell in hyperglycemia. Front Endocrinol (Lausanne) 2023; 14:1150068. [PMID: 37415664 PMCID: PMC10321525 DOI: 10.3389/fendo.2023.1150068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 06/05/2023] [Indexed: 07/08/2023] Open
Abstract
Diabetes mellitus (DM) has been shown to be a clinical risk factor for bone diseases including osteoporosis and fragility. Bone metabolism is a complicated process that requires coordinated differentiation and proliferation of bone marrow mesenchymal stem cells (BMSCs). Owing to the regenerative properties, BMSCs have laid a robust foundation for their clinical application in various diseases. However, mounting evidence indicates that the osteogenic capability of BMSCs is impaired under high glucose conditions, which is responsible for diabetic bone diseases and greatly reduces the therapeutic efficiency of BMSCs. With the rapidly increasing incidence of DM, a better understanding of the impacts of hyperglycemia on BMSCs osteogenesis and the underlying mechanisms is needed. In this review, we aim to summarize the current knowledge of the osteogenesis of BMSCs in hyperglycemia, the underlying mechanisms, and the strategies to rescue the impaired BMSCs osteogenesis.
Collapse
Affiliation(s)
- Meng Luo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhihe Zhao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jianru Yi
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| |
Collapse
|
|
7
|
Fu Z, Zhang Y, Geng X, Chi K, Liu C, Song C, Cai G, Chen X, Hong Q. Optimization strategies of mesenchymal stem cell-based therapy for acute kidney injury. Stem Cell Res Ther 2023; 14:116. [PMID: 37122024 PMCID: PMC10150535 DOI: 10.1186/s13287-023-03351-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 04/20/2023] [Indexed: 05/02/2023] Open
Abstract
Considering the high prevalence and the lack of targeted pharmacological management of acute kidney injury (AKI), the search for new therapeutic approaches for it is in urgent demand. Mesenchymal stem cells (MSCs) have been increasingly recognized as a promising candidate for the treatment of AKI. However, clinical translation of MSCs-based therapies is hindered due to the poor retention and survival rates as well as the impaired paracrine ability of MSCs post-delivery. To address these issues, a series of strategies including local administration, three-dimensional culture, and preconditioning have been applied. Owing to the emergence and development of these novel biotechnologies, the effectiveness of MSCs in experimental AKI models is greatly improved. Here, we summarize the different approaches suggested to optimize the efficacy of MSCs therapy, aiming at promoting the therapeutic effects of MSCs on AKI patients.
Collapse
Affiliation(s)
- Zhangning Fu
- Medical School of Chinese PLA, Beijing, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese PLA, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Yifan Zhang
- Medical School of Chinese PLA, Beijing, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese PLA, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Xiaodong Geng
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese PLA, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
- Beidaihe Rehabilitation and Recuperation Center, Chinese People's Liberation Army Joint Logistics Support Force, Qinhuangdao, China
| | - Kun Chi
- Medical School of Chinese PLA, Beijing, China
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese PLA, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Chao Liu
- Department of Critical Care Medicine, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Chengcheng Song
- Department of Nephrology, Beijing Electric Power Hospital, Beijing, China
| | - Guangyan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese PLA, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese PLA, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Quan Hong
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese PLA, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China.
| |
Collapse
|
|
8
|
Advances in Molecular Regulation of Prostate Cancer Cells by Top Natural Products of Malaysia. Curr Issues Mol Biol 2023; 45:1536-1567. [PMID: 36826044 PMCID: PMC9954984 DOI: 10.3390/cimb45020099] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Prostate cancer (PCa) remains both a global health burden and a scientific challenge. We present a review of the molecular targets driving current drug discovery to fight this disease. Moreover, the preventable nature of most PCa cases represents an opportunity for phytochemicals as chemopreventive when adequately integrated into nutritional interventions. With a renovated interest in natural remedies as a commodity and their essential role in cancer drug discovery, Malaysia is looking towards capitalizing on its mega biodiversity, which includes the oldest rainforest in the world and an estimated 1200 medicinal plants. We here explore whether the list of top Malay plants prioritized by the Malaysian government may fulfill the potential of becoming newer, sustainable sources of prostate cancer chemotherapy. These include Andrographis paniculate, Centella asiatica, Clinacanthus nutans, Eurycoma longifolia, Ficus deltoidea, Hibiscus sabdariffa, Marantodes pumilum (syn. Labisia pumila), Morinda citrifolia, Orthosiphon aristatus, and Phyllanthus niruri. Our review highlights the importance of resistance factors such as Smac/DIABLO in cancer progression, the role of the CXCL12/CXCR4 axis in cancer metastasis, and the regulation of PCa cells by some promising terpenes (andrographolide, Asiatic acid, rosmarinic acid), flavonoids (isovitexin, gossypin, sinensetin), and alkylresorcinols (labisiaquinones) among others.
Collapse
|
|
9
|
Thavayogarajah T, Sinitski D, Bounkari OE, Torres-Garcia L, Lewinsky H, Harjung A, Chen HR, Panse J, Vankann L, Shachar I, Bernhagen J, Koschmieder S. CXCR4 and CD74 together enhance cell survival in response to macrophage migration-inhibitory factor in chronic lymphocytic leukemia. Exp Hematol 2022; 115:30-43. [PMID: 36096455 DOI: 10.1016/j.exphem.2022.08.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/16/2022] [Accepted: 08/29/2022] [Indexed: 11/04/2022]
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of small, mature CD5+ B lymphocytes in the blood, marrow, and lymphoid organs. Cell survival depends on interaction with the leukemic microenvironment. However, the mechanisms controlling CLL cell survival are still incompletely understood. Macrophage migration-inhibitory factor (MIF), a pro-inflammatory and immunoregulatory chemokine-like cytokine, interacts with CXCR4, a major chemokine receptor, as well as with CD74/invariant chain, a single-pass type II receptor. In this study, we analyzed the roles of CXCR4, CD74, and MIF in CLL. Mononuclear cells from patients with hematological malignancies were analyzed for coexpression of CXCR4 and CD74 by flow cytometry. Strong co- and overexpression of CXCR4 and CD74 were observed on B cells of CLL patients (n = 10). Survival and chemotaxis assays indicated that CXCR4 and CD74 work together to enhance the survival and migration of malignant cells in CLL. Blockade of the receptors, either individually or in combination, promoted cell death and led to an abrogation of MIF-driven migration responses in murine and human CLL cells, suggesting that joint activation of both receptors is crucial for CLL cell survival and mobility. These findings indicate that the MIF/CXCR4/CD74 axis represents a novel therapeutic target in CLL.
Collapse
Affiliation(s)
- Tharshika Thavayogarajah
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany; Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany; Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Dzmitry Sinitski
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Omar El Bounkari
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Laura Torres-Garcia
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Hadas Lewinsky
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Alexander Harjung
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Hong-Ru Chen
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Jens Panse
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany
| | - Lucia Vankann
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany
| | - Idit Shachar
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Jürgen Bernhagen
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany; SyNergy Excellence Cluster, Munich, Germany.
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany.
| |
Collapse
|
|
10
|
Eweida A, Flechtenmacher S, Sandberg E, Schulte M, Schmidt VJ, Kneser U, Harhaus L. Systemically injected bone marrow mononuclear cells specifically home to axially vascularized tissue engineering constructs. PLoS One 2022; 17:e0272697. [PMID: 35951604 PMCID: PMC9371259 DOI: 10.1371/journal.pone.0272697] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 07/26/2022] [Indexed: 11/18/2022] Open
Abstract
Inducing axial vascularisation of tissue engineering constructs is a well-established method to support tissue growth in large 3-dimensional tissues. Progenitor cell chemotaxis towards axially vascularized tissues has not been well characterized. In a prospective randomized controlled study including 32 male syngeneic Lewis rats we investigated the capability of the axially vascularized constructs to attract systemically injected bone marrow mononuclear cells (BMMNCs). The underlying mechanism for cell homing was investigated focusing on the role of hypoxia and the SDF1-CXCR4-7 axis. Sixteen animals were used as donors for BMMNCs. The other animals were subjected to implantation of a tissue engineering construct in the subcutaneous groin region. These constructs were axially vascularized either via an arteriovenous loop (AVL, n = 6) or via uninterrupted flow-through vessels (non-AVL, n = 10). BMMNCs were labelled with quantum dots (Qdot® 655) and injected 12 days after surgery either via intra-arterial or intravenous routes. 2 days after cell injection, the animals were sacrificed and examined using fluorescence microscopy. The Qdot® 655 signals were detected exclusively in the liver, spleen, AVL constructs and to a minimal extent in the non-AVL constructs. A significant difference could be detected between the number of labelled cells in the AVL and non-AVL constructs with more cells detected in the AVL constructs specially in central zones (p <0.0001). The immunohistological analysis showed a significant increase in the absolute expression of HIF-1 in the AVL group in comparison to the non-AVL group. The PCR analysis confirmed a 1.4-fold increase in HIF-1 expression in AVL constructs. Although PCR analysis showed an enhanced expression of CXCR4 and CXCR7 in AVL constructs, no significant differences in SDF1 expression were detected via immunohistological or PCR analysis. At the examined time point, the AVL constructs can attract BMMNCs in a mechanism probably related to the hypoxia associated with a robust tissue formation.
Collapse
Affiliation(s)
- Ahmad Eweida
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
- Department of Head, Neck and Endocrine Surgery, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Sophia Flechtenmacher
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Elli Sandberg
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Matthias Schulte
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Volker J. Schmidt
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
- Department for Plastic and Breast Surgery, Zealand University Hospital, Roskilde, Copenhagen University, Copenhagen, Denmark
| | - Ulrich Kneser
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| | - Leila Harhaus
- Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Ludwigshafen, Germany
| |
Collapse
|
|
11
|
Circulating SSEA-1 + stem cell-mediated tissue repair in allergic airway inflammation. Cell Mol Life Sci 2022; 79:347. [PMID: 35670856 PMCID: PMC9174110 DOI: 10.1007/s00018-022-04366-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/30/2022] [Accepted: 05/10/2022] [Indexed: 11/22/2022]
Abstract
Structural changes known as airway remodeling characterize chronic/severe asthma and contribute to lung dysfunction. We previously reported that neonatal SSEA-1+ pulmonary stem/progenitor cells (PSCs) ameliorated airway inflammation in asthmatic mice. However, the molecular mechanisms by which endogenous SSEA-1+ PSC of adult mice afford beneficial effects in alveolar homeostasis and lung repair after allergen challenge remain incompletely understood. To analyze the expression profile and clarify the biological significance of endogenous adult lung SSEA-1+ cells in asthmatic mice. Lung SSEA-1+ cells and circulating SSEA-1+ cells in peripheral blood were determined by confocal microscopy and cytometric analysis. GFP chimeric mice were used to trace cell lineage in vivo. The roles of circulating SSEA-1+ cells were verified in ovalbumin-induced and house dust mite-induced allergic asthmatic models. In asthmatic mice, endogenous lung SSEA-1+ cells almost disappeared; however, a unique population of circulating SSEA-1+ cells was enriched after the challenge phase. In asthmatic mice, adoptive transfer of circulating SSEA-1+ cells had a specific homing preference for the lung in response to inhaled antigen through upregulating CXCR7–CXCL11 chemokine axis. Circulating SSEA-1+ cells can transdifferentiate in the alveolar space and ameliorate lung inflammation and structural damage through inhibiting the infiltration of inflammatory cells into peribronchovascular and goblet cell hyperplasia areas, reducing the thickened smooth muscle layers and PAS-positive mucus-containing goblet cells. Reinforcing bone marrow-derived circulating SSEA-1+ cells from peripheral blood into lung tissue which create a rescue mechanism in maintaining alveolar homeostasis and tissue repair to mediate lung protection for emergency responses after allergen challenge in asthmatic conditions.
Collapse
|
|
12
|
Miloradovic D, Miloradovic D, Ljujic B, Jankovic MG. Optimal Delivery Route of Mesenchymal Stem Cells for Cardiac Repair: The Path to Good Clinical Practice. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022:83-100. [PMID: 35389200 DOI: 10.1007/5584_2022_709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Research has shown that mesenchymal stem cells (MSCs) could be a promising therapy for treating progressive heart disease. However, translation into clinics efficiently and successfully has proven to be much more complicated. Many questions remain for optimizing treatment. Application method influences destiny of MSCs and afterwards impacts results of procedure, yet there is no general agreement about most suitable method of MSC delivery in the clinical setting. Herein, we explain principle of most-frequent MSCs delivery techniques in cardiology. This chapter summarizes crucial translational obstacles of clinical employment of MSCs for cardiac repair when analysed trough a prism of latest research centred on different techniques of MSCs application.
Collapse
Affiliation(s)
- Dragica Miloradovic
- Faculty of Medical Sciences, Department of Genetics, University of Kragujevac, Kragujevac, Serbia
| | - Dragana Miloradovic
- Faculty of Medical Sciences, Department of Genetics, University of Kragujevac, Kragujevac, Serbia
| | - Biljana Ljujic
- Faculty of Medical Sciences, Department of Genetics, University of Kragujevac, Kragujevac, Serbia
| | - Marina Gazdic Jankovic
- Faculty of Medical Sciences, Department of Genetics, University of Kragujevac, Kragujevac, Serbia.
| |
Collapse
|
|
13
|
Non-clinical assessment of safety, biodistribution and tumorigenicity of human mesenchymal stromal cells. Toxicol Rep 2021; 8:1960-1969. [PMID: 34926173 PMCID: PMC8649581 DOI: 10.1016/j.toxrep.2021.11.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/19/2021] [Accepted: 11/24/2021] [Indexed: 12/15/2022] Open
Abstract
Good safety profile of mesenchymal stromal cells (MSCs) without toxicity findings. MSC biodistribution showed primary distribution to the lung and short persistence. No tumor formation observed after 6 months of repeated MSC dosing. qPCR and in situ hybridization were combined for the detection of MSCs. Data allow progression into clinical trials for acute Graft-versus-Host disease. Guidelines regulating the development of advanced therapy medicinal products (ATMPs) request nonclinical data for toxicity, biodistribution and tumorigenicity before mesenchymal stromal cell (MSC) products can be administered in large clinical trials. We assessed the biodistribution/persistence, safety and tumorigenicity of MC0518, a human allogeneic MSC product from pooled bone marrow mononuclear cells of eight healthy, adult, unrelated donors, which is currently investigated for the treatment of steroid-refractory acute Graft-versus-Host Disease (aGvHD) after hematopoietic stem cell transplantation. In our GLP studies, immuno-deficient mice were administered repeat doses of MC0518 (once weekly for 6 weeks, i.v.) at doses exceeding the proposed human clinical dose 20-60-fold. No signs of toxicity were observed in the combined biodistribution/toxicity study. Human MSCs in mouse tissues were detected by quantitative PCR (qPCR) and in situ hybridization (ISH). MC0518 showed initial trapping in the lung, occasional distribution into other organs and low tissue persistence beyond 24 h after application. No MSC-induced tumors of human origin were identified after a follow-up of six months. Additionally, we found that the combination of different detection methods (qPCR and ISH) is crucial for a reliable interpretation of biodistribution results. Our data suggest that MC0518 is safe for use in human.
Collapse
|
|
14
|
Hu JL, Kwon ST, Kim SW, Nam HJ, Kim BJ. Effects of Administration Route of Adipose-Derived Stem Cells on the Survival of Allogeneic Skin Grafts in Mice. Transplant Proc 2021; 53:2397-2406. [PMID: 34376314 DOI: 10.1016/j.transproceed.2021.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/16/2021] [Accepted: 07/19/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Composite tissue allotransplantation presents considerable potential for defective tissue reconstruction. However, the high immunogenicity of the allogeneic skin grafts can cause acute rejection. Adipose-derived stem cells (ADSCs) reportedly have an immunomodulation potential, which may improve the survival of allogeneic skin grafts. However, there is currently no consensus on administration route of ADSCs. This study compared the effectiveness of local injection vs intravenous (IV) administration of ADSCs in improving the survival of allogenic skin grafts in mice. METHODS BALB/c and C57BL/6 mice were used as skin graft donors and recipients, respectively. Mice were divided into 3 groups for IV injection of ADSCs (IV group) or phosphate-buffered saline (PBS; control), or for local injection in the fascial layer of the recipient bed (FL group). After allogeneic skin transplantation, 0.1 mL of PBS alone or with 1.5 × 105 ADSCs was immediately injected. The grafts were histologically evaluated on days 7 and 14 postoperation. RESULTS The graft necrotic area was significantly smaller in the IV and FL groups than in the control group. Additionally, the grafts in these 2 groups exhibited decreased interleukin 17/6, tumor necrosis factor-α, and interferon-γ messenger mRNA levels; inflammatory changes; and cluster of differentiation 4 expression, and increased expression of vascular endothelial growth factor expression (P < .05). However, these 2 groups did not significantly differ (P > .05). CONCLUSIONS ADSCs increased the survival of allogeneic skin grafts in mice regardless of IV or FL route of administration, and this effect is likely through anti-inflammatory and angiogenic effects of ADSCs.
Collapse
Affiliation(s)
- Ju Long Hu
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sung Tack Kwon
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sang Wha Kim
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hee Jin Nam
- Biomedical Research Institute, Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Byung Jun Kim
- Department of Plastic and Reconstructive Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
15
|
Ferrini E, Stellari FF, Franceschi V, Macchi F, Russo L, Murgia A, Grisendi G, Villetti G, Dominici M, Donofrio G. Persistency of Mesenchymal Stromal/Stem Cells in Lungs. Front Cell Dev Biol 2021; 9:709225. [PMID: 34336863 PMCID: PMC8322774 DOI: 10.3389/fcell.2021.709225] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 06/17/2021] [Indexed: 01/03/2023] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are a fibroblast-like cell population with high regenerative potential that can be isolated from many different tissues. Several data suggest MSCs as a therapeutic tool capable of migrating to a site of injury and guide tissue regeneration mainly through their secretome. Pulmonary first-pass effect occurs during intravenous administration of MSCs, where 50 to 80% of the cells tend to localize in the lungs. This phenomenon has been exploited to study MSC potential therapeutic effects in several preclinical models of lung diseases. Data demonstrated that, regardless of the lung disease severity and the delivery route, MSCs were not able to survive longer than 24 h in the respiratory tract but still surprisingly determined a therapeutic effect. In this work, two different mouse bone marrow-derived mesenchymal stromal/stem cell (mBM-MSC) lines, stably transduced with a third-generation lentiviral vector expressing luciferase and green fluorescent protein reporter genes tracking MSCs in vivo biodistribution and persistency, have been generated. Cells within the engrafted lung were in vivo traced using the high-throughput bioluminescence imaging (BLI) technique, with no invasiveness on animal, minimizing biological variations and costs. In vivo BLI analysis allowed the detection and monitoring of the mBM-MSC clones up to 28 days after implantation independently from the delivery route. This longer persistency than previously observed (24 h) could have a strong impact in terms of pharmacokinetics and pharmacodynamics of MSCs as a therapeutic tool.
Collapse
Affiliation(s)
- Erica Ferrini
- Chiesi Farmaceutici S.p.A., Corporate Pre-Clinical R&D, Parma, Italy.,Department of Veterinary Science, University of Parma, Parma, Italy
| | | | | | - Francesca Macchi
- Department of Veterinary Science, University of Parma, Parma, Italy
| | - Luca Russo
- Department of Veterinary Science, University of Parma, Parma, Italy
| | - Alba Murgia
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Hospital of Modena, Modena, Italy.,Scientific and Technological Park of Medicine "Mario Veronesi," Mirandola, Italy
| | - Giulia Grisendi
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Hospital of Modena, Modena, Italy
| | - Gino Villetti
- Chiesi Farmaceutici S.p.A., Corporate Pre-Clinical R&D, Parma, Italy
| | - Massimo Dominici
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Hospital of Modena, Modena, Italy.,Scientific and Technological Park of Medicine "Mario Veronesi," Mirandola, Italy
| | - Gaetano Donofrio
- Department of Veterinary Science, University of Parma, Parma, Italy
| |
Collapse
|
|
16
|
Singh P, Kacena MA, Orschell CM, Pelus LM. Aging-Related Reduced Expression of CXCR4 on Bone Marrow Mesenchymal Stromal Cells Contributes to Hematopoietic Stem and Progenitor Cell Defects. Stem Cell Rev Rep 2021; 16:684-692. [PMID: 32418119 DOI: 10.1007/s12015-020-09974-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Aging impairs the regenerative potential of hematopoietic stem cells (HSC) and skews differentiation towards the myeloid lineage. The bone marrow (BM) microenvironment has recently been suggested to influence HSC aging, however the mechanisms whereby BM stromal cells mediate this effect is unknown. Here we show that aging-associated decreased expression of CXCR4 expression on BM mesenchymal stem cells (MSC) plays a crucial role in the development of the hematopoietic stem and progenitor cells (HSPC) aging phenotype. The BM MSC from old mice was sufficient to drive a premature aging phenotype of young HSPC when cultured together ex vivo. The impaired ability of old MSC to support HSPC function is associated with reduced expression of CXCR4 on BM MSC of old mice. Deletion of the CXCR4 gene in young MSC accelerates an aging phenotype in these cells characterized by increased production of reactive oxygen species (ROS), DNA damage, senescence, and reduced proliferation. Culture of HSPC from young mice with CXCR4 deficient MSC also from young mice led to a premature aging phenotype in the young HSPC, as evidenced by reduced hematopoietic regeneration and enhanced myeloid differentiation. Mechanistically, CXCR4 signaling prevents BM MSC dysfunction by suppressing oxidative stress, as treatment of old or CXCR4 deficient MSC with N-acetyl-L-cysteine (NAC), improved their niche supporting activity, and attenuated the HSPC aging phenotype. Our studies suggest that age-associated reduction in CXCR4 expression on BM MSC impairs hematopoietic niche activity with increased ROS production, driving an HSC aging phenotype. Thus, modulation of the SDF-1/CXCR4 axis in MSC may lead to novel interventions to alleviate the age-associated decline in immune/hematopoietic function.
Collapse
Affiliation(s)
- Pratibha Singh
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States.
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States.
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| | - Christie M Orschell
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| | - Louis M Pelus
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| |
Collapse
|
|
17
|
Amin SN, Sharawy N, El Tablawy N, Elberry DA, Youssef MF, Abdelhady EG, Rashed LA, Hassan SS. Melatonin-Pretreated Mesenchymal Stem Cells Improved Cognition in a Diabetic Murine Model. Front Physiol 2021; 12:628107. [PMID: 33815140 PMCID: PMC8012759 DOI: 10.3389/fphys.2021.628107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 02/11/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes mellitus (DM) is a multisystem endocrine disorder affecting the brain. Mesenchymal stem cells (MSCs) pretreated with Melatonin have been shown to increase the potency of MSCs. This work aimed to compare Melatonin, stem cells, and stem cells pretreated with Melatonin on the cognitive functions and markers of synaptic plasticity in an animal model of type I diabetes mellitus (TIDM). Thirty-six rats represented the animal model; six rats for isolation of MSCs and 30 rats were divided into five groups: control, TIDM, TIDM + Melatonin, TIDM + Stem cells, and TIDM + Stem ex vivo Melatonin. Functional assessment was performed with Y-maze, forced swimming test and novel object recognition. Histological and biochemical evaluation of hippocampal Neuroligin 1, Sortilin, Brain-Derived Neurotrophic Factor (BDNF), inducible nitric oxide synthase (iNOS), toll-like receptor 2 (TLR2), Tumor necrosis factor-alpha (TNF-α), and Growth Associated Protein 43 (GAP43). The TIDM group showed a significant decrease of hippocampal Neuroligin, Sortilin, and BDNF and a significant increase in iNOS, TNF-α, TLR2, and GAP43. Melatonin or stem cells groups showed improvement compared to the diabetic group but not compared to the control group. TIDM + Stem ex vivo Melatonin group showed a significant improvement, and some values were restored to normal. Ex vivo melatonin-treated stem cells had improved spatial working and object recognition memory and depression, with positive effects on glucose homeostasis, inflammatory markers levels and synaptic plasticity markers expression.
Collapse
Affiliation(s)
- Shaimaa Nasr Amin
- Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan.,Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nivin Sharawy
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nashwa El Tablawy
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Dalia Azmy Elberry
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mira Farouk Youssef
- Department of Histology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ebtehal Gamal Abdelhady
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Beni-Suef University, Beni Suef, Egypt
| | - Laila Ahmed Rashed
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Sherif Sabry Hassan
- Department of Medical Education, School of Medicine, California University of Science and Medicine, San Bernardino, CA, United States.,Department of Anatomy, Faculty of Medicine, Cairo University, Cairo, Egypt
| |
Collapse
|
|
18
|
In Vitro Generation of Vascular Wall-Typical Mesenchymal Stem Cells (VW-MSC) from Murine Induced Pluripotent Stem Cells Through VW-MSC-Specific Gene Transfer. Methods Mol Biol 2021. [PMID: 32474869 DOI: 10.1007/978-1-0716-0655-1_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] [Indexed: 10/13/2023]
Abstract
Among the adult stem cells, multipotent mesenchymal stem cells (MSCs) turned out to be a promising option for cell-based therapies for the treatment of various diseases including autoimmune and cardiovascular disorders. MSCs bear a high proliferation and differentiation capability and exert immunomodulatory functions while being still clinically safe. As tissue-resident stem cells, MSCs can be isolated from various tissue including peripheral or umbilical cord blood, placenta, blood, fetal liver, lung, adipose tissue, and blood vessels, although the most commonly used source for MSCs is the bone marrow. However, the proportion of MSCs in primary isolates from adult tissue biopsies is rather low, and therefore MSCs must be intensively expanded in vitro before the MSCs find particular use in therapies that may require extensive and repetitive cell replacement. Therefore, more easily accessible sources of MSCs are needed. Here, we present a detailed protocol to generate tissue-typical MSCs by direct linage conversion using transcription factors defining target MSC identity from murine induced pluripotent stem cells (iPSCs).
Collapse
|
|
19
|
Hu C, Zhao L, Li L. Genetic modification by overexpression of target gene in mesenchymal stromal cell for treating liver diseases. J Mol Med (Berl) 2021; 99:179-192. [PMID: 33388882 DOI: 10.1007/s00109-020-02031-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 11/02/2020] [Accepted: 12/21/2020] [Indexed: 12/31/2022]
Abstract
Different hepatoxic factors cause irreversible liver injury, leading to liver failure, cirrhosis, and cancer in mammals. Liver transplantation is the only effective strategy, which can improve the prognosis of patients with end-stage liver diseases, but it is limited by liver donor shortage, expensive costs, liver graft rejection and dysfunction, and recurring liver failure. Recently, mesenchymal stromal cells (MSCs) isolated from various tissues are regarded as the main stem cell type with therapeutic effects in liver diseases because of their hepatogenic differentiation, anti-inflammatory, immuoregulatory, anti-apoptotic, antifibrotic, and antitumor capacities. To further improve the therapeutic effects of MSCs, multiple studies showed that genetically engineered MSCs have increased regenerative capacities and are able to more effectively inhibit cell death. Moreover, they are able to secrete therapeutic proteins for attenuating liver injury in liver diseases. In this review, we mainly focus on gene overexpression for reprogramming MSCs to increase their therapeutic effects in treating various liver diseases. We described the potential mechanisms of MSCs with gene overexpression in attenuating liver injury, and we recommend further expansion of experiments to discover more gene targets and optimized gene delivery methods for MSC-based regenerative medicine. We also discussed the potential hurdles in genetic engineering MSCs. In conclusion, we highlight that we need to overcome all scientific hurdles before genetically modified MSC therapy can be translated into clinical practices for patients with liver diseases.
Collapse
Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, Institute of Nephrology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
| |
Collapse
|
|
20
|
Abdelhafez D, Aboelkomsan E, El Sadik A, Lasheen N, Ashur S, Elshimy A, Morcos GNB. The Role of Mesenchymal Stem Cells with Ascorbic Acid and N-Acetylcysteine on TNF- α, IL 1 β, and NF- κβ Expressions in Acute Pancreatitis in Albino Rats. J Diabetes Res 2021; 2021:6229460. [PMID: 34697592 PMCID: PMC8541853 DOI: 10.1155/2021/6229460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/30/2021] [Accepted: 10/04/2021] [Indexed: 01/16/2023] Open
Abstract
Severe acute pancreatitis (SAP) is a necrotic pancreatic inflammation associated with high mortality rate (up to 70%). Bone marrow (BM) mesenchymal stem cells (MSCs) have been investigated in pancreatic cellular regeneration, but still their effects are controversial. Therefore, the present study is aimed at examining the enrichment of the stem cells with ascorbic acid (AA) and N-acetylcysteine (NAC) and explore their combined action on the expression of the inflammatory cytokines: interleukin 1β (IL 1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κβ (NF-κβ). A total of twenty adult male Sprague-Dawley albino rats were divided into four groups: the control group, cerulein group (to induce acute pancreatitis), BM-MSCs group, and combined BM-MSCs with AA and NAC group. Homing and proliferation of stem cells were revealed by the appearance of PKH26-labelled BM-MSCs in the islets of Langerhans. AA and NAC combination with BM-MSCs (group IV) was demonstrated to affect the expression of the inflammatory cytokines: IL 1β, TNF-α, and NF-κβ. In addition, improvement of the biochemical and histological parameters is represented in increasing body weight, normal blood glucose, and insulin levels and regeneration of the islet cells. Immunohistochemical studies showed an increase in proliferating cell nuclear antigen (PCNA) and decrease in caspase-3 reactions, detected markedly in group IV, after the marked distortion of the classic pancreatic lobular architecture was induced by cerulein. It could be concluded that treatment with BM-MSCs combined with antioxidants could provide a promising therapy for acute pancreatitis and improve the degeneration, apoptosis, necrosis, and inflammatory processes of the islets of Langerhans. TNF-α, IL 1β, and NF-κβ are essential biomarkers for the evaluation of MSC regenerative effectiveness.
Collapse
Affiliation(s)
- Dalia Abdelhafez
- Department of Pathology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | | | - Abir El Sadik
- Department of Anatomy and Histology, College of Medicine, Qassim University, Saudi Arabia and Department of Anatomy and Embryology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Noha Lasheen
- Department of Physiology, Faculty of Medicine, Ain Shams and Galala Universities, Cairo, Egypt
| | - Sara Ashur
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amal Elshimy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - George N. B. Morcos
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, and Department of Basic Medical Science, Faculty of Medicine, King Salman International University, Cairo, Egypt
| |
Collapse
|
|
21
|
Chen L, Li Y, Chen W, Han N, Li K, Guo R, Liu Z, Xiao Y. Enhanced recruitment and hematopoietic reconstitution of bone marrow-derived mesenchymal stem cells in bone marrow failure by the SDF-1/CXCR4. J Tissue Eng Regen Med 2020; 14:1250-1260. [PMID: 32633015 DOI: 10.1002/term.3096] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 06/08/2020] [Accepted: 06/22/2020] [Indexed: 12/13/2022]
Abstract
Aplastic anemia (AA) is a bone marrow failure disease. It is difficult to treat AA, and in addition, relapses are common because of its complex disease pathogenesis. Allogeneic bone marrow-derived mesenchymal stem cells (BMSCs) infusion is an effective and safe treatment option for the AA patients. However, it found that BMSCs infusion in AA patients is less than 30% effective. Therefore, the key to improve the efficacy of BMSCs treatment in these patients is to enhance their homing efficiency to the target sites. Studies have shown that stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays an important role in promoting BMSCs homing. In this study, human BMSCs were transduced with lentivirus stably expressing CXCR4-BMSCs. Transduced BMSCs resemble normal BMSCs in many ways. Migration ability of CXCR4-BMSCs toward SDF-1 was increased because of the overexpression of CXCR4. In the mice with bone marrow failure, the migration and colonization ability of CXCR4-BMSCs to the bone marrow was significantly improved as seen by IVIS imaging and FACS. The SDF-1 level in the bone marrow failure mice was significantly higher than in the normal mice. Thus, from our study, it is clear that after CXCR4-BMSCs were infused into mice with bone marrow failure, SDF-1 interacted with CXCR4 receptor, leading cells to migrate and colonize to bone marrow. Because of the high SDF-1 expression in mouse bone marrow and CXCR4 receptor expression in cells, BMSCs homing was increased.
Collapse
Affiliation(s)
- Lixuan Chen
- Department of Hematology, Jiangmen Central Hospital, Jiangmen, China
| | - Yonghua Li
- Department of Hematology, General Hospital of Southern Theatre Command of PLA, Guangzhou, China.,The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wancheng Chen
- Department of Hematology, Jiangmen Central Hospital, Jiangmen, China
| | - Na Han
- Department of Hematology, General Hospital of Southern Theatre Command of PLA, Guangzhou, China
| | - Keke Li
- Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Rui Guo
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou, China
| | - Zenghui Liu
- Department of Hematology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yang Xiao
- Department of Hematology, Jiangmen Central Hospital, Jiangmen, China.,Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
22
|
Levy O, Kuai R, Siren EMJ, Bhere D, Milton Y, Nissar N, De Biasio M, Heinelt M, Reeve B, Abdi R, Alturki M, Fallatah M, Almalik A, Alhasan AH, Shah K, Karp JM. Shattering barriers toward clinically meaningful MSC therapies. SCIENCE ADVANCES 2020; 6:eaba6884. [PMID: 32832666 PMCID: PMC7439491 DOI: 10.1126/sciadv.aba6884] [Citation(s) in RCA: 405] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 06/05/2020] [Indexed: 05/11/2023]
Abstract
More than 1050 clinical trials are registered at FDA.gov that explore multipotent mesenchymal stromal cells (MSCs) for nearly every clinical application imaginable, including neurodegenerative and cardiac disorders, perianal fistulas, graft-versus-host disease, COVID-19, and cancer. Several companies have or are in the process of commercializing MSC-based therapies. However, most of the clinical-stage MSC therapies have been unable to meet primary efficacy end points. The innate therapeutic functions of MSCs administered to humans are not as robust as demonstrated in preclinical studies, and in general, the translation of cell-based therapy is impaired by a myriad of steps that introduce heterogeneity. In this review, we discuss the major clinical challenges with MSC therapies, the details of these challenges, and the potential bioengineering approaches that leverage the unique biology of MSCs to overcome the challenges and achieve more potent and versatile therapies.
Collapse
Affiliation(s)
- Oren Levy
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Rui Kuai
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Erika M. J. Siren
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Deepak Bhere
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Yuka Milton
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Nabeel Nissar
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael De Biasio
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Martina Heinelt
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
| | - Brock Reeve
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Reza Abdi
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Meshael Alturki
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Mohanad Fallatah
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Abdulaziz Almalik
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Ali H. Alhasan
- National Center of Pharmaceutical Technology, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
- KACST Center of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Khalid Shah
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Center for Stem Cell Therapeutics and Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Jeffrey M. Karp
- Center for Nanomedicine and Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Harvard-MIT Division of Health Sciences and Technology, Boston, MA, USA
- BWH Center of Excellence for Biomedicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| |
Collapse
|
|
23
|
Zhao L, Hu C, Han F, Cai F, Wang J, Chen J. Preconditioning is an effective strategy for improving the efficiency of mesenchymal stem cells in kidney transplantation. Stem Cell Res Ther 2020; 11:197. [PMID: 32448356 PMCID: PMC7245776 DOI: 10.1186/s13287-020-01721-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/22/2020] [Accepted: 05/08/2020] [Indexed: 12/13/2022] Open
Abstract
The inevitable side effects caused by lifelong immunosuppressive agents in kidney transplantation patients spurred the exploration of novel immunosuppressive strategies with definite curative effects and minimal adverse effects. Mesenchymal stem cells (MSCs) have become a promising candidate due to their role in modulating the immune system. Encouraging results obtained from experimental models have promoted the translation of this strategy into clinical settings. However, the demonstration of only marginal or transient benefits by several recent clinical controlled studies has made physicians hesitant to adopt the routine utilization of this procedure in clinical settings. Impaired MSC function after infusion in vivo was thought to be the main reason for their limited effects. For this reason, some preconditioning methods were developed. In this review, we aim to outline the current understanding of the preconditioning methods being explored as a strategy to improve the therapeutic effects of MSCs in kidney transplantation and promote its clinical translation.
Collapse
Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Fei Han
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Fanghao Cai
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Junni Wang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. .,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China. .,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
| |
Collapse
|
|
24
|
Kamaldinov T, Erndt-Marino J, Levin M, Kaplan DL, Hahn MS. Assessment of Enrichment of Human Mesenchymal Stem Cells Based on Plasma and Mitochondrial Membrane Potentials. Bioelectricity 2020; 2:21-32. [PMID: 32292894 DOI: 10.1089/bioe.2019.0024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: Human mesenchymal stem cells (hMSCs) are utilized preclinically and clinically as a candidate cell therapy for a wide range of inflammatory and degenerative diseases. Despite promising results in early clinical trials, consistent outcomes with hMSC-based therapies have proven elusive in many of these applications. In this work, we attempt to address this limitation through the design of a stem cell therapy to enrich hMSCs for desired electrical and ionic properties with enhanced stemness and immunomodulatory/regenerative capacity. Materials and Methods: In this study, we sought to develop initial protocols to achieve electrically enriched hMSCs (EE-hMSCs) with distinct electrical states and assess the potential relationship with respect to hMSC state and function. We sorted hMSCs based on fluorescence intensity of tetramethylrhodamine ethyl ester (TMRE) and investigated phenotypic differences between the sorted populations. Results: Subpopulations of EE-hMSCs exhibit differential expression of genes associated with senescence, stemness, immunomodulation, and autophagy. EE-hMSCs with low levels of TMRE, indicative of depolarized membrane potential, have reduced mRNA expression of senescence-associated markers, and increased mRNA expression of autophagy and immunomodulatory markers relative to EE-hMSCs with high levels of TMRE (hyperpolarized). Conclusions : This work suggests that the utilization of EE-hMSCs may provide a novel strategy for cell therapies, enabling live cell enrichment for distinct phenotypes that can be exploited for different therapeutic outcomes.
Collapse
Affiliation(s)
- Timothy Kamaldinov
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York
| | - Josh Erndt-Marino
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York.,Department of Biomedical Engineering, Tufts University, Medford, Massachusetts.,Allen Discovery Center at Tufts University, Department of Biology, Tufts University, Medford, Massachusetts
| | - Michael Levin
- Allen Discovery Center at Tufts University, Department of Biology, Tufts University, Medford, Massachusetts
| | - David L Kaplan
- Department of Biomedical Engineering, Tufts University, Medford, Massachusetts.,Allen Discovery Center at Tufts University, Department of Biology, Tufts University, Medford, Massachusetts
| | - Mariah S Hahn
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York
| |
Collapse
|
|
25
|
Shammaa R, El-Kadiry AEH, Abusarah J, Rafei M. Mesenchymal Stem Cells Beyond Regenerative Medicine. Front Cell Dev Biol 2020; 8:72. [PMID: 32133358 PMCID: PMC7040370 DOI: 10.3389/fcell.2020.00072] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/27/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are competent suitors of cellular therapy due to their therapeutic impact on tissue degeneration and immune-based pathologies. Additionally, their homing and immunomodulatory properties can be exploited in cancer malignancies to transport pharmacological entities, produce anti-neoplastic agents, or induce anti-tumor immunity. Herein, we create a portfolio for MSC properties, showcasing their distinct multiple therapeutic utilities and successes/challenges thereof in both animal studies and clinical trials. We further highlight the promising potential of MSCs not only in cancer management but also in instigating tumor-specific immunity - i.e., cancer vaccination. Finally, we reflect on the possible reasons impeding the clinical advancement of MSC-based cancer vaccines to assist in contriving novel methodologies from which a therapeutic milestone might emanate.
Collapse
Affiliation(s)
- Riam Shammaa
- Canadian Centre for Regenerative Therapy, Toronto, ON, Canada.,IntelliStem Technologies Inc., Toronto, ON, Canada.,Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
| | - Abed El-Hakim El-Kadiry
- Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Montreal, QC, Canada.,Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
| | - Jamilah Abusarah
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Moutih Rafei
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.,Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada.,Molecular Biology Program, Université de Montréal, Montreal, QC, Canada
| |
Collapse
|
|
26
|
Alijani N, Johari B, Moradi M, Kadivar M. A review on transcriptional regulation responses to hypoxia in mesenchymal stem cells. Cell Biol Int 2020; 44:14-26. [PMID: 31393053 DOI: 10.1002/cbin.11211] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 08/03/2019] [Indexed: 01/24/2023]
Abstract
Mesenchymal stem cells (MSCs), which are known for having therapeutic applications, reside in stem cell niches where the oxygen concentration is low. At the molecular level, the master regulator of the cellular reaction to hypoxia is hypoxia-inducible transcription factor (HIF). The transcriptional response of a cell to hypoxia is affected by two major components; first, the structure of hypoxia-response elements (HREs), which primarily define how much of the HIF signal is integrated into the transcriptional output of individual genes. Second, the availability of other transcriptional factors cooperating with HIF in the context of HRE. In MSCs, the expression of a single gene by hypoxia depends on elements such as factors influencing the HIF activity, metabolic pathways, the real oxygen concentration in the cellular microenvironment, and duration of culture. In addition, specific growth factors and pro-infection cytokines, hormones, oncogenic signaling, as well as ultrasound are potent regulators of HIF in MSCs. Altogether, the response of MSCs to hypoxia is complex and mediated by several genes and molecular agents. Regarding the influence of hypoxia on MSCs, oxygen concentration must be taken into consideration based on the cell type and the aim of culture before a particular MSCs culture.
Collapse
Affiliation(s)
- Najva Alijani
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | - Behrooz Johari
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohammad Moradi
- Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Mehdi Kadivar
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| |
Collapse
|
|
27
|
Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol 2019; 65:176-188. [PMID: 31874281 DOI: 10.1016/j.semcancer.2019.12.007] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/03/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.
Collapse
Affiliation(s)
- Sara K Daniel
- University of Washington, Dept. of Surgery, Seattle, WA, USA
| | - Y David Seo
- University of Washington, Dept. of Surgery, Seattle, WA, USA
| | | |
Collapse
|
|
28
|
Vangala G, Imhoff FM, Squires CM, Cridge AG, Baird SK. Mesenchymal stem cell homing towards cancer cells is increased by enzyme activity of cathepsin D. Exp Cell Res 2019; 383:111494. [DOI: 10.1016/j.yexcr.2019.07.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 12/13/2022]
|
|
29
|
Alloreactive T Cells Display a Distinct Chemokine Profile in Response to Conditioning in Xenogeneic GVHD Models. Transplantation 2019; 103:1834-1843. [DOI: 10.1097/tp.0000000000002756] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
30
|
Mesenchymal Stem Cells Exhibit Both a Proinflammatory and Anti-Inflammatory Effect on Saccular Aneurysm Formation in a Rabbit Model. Stem Cells Int 2019; 2019:3618217. [PMID: 31428158 PMCID: PMC6679866 DOI: 10.1155/2019/3618217] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 05/14/2019] [Accepted: 06/11/2019] [Indexed: 12/29/2022] Open
Abstract
Several studies have demonstrated a potential interaction between mesenchymal stem cells (MSCs) and saccular aneurysms. In this study, we sought to determine whether allogenic bone marrow-derived MSCs had the ability to prevent aneurysm formation in a known rabbit elastase aneurysm model. MSCs were injected intravenously in experimental rabbits at the time of surgical creation and two weeks postcreation and compared with control rabbits receiving vehicle injection. Angiography was used to compare aneurysm measurements four weeks postcreation, and aneurysms were harvested for histological properties. Serum was collected longitudinally to evaluate cytokine alterations. Serum from control animals was also utilized to perform in vitro tests with MSCs to compare the effect of the serologic environment in animals with and without aneurysms on MSC proliferation and cytokine production. While aneurysm morphometric comparisons revealed no differences, significant cytokine alterations were observed in vitro and in vivo, suggesting both anti-inflammatory and proinflammatory processes were occurring in the presence of MSCs. Histological analyses suggested that tunica intima hyperplasia was inhibited in the presence of MSCs.
Collapse
|
|
31
|
Abdal Dayem A, Lee SB, Kim K, Lim KM, Jeon TI, Seok J, Cho ASG. Production of Mesenchymal Stem Cells Through Stem Cell Reprogramming. Int J Mol Sci 2019; 20:ijms20081922. [PMID: 31003536 PMCID: PMC6514654 DOI: 10.3390/ijms20081922] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/10/2019] [Accepted: 04/15/2019] [Indexed: 12/26/2022] Open
Abstract
Mesenchymal stem cells (MSCs) possess a broad spectrum of therapeutic applications and have been used in clinical trials. MSCs are mainly retrieved from adult or fetal tissues. However, there are many obstacles with the use of tissue-derived MSCs, such as shortages of tissue sources, difficult and invasive retrieval methods, cell population heterogeneity, low purity, cell senescence, and loss of pluripotency and proliferative capacities over continuous passages. Therefore, other methods to obtain high-quality MSCs need to be developed to overcome the limitations of tissue-derived MSCs. Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are considered potent sources for the derivation of MSCs. PSC-derived MSCs (PSC-MSCs) may surpass tissue-derived MSCs in proliferation capacity, immunomodulatory activity, and in vivo therapeutic applications. In this review, we will discuss basic as well as recent protocols for the production of PSC-MSCs and their in vitro and in vivo therapeutic efficacies. A better understanding of the current advances in the production of PSC-MSCs will inspire scientists to devise more efficient differentiation methods that will be a breakthrough in the clinical application of PSC-MSCs.
Collapse
Affiliation(s)
- Ahmed Abdal Dayem
- Department of Stem Cell & Regenerative Biotechnology, Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Gwangjin-gu, Seoul 05029, Korea.
| | | | | | | | | | | | | |
Collapse
|
|
32
|
Liu J, Lu X, Lou Y, Cai Y, Cui W, Wang J, Nie P, Chen L, Li B, Luo P. Xenogeneic Transplantation of Human Placenta-Derived Mesenchymal Stem Cells Alleviates Renal Injury and Reduces Inflammation in a Mouse Model of Lupus Nephritis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:9370919. [PMID: 30941373 PMCID: PMC6421051 DOI: 10.1155/2019/9370919] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/19/2019] [Accepted: 02/03/2019] [Indexed: 12/12/2022]
Abstract
Human placenta-derived mesenchymal stem cells (pMSCs) are considered a good source for cell therapy. The purpose of this study was to observe whether the transplantation of human pMSCs would affect the treatment of lupus nephritis (LN)-prone MRL/lpr mice. Multiple injections (at the 16th, 18th, and 20th week of age) of 1 × 106 pMSCs were administered. Urine was collected to evaluate proteinuria and urine creatinine levels. Blood was collected for the measurement of serum antinuclear antibody (ANA) and anti-double-stranded DNA (dsDNA) antibody levels. Renal tissues were collected for histological staining and examination by light and electron microscopy quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western Blot. The results confirmed that pMSC treatment reduced the severity of 24-h proteinuria, decreased the production of anti-dsDNA antibodies, and ameliorated renal pathological changes in MRL/lpr mice. Furthermore, pMSCs reduced renal inflammation by inhibiting the expression of nuclear factor kappa B (NF-κB) and then downregulating the expression of tumor necrosis factor-α (TNF-α), intercellular cell adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1). Therefore, our present study demonstrated a protective effect of pMSCs against renal injury and inflammation in MRL/lpr mice.
Collapse
Affiliation(s)
- Juan Liu
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China
| | - Xuehong Lu
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China
| | - Yan Lou
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China
| | - Yong Cai
- School of Life Sciences, Jilin University, Changchun, Jilin Province, 130012, China
| | - Wenpeng Cui
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China
| | - Jing Wang
- Department of Nephropathy, FAW General Hospital (The Fourth Hospital of Jilin University), Changchun, Jilin Province, 130011, China
| | - Ping Nie
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China
| | - Liangmei Chen
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China
| | - Bing Li
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China
| | - Ping Luo
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, 130041, China
| |
Collapse
|
|
33
|
Current Strategies to Generate Human Mesenchymal Stem Cells In Vitro. Stem Cells Int 2018; 2018:6726185. [PMID: 30224922 PMCID: PMC6129345 DOI: 10.1155/2018/6726185] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 07/31/2018] [Accepted: 08/09/2018] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are heterogeneous multipotent stem cells that are involved in the development of mesenchyme-derived evolving structures and organs during ontogeny. In the adult organism, reservoirs of MSCs can be found in almost all tissues where MSCs contribute to the maintenance of organ integrity. The use of these different MSCs for cell-based therapies has been extensively studied over the past years, which highlights the use of MSCs as a promising option for the treatment of various diseases including autoimmune and cardiovascular disorders. However, the proportion of MSCs contained in primary isolates of adult tissue biopsies is rather low and, thus, vigorous ex vivo expansion is needed especially for therapies that may require extensive and repetitive cell substitution. Therefore, more easily and accessible sources of MSCs are needed. This review summarizes the current knowledge of the different strategies to generate human MSCs in vitro as an alternative method for their applications in regenerative therapy.
Collapse
|
|
34
|
Kalimuthu S, Zhu L, Oh JM, Gangadaran P, Lee HW, Baek SH, Rajendran RL, Gopal A, Jeong SY, Lee SW, Lee J, Ahn BC. Migration of mesenchymal stem cells to tumor xenograft models and in vitro drug delivery by doxorubicin. Int J Med Sci 2018; 15:1051-1061. [PMID: 30013447 PMCID: PMC6036160 DOI: 10.7150/ijms.25760] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 06/01/2018] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) show therapeutic effects in various types of diseases. MSCs have been shown to migrate towards inflamed or cancerous tissues, and visualized after sacrificing the animal. MSCs are able to deliver drugs to target cells, and are an ideal candidate for cancer therapy. The purpose of this study was to track the migration of MSCs in tumor-bearing mice; MSCs were also used as drug delivery vehicles. Human breast cancer cells (MDA-MB-231) and anaplastic thyroid cancer cells (CAL62) were transduced with lentiviral particles, to express the Renilla luciferase and mCherry (mCherry-Rluc) reporter genes. Human bone marrow-derived MSCs were transduced with lentiviral particles, to express the firefly luciferase and enhanced green fluorescence protein (Fluc2-eGFP) reporter genes (MSC/Fluc). Luciferase activity of the transduced cells was measured by bioluminescence imaging (BLI). Further in vitro migration assays were performed to confirm cancer cells conditioned medium dependent MSC and doxorubicin (DOX) treated MSC migration. MSCs were loaded with DOX, and their therapeutic effects against the cancer cells were studied in vitro. In vivo MSC/Fluc migration in mice having thyroid or breast cancer xenografts was evaluated after systemic injection. Rluc activity of CAL62/Rluc (R2=0.911), MDA-MB-231/Rluc (R2=0.934) cells and Fluc activity of MSC/Fluc (R2=0.91) cells increased with increasing cell numbers, as seen by BLI. eGFP expression of MSC/Fluc was confirmed by confocal microscopy. Similar migration potential was observed between MSC/Fluc and naïve MSCs in migration assay. DOX treated MSCs migration was not decreased compared than MSCs. Migration of the systemically injected MSC/Fluc cells into tumor xenografts (thyroid and breast cancer) was visualized in animal models (p<0.05) and confirmed by ex vivo (p<0.05) BLI. Additionally, MSCs delivered DOX to CAL62/Rluc and MDA-MB-231/Rluc cells, thereby decreasing their Rluc activities. In this study, we confirmed the migration of MSCs to tumor sites in cancer xenograft models using both in vivo and ex vivo BLI imaging. DOX-pretreated MSCs showed enhanced cytotoxic effects. Therefore, this noninvasive reporter gene (Fluc2)-based BLI may be useful for visualizing in vivo tracking of MSCs, which can be used as a drug delivery vehicle for cancer therapy.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| |
Collapse
|
|
35
|
Zheng XB, He XW, Zhang LJ, Qin HB, Lin XT, Liu XH, Zhou C, Liu HS, Hu T, Cheng HC, He XS, Wu XR, Chen YF, Ke J, Wu XJ, Lan P. Bone marrow-derived CXCR4-overexpressing MSCs display increased homing to intestine and ameliorate colitis-associated tumorigenesis in mice. Gastroenterol Rep (Oxf) 2018; 7:127-138. [PMID: 30976426 PMCID: PMC6454852 DOI: 10.1093/gastro/goy017] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 01/28/2018] [Accepted: 02/08/2018] [Indexed: 12/13/2022] Open
Abstract
Background and Objective Increasing interest has developed in the therapeutic potential of bone marrow-derived mesenchymal stem cells (MSCs) for the treatment of inflammatory bowel disease (IBD) and IBD-induced cancer. However, whether MSCs have the ability to suppress or promote tumor development remains controversial. The stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis is well known to play a critical role in the homing of MSCs. In this study, we aimed to evaluate the role of CXCR4-overexpressing MSCs on the tumorigenesis of IBD. Methods MSCs were transduced with lentiviral vector carrying either CXCR4 or green fluorescent protein (GFP). Chemotaxis and invasion assays were used to detect CXCR4 expression. A mouse model of colitis-associated tumorigenesis was established using azoxymethane and dextran sulfate sodium (DSS). The mice were divided into three groups and then injected with phosphate buffer saline (PBS), MSC-GFP or MSC-CXCR4. Results Compared with the mice injected with MSC-GFP, the mice injected with MSC-CXCR4 showed relieved weight loss, longer colons, lower tumor numbers and decreased tumor load; expression of pro-inflammatory cytokines decreased, and signal transducer and activator of transcription 3 (STAT3) phosphorylation level in colon tissue was down-regulated. Conclusion CXCR4-overexpressing MSCs exhibited effective anti-tumor function, which may be associated with enhanced homing to inflamed intestinal tissues.
Collapse
Affiliation(s)
- Xiao-Bin Zheng
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xiao-Wen He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Long-Juan Zhang
- Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Hua-Bo Qin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xu-Tao Lin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xuan-Hui Liu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Chi Zhou
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Hua-Shan Liu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Tuo Hu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Hai-Chun Cheng
- Department of Gastrointestinal Surgery, Shenzhen Baoan Shajing People's Hospital, Guangzhou Medical University, Shenzhen, Guangdong, P.R. China
| | - Xiao-Sheng He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xian-Rui Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Yu-Feng Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Jia Ke
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Xiao-Jian Wu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| |
Collapse
|
|
36
|
Yabuki H, Wakao S, Kushida Y, Dezawa M, Okada Y. Human Multilineage-differentiating Stress-Enduring Cells Exert Pleiotropic Effects to Ameliorate Acute Lung Ischemia-Reperfusion Injury in a Rat Model. Cell Transplant 2018; 27:979-993. [PMID: 29707971 PMCID: PMC6050908 DOI: 10.1177/0963689718761657] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 01/29/2018] [Indexed: 12/26/2022] Open
Abstract
Posttransplantation lung ischemia-reperfusion (IR) injuries affect both patient survival and graft function. In this study, we evaluated the protective effects of infused human multilineage-differentiating stress-enduring (Muse) cells, a novel, easily harvested type of nontumorigenic endogenous reparative stem cell, against acute IR lung injury in a rat model. After a 2-h warm IR injury induction in a left rat lung, human Muse cells, human mesenchymal stem cells (MSCs), and vehicle were injected via the left pulmonary artery after reperfusion. Functionality, histological findings, and protein expression were subsequently assessed in the injured lung. In vitro, we also compared human Muse cells with human MSCs in terms of migration abilities and the secretory properties of protective substances. The arterial oxygen partial pressure to fractional inspired oxygen ratio, alveolar-arterial oxygen gradient, left lung compliance, and histological injury score on hematoxylin-eosin sections were significantly better in the Muse group relative to the MSC and vehicle groups. Compared to MSCs, human Muse cells homed more efficiently to the injured lung, where they suppressed the apoptosis and stimulated proliferation of host alveolar cells. Human Muse cells also migrated to serum from lung-injured model rats and produced beneficial substances (keratinocyte growth factor [KGF], hepatocyte growth factor, angiopoietin-1, and prostaglandin E2) in vitro. Western blot of lung tissue confirmed high expression of KGF and their target molecules (interleukin-6, protein kinase B, and B-cell lymphoma-2) in the Muse group. Thus, Muse cells efficiently ameliorated lung IR injury via pleiotropic effects in a rat model. These findings support further investigation on the use of human Muse cells for lung IR injury.
Collapse
Affiliation(s)
- Hiroshi Yabuki
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer,
Tohoku University, Sendai, Miyagi, Japan
| | - Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Yoshihiro Kushida
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Mari Dezawa
- Department of Stem Cell Biology and Histology, Tohoku University Graduate
School of Medicine, Sendai, Miyagi, Japan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging and Cancer,
Tohoku University, Sendai, Miyagi, Japan
| |
Collapse
|
|
37
|
Recent formulation approaches to oral delivery of herbal medicines. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2018. [DOI: 10.1007/s40005-018-0394-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
|
|
38
|
Kwon H, Kim M, Seo Y, Moon YS, Lee HJ, Lee K, Lee H. Emergence of synthetic mRNA: In vitro synthesis of mRNA and its applications in regenerative medicine. Biomaterials 2017; 156:172-193. [PMID: 29197748 DOI: 10.1016/j.biomaterials.2017.11.034] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 10/25/2017] [Accepted: 11/21/2017] [Indexed: 12/15/2022]
Abstract
The field of gene therapy has evolved over the past two decades after the first introduction of nucleic acid drugs, such as plasmid DNA (pDNA). With the development of in vitro transcription (IVT) methods, synthetic mRNA has become an emerging class of gene therapy. IVT mRNA has several advantages over conventional pDNA for the expression of target proteins. mRNA does not require nuclear localization to mediate protein translation. The intracellular process for protein expression is much simpler and there is no potential risk of insertion mutagenesis. Having these advantages, the level of protein expression is far enhanced as comparable to that of viral expression systems. This makes IVT mRNA a powerful alternative gene expression system for various applications in regenerative medicine. In this review, we highlight the synthesis and preparation of IVT mRNA and its therapeutic applications. The article includes the design and preparation of IVT mRNA, chemical modification of IVT mRNA, and therapeutic applications of IVT mRNA in cellular reprogramming, stem cell engineering, and protein replacement therapy. Finally, future perspectives and challenges of IVT mRNA are discussed.
Collapse
Affiliation(s)
- Hyokyoung Kwon
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Minjeong Kim
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yunmi Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yae Seul Moon
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Hwa Jeong Lee
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Kyuri Lee
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
| | - Hyukjin Lee
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
| |
Collapse
|
|
39
|
Naguib E, Kamel A, Fekry O, Abdelfattah G. Comparative study on the effect of low intensity laser and growth factors on stem cells used in experimentally-induced liver fibrosis in mice. Arab J Gastroenterol 2017. [PMID: 28625529 DOI: 10.1016/j.ajg.2017.05.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND STUDY AIMS The therapeutic effects of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) exposed to diode laser and/or hepatocyte growth factor (HGF) were compared in mice with experimental liver fibrosis induced by carbon tetra chloride (CCl4). MATERIAL AND METHODS Animal model of liver cirrhosis was induced by intraperitoneal injection of CCl4 in a dose of 0.4ml/kg, twice a week for 6weeks. UC-MSCs were obtained from normal full term placentas and were exposed to diode laser and/or HGF. Before treatment, UC-MSCs were labelled with red fluorescent PKH26. Fifty four male mice weighing 25-35g were randomly divided into four groups control, stem cells, CCl4, and treated groups. After the experimental period, body and liver weights were recorded, and the liver specimens were processed for histological examination using haematoxylin and eosin, Periodic Acid-Schiff (PAS), and Masson's Trichrome staining (MT). RESULTS Results showed that administration of UC-MSCs stimulated by diode laser and/or HGF improved body and liver weights, reduced vascular dilatation and congestion, reduced mononuclear cellular infiltration, reduced hepatocyte vacuolation, eosinophilia, and pyknosis. Furthermore, periportal fibrosis was minimized and PAS reaction was increased. These effects were maximum when UC-MSCs were exposed to both diode laser and HGF. CONCLUSION UC-MSCs stimulated by both diode laser and HGF proved to be an effective therapeutic option in experimental liver fibrosis induced by CCl4 in mice.
Collapse
Affiliation(s)
- Eman Naguib
- Department of Laser Sciences and Interactions, National Institute of Laser and Enhanced Sciences, Cairo University, Cairo, Egypt.
| | - Ashraf Kamel
- Department of Histology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Osama Fekry
- Department of Medical Laser Applications, National Institute of Laser and Enhanced Sciences, Cairo University, Cairo, Egypt
| | - Gamal Abdelfattah
- Department of Laser Sciences and Interactions, National Institute of Laser and Enhanced Sciences, Cairo University, Cairo, Egypt
| |
Collapse
|
|
40
|
Steens J, Zuk M, Benchellal M, Bornemann L, Teichweyde N, Hess J, Unger K, Görgens A, Klump H, Klein D. In Vitro Generation of Vascular Wall-Resident Multipotent Stem Cells of Mesenchymal Nature from Murine Induced Pluripotent Stem Cells. Stem Cell Reports 2017; 8:919-932. [PMID: 28366456 PMCID: PMC5390238 DOI: 10.1016/j.stemcr.2017.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Revised: 03/05/2017] [Accepted: 03/06/2017] [Indexed: 02/06/2023] Open
Abstract
The vascular wall (VW) serves as a niche for mesenchymal stem cells (MSCs). In general, tissue-specific stem cells differentiate mainly to the tissue type from which they derive, indicating that there is a certain code or priming within the cells as determined by the tissue of origin. Here we report the in vitro generation of VW-typical MSCs from induced pluripotent stem cells (iPSCs), based on a VW-MSC-specific gene code. Using a lentiviral vector expressing the so-called Yamanaka factors, we reprogrammed tail dermal fibroblasts from transgenic mice containing the GFP gene integrated into the Nestin-locus (NEST-iPSCs) to facilitate lineage tracing after subsequent MSC differentiation. A lentiviral vector expressing a small set of recently identified human VW-MSC-specific HOX genes then induced MSC differentiation. This direct programming approach successfully mediated the generation of VW-typical MSCs with classical MSC characteristics, both in vitro and in vivo.
In vitro generation of (VW)-typical MSCs from iPSCs based on a specific HOX code Reprogrammed fibroblasts (NEST-iPSCs) facilitated lineage tracing A lentiviral vector expressing HOXB7, HOXC6, and HOXC8 induced MSC differentiation Generated VW-MSCs showed classical MSC characteristics in vitro and in vivo
Collapse
Affiliation(s)
- Jennifer Steens
- Institute of Cell Biology (Cancer Research), University Hospital Essen, Medical Faculty, University of Duisburg-Essen, 45122 Essen, Germany
| | - Melanie Zuk
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Mohamed Benchellal
- Institute of Cell Biology (Cancer Research), University Hospital Essen, Medical Faculty, University of Duisburg-Essen, 45122 Essen, Germany
| | - Lea Bornemann
- Institute of Cell Biology (Cancer Research), University Hospital Essen, Medical Faculty, University of Duisburg-Essen, 45122 Essen, Germany
| | - Nadine Teichweyde
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Julia Hess
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
| | - Kristian Unger
- Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
| | - André Görgens
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Hannes Klump
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Diana Klein
- Institute of Cell Biology (Cancer Research), University Hospital Essen, Medical Faculty, University of Duisburg-Essen, 45122 Essen, Germany.
| |
Collapse
|
|
41
|
Atesok K, Fu FH, Sekiya I, Stolzing A, Ochi M, Rodeo SA. Stem cells in degenerative orthopaedic pathologies: effects of aging on therapeutic potential. Knee Surg Sports Traumatol Arthrosc 2017; 25:626-636. [PMID: 26298714 DOI: 10.1007/s00167-015-3763-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 08/13/2015] [Indexed: 02/06/2023]
Abstract
PURPOSE The purpose of this study was to summarize the current evidence on the use of stem cells in the elderly population with degenerative orthopaedic pathologies and to highlight the pathophysiologic mechanisms behind today's therapeutic challenges in stem cell-based regeneration of destructed tissues in the elderly patients with osteoarthritis (OA), degenerative disc disease (DDD), and tendinopathies. METHODS Clinical and basic science studies that report the use of stem cells in the elderly patients with OA, DDD, and tendinopathies were identified using a PubMed search. The studies published in English have been assessed, and the best and most recent evidence was included in the current study. RESULTS Evidence suggests that, although short-term results regarding the effects of stem cell therapy in degenerative orthopaedic pathologies can be promising, stem cell therapies do not appear to reverse age-related tissue degeneration. Causes of suboptimal outcomes can be attributed to the decrease in the therapeutic potential of aged stem cell populations and the regenerative capacity of these cells, which might be negatively influenced in an aged microenvironment within the degenerated tissues of elderly patients with OA, DDD, and tendinopathies. CONCLUSIONS Clinical protocols guiding the use of stem cells in the elderly patient population are still under development, and high-level randomized controlled trials with long-term outcomes are lacking. Understanding the consequences of age-related changes in stem cell function and responsiveness of the in vivo microenvironment to stem cells is critical when designing cell-based therapies for elderly patients with degenerative orthopaedic pathologies.
Collapse
Affiliation(s)
- Kivanc Atesok
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 3471 Fifth Avenue, Suite 1011, Pittsburgh, PA, 15213, USA.
| | - Freddie H Fu
- Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 3471 Fifth Avenue, Suite 1011, Pittsburgh, PA, 15213, USA
| | - Ichiro Sekiya
- Department of Cartilage Regeneration, Tokyo Medical and Dental University, Tokyo, Japan
| | - Alexandra Stolzing
- Center for Biological Engineering, Wolfson School, Loughborough University, Loughborough, UK.,Translational Center for Regenerative Medicine (TRM), University Leipzig, Leipzig, Germany
| | - Mitsuo Ochi
- Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Scott A Rodeo
- Sports Medicine and Shoulder Service, Hospital for Special Surgery, New York, NY, USA
| |
Collapse
|
|
42
|
Emerging role of mesenchymal stem cells during tuberculosis: The fifth element in cell mediated immunity. Tuberculosis (Edinb) 2016; 101S:S45-S52. [DOI: 10.1016/j.tube.2016.09.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
43
|
Li W, Ding Q, Ding Y, Lu L, Wang X, Zhang Y, Zhang X, Guo Q, Zhao L. Oroxylin A reverses the drug resistance of chronic myelogenous leukemia cells to imatinib through CXCL12/CXCR7 axis in bone marrow microenvironment. Mol Carcinog 2016; 56:863-876. [PMID: 27533597 DOI: 10.1002/mc.22540] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 07/11/2016] [Accepted: 08/15/2016] [Indexed: 01/27/2023]
Abstract
Imatinib (IM), a tyrosine-kinase inhibitor, is used in treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+ ) chronic myelogenous leukemia (CML). However, the majority of patients continue to present with minimal residual disease occurred in the bone marrow (BM) microenvironment. One of the key factors that contribute to leukemia cell drug resistance is chemokine CXCL12. In the current study, co-culturing CML cell K562 and KU812 with BM stromal cell M2-10B4 attenuated IM-induced apoptosis. CXCL12/CXCR7 pathway was activated in co-culture models, which was further proved to be related to drug resistance by silencing CXCR7. ERK phosphorylation and downstream apoptosis related proteins' activation were also observed in co-culture group after the activation of CXCR7. Moreover, oroxylin A, a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi, was found to be effective in reversing BM stroma induced CML resistance to IM. After cells were treated with weakly toxic concentration of oroxylin A, cell apoptosis induced by IM in co-culture model was enhanced. And the activated CXCL12/CXCR7 pathway, the expression of p-ERK and downstream apoptosis related proteins were suppressed. The in vivo study also showed that oroxylin A increased apoptosis of CML cells with low systemic toxicity, and the mechanism was consistent with the in vitro study. In conclusion, oroxylin A improved sensitivity of CML cells to IM treatment in BM microenvironment through regulating CXCL12/CXCR7 pathway. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Wenjun Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Qilong Ding
- Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Youxiang Ding
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Lu Lu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Xiaoping Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yi Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Xiaobo Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Qinglong Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Li Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, People's Republic of China
| |
Collapse
|
|
44
|
Rath D, Schaeffeler E, Winter S, Hewer J, Müller K, Droppa M, Stimpfle F, Gawaz M, Schwab M, Geisler T. SDF1 Polymorphisms Influence Outcome in Patients with Symptomatic Cardiovascular Disease. PLoS One 2016; 11:e0161933. [PMID: 27607427 PMCID: PMC5015912 DOI: 10.1371/journal.pone.0161933] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 08/14/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND SDF1 and its cognate receptors CXCR4 and CXCR7 are involved in myocardial repair and are associated with outcome in cardiovascular patients. Hence, we aimed to investigate clinically significant SDF1 SNPs for their prognostic impact in patients with cardiovascular disease. METHODS AND RESULTS Genotyping for selected SDF1 variants (rs1065297, rs2839693, rs1801157, rs266087, rs266085 and rs266089 was performed in patients (n = 872) who underwent percutaneous coronary intervention. Carriers of variant rs2839693 and rs266089 showed significantly higher cumulative event-free survival compared with non-carriers. All other polymorphisms had no relevant influence on outcome. Multivariate Cox regression analysis showed a significant correlation of these SNPs with cardiovascular outcome after inclusion of clinical and prognostic relevant variables (hazard ratio (HR) 0.51 (95% CI 0.30-0.88), p = 0.015 and [HR 0.51 (95% CI 0.30-0.88), p = 0.016, respectively). In addition, multivariate Cox regression with SDF1 haplotypes revealed a significantly reduced risk for the haplotype carrying the minor alleles of rs2839693 and rs266089 (HR 0.47 (95% CI 0.27-0.84), p = 0.011). CONCLUSION Distinct SDF1 polymorphisms are associated with improved cardiovascular prognosis in CAD patients. Further studies are warranted to validate these results and to better describe the endogenous regeneration potential in carriers of these SNPs. Targeted, genotype guided therapeutic approaches to foster myocardial regeneration and thus cardiovascular prognosis should be evaluated in future.
Collapse
Affiliation(s)
- Dominik Rath
- Department of Cardiology, University Hospital Tuebingen, Otfried-Mueller-Straße 10, Tuebingen, Germany
| | - Elke Schaeffeler
- Dr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, Germany
| | - Stefan Winter
- Dr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, Germany
| | - Jens Hewer
- Department of Cardiology, University Hospital Tuebingen, Otfried-Mueller-Straße 10, Tuebingen, Germany
| | - Karin Müller
- Department of Cardiology, University Hospital Tuebingen, Otfried-Mueller-Straße 10, Tuebingen, Germany
| | - Michal Droppa
- Department of Cardiology, University Hospital Tuebingen, Otfried-Mueller-Straße 10, Tuebingen, Germany
| | - Fabian Stimpfle
- Department of Cardiology, University Hospital Tuebingen, Otfried-Mueller-Straße 10, Tuebingen, Germany
| | - Meinrad Gawaz
- Department of Cardiology, University Hospital Tuebingen, Otfried-Mueller-Straße 10, Tuebingen, Germany
| | - Matthias Schwab
- Dr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, Germany
- Department of Clinical Pharmacology, University Hospital Tuebingen, Auf der Morgenstelle 8, Tuebingen, Germany
| | - Tobias Geisler
- Department of Cardiology, University Hospital Tuebingen, Otfried-Mueller-Straße 10, Tuebingen, Germany
| |
Collapse
|
|
45
|
Wang M, Liang C, Hu H, Zhou L, Xu B, Wang X, Han Y, Nie Y, Jia S, Liang J, Wu K. Intraperitoneal injection (IP), Intravenous injection (IV) or anal injection (AI)? Best way for mesenchymal stem cells transplantation for colitis. Sci Rep 2016; 6:30696. [PMID: 27488951 PMCID: PMC4973258 DOI: 10.1038/srep30696] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 07/06/2016] [Indexed: 12/13/2022] Open
Abstract
Stem cell transplantation showed promising results in IBD management. However, the therapeutic impacts of cell delivery route that is critical for clinical translation are currently poorly understood. Here, three different MSCs delivery routes: intraperitoneal (IP), intravenous (IV), and anal injection (AI) were compared on DSS-induced colitic mice model. The overall therapeutic factors, MSCs migration and targeting as well as local immunomodulatory cytokines and FoxP3+ cells infiltration were analyzed. Colitis showed varying degrees of alleviation after three ways of MSCs transplantation, and the IP injection showed the highest survival rate of 87.5% and displayed the less weight loss and quick weight gain. The fecal occult blood test on the day 3 also showed nearly complete absence of occult blood in IP group. The fluorescence imaging disclosed higher intensity of engrafted cells in inflamed colon and the corresponding mesentery lymph nodes (MLNs) in IP and AI groups than the IV group. Real time-PCR and ELISA also demonstrate lower TNF-α and higher IL-10, TSG-6 levels in IP group. The immunohistochemistry indicated higher repair proliferation (Ki-67) and more FoxP3+ cells accumulation of IP group. IP showed better colitis recovery and might be the optimum MSCs delivery route for the treatment of DSS-induced colitis.
Collapse
Affiliation(s)
- Min Wang
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.,Department of Gastroenterology, Xi'an Children's Hospital, 710006, China
| | - Cong Liang
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.,Department of Respiratory and Gastroenterology, Second People's Hospital, Xi'an, 710005, China
| | - Hao Hu
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.,Department of Gastroenterology, PLA No.5 Hospital, Yinchuan, 750004, China
| | - Lin Zhou
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Bing Xu
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Xin Wang
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Ying Han
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Shuyun Jia
- Department of Gastroenterology, PLA No.5 Hospital, Yinchuan, 750004, China
| | - Jie Liang
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| |
Collapse
|
|
46
|
Rath D, Chatterjee M, Bongartz A, Müller K, Droppa M, Stimpfle F, Borst O, Zuern C, Vogel S, Gawaz M, Geisler T. Platelet surface expression of SDF-1 is associated with clinical outcomes in the patients with cardiovascular disease. Platelets 2016; 28:34-39. [PMID: 27463607 DOI: 10.1080/09537104.2016.1203399] [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] [Indexed: 01/03/2023]
Abstract
Platelet surface expression levels of stromal cell derived factor 1 (SDF-1) are elevated in acute coronary syndrome and associated with LVEF% improvement after myocardial infarction (MI). Platelet SDF-1 might facilitate thrombus formation and endomyocardial expression of SDF-1 is enhanced in inflammatory cardiomyopathy and positively correlates with myocardial fibrosis. The influence of platelet SDF-1 on outcome in the patients with symptomatic coronary artery disease (CAD) is to the best of our knowledge unknown. Blood samples of 608 consecutive CAD patients were collected during the percutaneous coronary intervention and analyzed for surface expression of SDF-1 by flow cytometry. The primary combined endpoint was defined as the composite of either MI, or ischemic stroke, or all-cause death. Secondary endpoints were defined as the aforementioned single events. The patients with baseline platelet SDF-1 levels above the third quartile showed a significantly worse cumulative event-free survival when compared to the patients with lower baseline SDF-1 levels (first to third quartile) (log rank 0.009 for primary combined endpoint and log rank 0.016 for secondary endpoint all-cause death). Multivariate Cox regression analysis showed that SDF-1 levels above the third quartile were independently associated with the primary combined endpoint and the secondary endpoint all-cause death. We provide first clinical evidence that high platelet expression levels of SDF-1 influence clinical outcomes in CAD patients in a negative way.
Collapse
Affiliation(s)
- Dominik Rath
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Madhumita Chatterjee
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Angela Bongartz
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Karin Müller
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Michal Droppa
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Fabian Stimpfle
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Oliver Borst
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Christine Zuern
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Sebastian Vogel
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Meinrad Gawaz
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| | - Tobias Geisler
- a Medizinische Klinik III, Kardiologie und Kreislauferkrankungen , University Tübingen , Tübingen , Germany
| |
Collapse
|
|
47
|
Systemic and Local Administration of Antimicrobial and Cell Therapies to Prevent Methicillin-Resistant Staphylococcus epidermidis-Induced Femoral Nonunions in a Rat Model. Mediators Inflamm 2016; 2016:9595706. [PMID: 27478310 PMCID: PMC4961811 DOI: 10.1155/2016/9595706] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 06/06/2016] [Accepted: 06/08/2016] [Indexed: 12/27/2022] Open
Abstract
S. epidermidis is responsible for biofilm-related nonunions. This study compares the response to S. epidermidis-infected fractures in rats systemically or locally injected with vancomycin or bone marrow mesenchymal stem cells (BMSCs) in preventing the nonunion establishment. The 50% of rats receiving BMSCs intravenously (s-rBMSCs) died after treatment. A higher cytokine trend was measured in BMSCs locally injected rats (l-rBMSCs) at day 3 and in vancomycin systemically injected rats (l-VANC) at day 7 compared to the other groups. At day 14, the highest cytokine values were measured in l-VANC and in l-rBMSCs for IL-10. µCT showed a good bony bridging in s-VANC and excellent both in l-VANC and in l-rBMSCs. The bacterial growth was lower in s-VANC and l-VANC than in l-rBMSCs. Histology demonstrated the presence of new woven bone in s-VANC and a more mature bony bridging was found in l-VANC. The l-rBMSCs showed a poor bony bridging of fibrovascular tissue. Our results could suggest the synergic use of systemic and local injection of vancomycin as an effective treatment to prevent septic nonunions. This study cannot sustain the systemic injection of BMSCs due to high risks, while a deeper insight into local BMSCs immunomodulatory effects is mandatory before developing cell therapies in clinics.
Collapse
|
|
48
|
Leovsky C, Fabian C, Naaldijk Y, Jäger C, Jang HJ, Böhme J, Rudolph L, Stolzing A. Biodistribution of in vitro-derived microglia applied intranasally and intravenously to mice: effects of aging. Cytotherapy 2016; 17:1617-26. [PMID: 26432561 DOI: 10.1016/j.jcyt.2015.07.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 07/13/2015] [Accepted: 07/30/2015] [Indexed: 12/28/2022]
Abstract
BACKGROUND AIMS The age of both the donor and the recipient has a potential influence on the efficacy of various cell therapies, but the underlying mechanisms are still being charted. We studied the effect of donor and recipient age in the context of microglia migration. METHODS Microglia were in vitro--differentiated from bone marrow of young (3 months) and aged (12 months) mice and transplanted into young (∼ 3 months) and aged (∼ 17 months) C57BL/6 mice (n = 25) through intravenous and intranasal application routes. Recipients were not immune-suppressed or irradiated. Transplanted microglia were tracked through the use of a sex-mismatched setup or histologically with the use of cells from enhanced green fluorescent protein enhanced green fluorescent protein transgenic mice. RESULTS No acute rejections or transplant-associated toxicity was observed. After 10 days, both intravenously and intranasally transplanted cells were detected in the brain. Transplanted cells were also found in the blood and the lymph system. The applied cells were also tracked in lungs and kidney but only after intravenous injection subjected to a "pulmonary first-pass effect." After 28 days, intravenously delivered cells were also found in the bone marrow and other organs, especially in aged recipients. Whereas in young recipients the transplanted microglia did not appear to persist, in aged brains the transplanted cells could still be identified up to 28 days after transplantation. However, when cells from aged donors were used, no signals of transplanted cells could be detected in the recipients. CONCLUSIONS This study establishes proof of principle that in vitro--derived microglia from young but not from aged donors, intravenously or intranasally transplanted, migrate to the brain in young and aged recipients.
Collapse
Affiliation(s)
| | - Claire Fabian
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany
| | - Yahaira Naaldijk
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany
| | - Carsten Jäger
- Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany
| | - Hwa Jin Jang
- Korea Ministry of Food and Drug Safety (MFDS), Hangul, Korea
| | - Josephine Böhme
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Lukas Rudolph
- Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany
| | - Alexandra Stolzing
- Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany; University of Loughborough, Centre for Biological Engineering, Wolfson School of Material and Manufacturing Engineering, Loughborough, United Kingdom.
| |
Collapse
|
|
49
|
Naderi-Meshkin H, Matin MM, Heirani-Tabasi A, Mirahmadi M, Irfan-Maqsood M, Edalatmanesh MA, Shahriyari M, Ahmadiankia N, Moussavi NS, Bidkhori HR, Bahrami AR. Injectable hydrogel delivery plus preconditioning of mesenchymal stem cells: exploitation of SDF-1/CXCR4 axis toward enhancing the efficacy of stem cells' homing. Cell Biol Int 2016; 40:730-41. [PMID: 25825165 DOI: 10.1002/cbin.10474] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Accepted: 02/16/2015] [Indexed: 12/13/2022]
Abstract
Clinical applications of mesenchymal stem cells (MSCs) rely on their capacity to home and engraft in the appropriate target injury tissues for the long term. However, their homing efficiency has been observed to be very poor because of the lack or modifications of homing factors SDF-1α and CXCR4 receptors. Hence, this study was designed to investigate the homing and retention of pretreated human adipose tissue-derived MSCs (hASCs) from three different delivery routes in response to SDF-1α, released from chitosan-based injectable hydrogels. After stimulation of ASCs with a hypoxia mimicking agent, the expression level and functionality of CXCR4 were analyzed by flowcytometric analysis (FACS), transwell migration assay and qPCR. Then, the homing/retention of pretreated DiI-labeled hASCs were compared through three different in vivo delivery routes, 2 weeks after transplantation in Wistar rats. The cells were tracked histologically by fluorescent microscope and by PCR for human-specific CXCR4 gene. Results showed CXCR4 has dynamic expression pattern and pretreatment of hASCs significantly up-regulates CXCR4, leading to an increase in migration capacity toward 100 ng/mL SDF-1α in vitro and homing into the subcutaneously implanted hydrogel releasing SDF-1α in vivo. Furthermore, it seems that SDF-1α is particularly important in the retention of ASCs, in addition to its chemoattraction role. In summary, the delivery route in which the ASCs were mixed with the hydrogel rather than systemic delivery and local injection and preconditioning undertaken to increase CXCR4 expression concomitant with SDF-1α delivery by the injectable hydrogel, allowed for further homing/retention of ASCs. This might be a promising way to get better therapeutic outcomes in stem cell therapy.
Collapse
Affiliation(s)
- Hojjat Naderi-Meshkin
- Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.,Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Maryam M Matin
- Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran.,Cell and Molecular Biotechnology Research Department, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Asieh Heirani-Tabasi
- Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.,Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mahdi Mirahmadi
- Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran
| | - Muhammad Irfan-Maqsood
- Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.,Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran
| | | | - Mina Shahriyari
- Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran
| | | | - Nasser Sanjar Moussavi
- Department of Surgery, Faculty of Medicine, Islamic Azad University-Mashhad Branch, Mashhad, Iran
| | - Hamid Reza Bidkhori
- Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran
| | - Ahmad Reza Bahrami
- Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.,Cell and Molecular Biotechnology Research Department, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| |
Collapse
|
|
50
|
De Becker A, Riet IV. Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy? World J Stem Cells 2016; 8:73-87. [PMID: 27022438 PMCID: PMC4807311 DOI: 10.4252/wjsc.v8.i3.73] [Citation(s) in RCA: 351] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 12/24/2015] [Accepted: 01/29/2016] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are currently being investigated for use in a wide variety of clinical applications. For most of these applications, systemic delivery of the cells is preferred. However, this requires the homing and migration of MSCs to a target tissue. Although MSC homing has been described, this process does not appear to be highly efficacious because only a few cells reach the target tissue and remain there after systemic administration. This has been ascribed to low expression levels of homing molecules, the loss of expression of such molecules during expansion, and the heterogeneity of MSCs in cultures and MSC culture protocols. To overcome these limitations, different methods to improve the homing capacity of MSCs have been examined. Here, we review the current understanding of MSC homing, with a particular focus on homing to bone marrow. In addition, we summarize the strategies that have been developed to improve this process. A better understanding of MSC biology, MSC migration and homing mechanisms will allow us to prepare MSCs with optimal homing capacities. The efficacy of therapeutic applications is dependent on efficient delivery of the cells and can, therefore, only benefit from better insights into the homing mechanisms.
Collapse
|