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1
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Zhuo H, Chen Y, Zhao G. Advances in application of hypoxia-preconditioned mesenchymal stem cell-derived exosomes. Front Cell Dev Biol 2024; 12:1446050. [PMID: 39239560 PMCID: PMC11375678 DOI: 10.3389/fcell.2024.1446050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/12/2024] [Indexed: 09/07/2024] Open
Abstract
Mesenchymal stem cells (MSCs) primarily secrete physiologically functional exosomes via paracrine effects that act on various adjacent and distant cells, thus exerting their therapeutic effects. In recent years, hypoxic preconditioning, as a novel MSC culture mode, has emerged as a research hotspot. Many previous studies have shown the role and underlying regulatory mechanisms of hypoxic preconditioning in various diseases, which has provided sufficient reference materials for the MSC research field. Therefore, this review summarizes the progress in application of hypoxia-preconditioned MSC-derived exosomes that substantially increases and improves the biological activity of specific molecules, such as microRNA.
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Affiliation(s)
- Haitao Zhuo
- The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, China
| | - Yunfei Chen
- Department of Nuroscience, Mayo Clinic, Jacksonville, FL, United States
| | - Guifang Zhao
- Department of Pathology, Jilin Medical University, Jilin, China
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2
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McGuirk JP, Metheny L, Pineiro L, Litzow M, Rowley SD, Avni B, Tamari R, Lazarus HM, Rowe JM, Sheleg M, Rothenstein D, Halevy N, Zuckerman T. Placental expanded mesenchymal-like cells (PLX-R18) for poor graft function after hematopoietic cell transplantation: A phase I study. Bone Marrow Transplant 2023; 58:1189-1196. [PMID: 37553467 PMCID: PMC10622312 DOI: 10.1038/s41409-023-02068-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 07/12/2023] [Accepted: 07/21/2023] [Indexed: 08/10/2023]
Abstract
Persistent cytopenia in the post-hematopoietic cell transplantation (HCT) setting can occur despite adequate engraftment of donor cells. PLX-R18, a placental-derived mesenchymal-like cell product, is expanded ex vivo in a 3-dimensional environment. PLX-R18 cells secrete a large array of hematopoietic factors, which promote regeneration, maturation, and differentiation of hematopoietic cells and stimulate their migration to peripheral blood. This phase 1, first-in-human study (NCT03002519), included 21 patients with incomplete hematopoietic recovery post-HCT. Patients were treated with escalating doses of PLX-R18: 3 patients received 1 million cells/kg, 6 received 2 million cells/kg, and 12 received 4 million cells/kg via multiple intramuscular injections. While patients received only two administrations of cells during the first week, peripheral blood counts continued to increase for months, peaking at 6 months for hemoglobin (Hb, p = 0.002), lymphocytes (p = 0.008), and neutrophils (ANC, p = 0.063), and at 9 months for platelets (p < 0.001) and was maintained until 12 months for all but ANC. The need for platelet transfusions was reduced from 5.09 units/month at baseline to 0.55 at month 12 (p = 0.05). Likewise, red blood cell transfusions decreased from 2.91 units/month at baseline to 0 at month 12 (p = 0.0005). PLX-R18 was safe and well tolerated and shows promise in improving incomplete hematopoietic recovery post-HCT.
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Affiliation(s)
- Joseph P McGuirk
- Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Leland Metheny
- Case Western Reserve University, Cleveland, OH, USA
- University Hospitals Seidman Cancer Center, Cleveland, OH, USA
| | - Luis Pineiro
- Apheresis and Marrow Processing Laboratories, Baylor University Medical Center, Dallas, TX, USA
| | - Mark Litzow
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Scott D Rowley
- Stem Cell Transplantation and Cellular Therapy Program, John Theurer Cancer Center, Hackensack, NJ, USA
| | - Batia Avni
- Hadassah University Medical Center, Jerusalem, Israel
| | - Roni Tamari
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hillard M Lazarus
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jacob M Rowe
- Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
| | | | | | | | - Tsila Zuckerman
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
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Huang H, Liu X, Wang J, Suo M, Zhang J, Sun T, Zhang W, Li Z. Umbilical cord mesenchymal stem cells for regenerative treatment of intervertebral disc degeneration. Front Cell Dev Biol 2023; 11:1215698. [PMID: 37601097 PMCID: PMC10439242 DOI: 10.3389/fcell.2023.1215698] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 07/27/2023] [Indexed: 08/22/2023] Open
Abstract
Intervertebral disc degeneration is thought to be a major contributor to low back pain, the etiology of which is complex and not yet fully understood. To compensate for the lack of drug and surgical treatment, mesenchymal stem cells have been proposed for regenerative treatment of intervertebral discs in recent years, and encouraging results have been achieved in related trials. Mesenchymal stem cells can be derived from different parts of the body, among which mesenchymal stem cells isolated from the fetal umbilical cord have excellent performance in terms of difficulty of acquisition, differentiation potential, immunogenicity and ethical risk. This makes it possible for umbilical cord derived mesenchymal stem cells to replace the most widely used bone marrow-derived and adipose tissue derived mesenchymal stem cells as the first choice for regenerating intervertebral discs. However, the survival of umbilical cord mesenchymal stem cells within the intervertebral disc is a major factor affecting their regenerative capacity. In recent years biomaterial scaffolds in tissue engineering have aided the survival of umbilical cord mesenchymal stem cells by mimicking the natural extracellular matrix. This seems to provide a new idea for the application of umbilical cord mesenchymal stem cells. This article reviews the structure of the intervertebral disc, disc degeneration, and the strengths and weaknesses of common treatment methods. We focus on the cell source, cell characteristics, mechanism of action and related experiments to summarize the umbilical cord mesenchymal stem cells and explore the feasibility of tissue engineering technology of umbilical cord mesenchymal stem cells. Hoping to provide new ideas for the treatment of disc degeneration.
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Affiliation(s)
- Huagui Huang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xin Liu
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinzuo Wang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Moran Suo
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jing Zhang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Tianze Sun
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Wentao Zhang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhonghai Li
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian, Liaoning, China
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4
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Chetty S, Yarani R, Swaminathan G, Primavera R, Regmi S, Rai S, Zhong J, Ganguly A, Thakor AS. Umbilical cord mesenchymal stromal cells-from bench to bedside. Front Cell Dev Biol 2022; 10:1006295. [PMID: 36313578 PMCID: PMC9597686 DOI: 10.3389/fcell.2022.1006295] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/27/2022] [Indexed: 11/27/2022] Open
Abstract
In recent years, mesenchymal stromal cells (MSCs) have generated a lot of attention due to their paracrine and immuno-modulatory properties. mesenchymal stromal cells derived from the umbilical cord (UC) are becoming increasingly recognized as having increased therapeutic potential when compared to mesenchymal stromal cells from other sources. The purpose of this review is to provide an overview of the various compartments of umbilical cord tissue from which mesenchymal stromal cells can be isolated, the differences and similarities with respect to their regenerative and immuno-modulatory properties, as well as the single cell transcriptomic profiles of in vitro expanded and freshly isolated umbilical cord-mesenchymal stromal cells. In addition, we discuss the therapeutic potential and biodistribution of umbilical cord-mesenchymal stromal cells following systemic administration while providing an overview of pre-clinical and clinical trials involving umbilical cord-mesenchymal stromal cells and their associated secretome and extracellular vesicles (EVs). The clinical applications of umbilical cord-mesenchymal stromal cells are also discussed, especially in relation to obstacles and potential solutions for their effective translation from bench to bedside.
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Affiliation(s)
- Shashank Chetty
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Reza Yarani
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
- Translational Type 1 Diabetes Research, Department of Clinical, Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Ganesh Swaminathan
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Rosita Primavera
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Shobha Regmi
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Sravanthi Rai
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Jim Zhong
- Department of Diagnostic and Interventional Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Abantika Ganguly
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
| | - Avnesh S Thakor
- Interventional Radiology Innovation at Stanford (IRIS), Stanford University, Department of Radiology, Palo Alto, CA, United States
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Akashi M, Maekawa K. Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident. JOURNAL OF RADIOLOGICAL PROTECTION : OFFICIAL JOURNAL OF THE SOCIETY FOR RADIOLOGICAL PROTECTION 2021; 41:S391-S405. [PMID: 34525457 DOI: 10.1088/1361-6498/ac270d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 09/15/2021] [Indexed: 06/13/2023]
Abstract
A criticality accident occurred at the uranium conversion plant in Tokaimura, Ibaraki Prefecture, Japan on 30 September 1999. When uranyl nitrate was overloaded to a critical mass level, uncontrolled fission reaction occurred. A procedure was carried out according to the JCO manual, although not an officially approved manual. Three workers were heavily exposed to neutrons andγ-rays produced by nuclear fission, and they subsequently developed acute radiation syndrome (ARS). The average doses to the whole body of the three workers were approximately 25, 9, and 3 GyEq (biologically equivalent dose ofγ-exposure), respectively; dose distribution analysis later revealed extreme heterogeneity of these doses in two workers. They were triaged according to the predicted clinical needs. Two of these workers developed severe bone marrow failure and received haematopoietic stem cell transplantation: one with peripheral stem cell transplantation from his Human Leukocyte Antigen compatible sister and the other with umbilical cord blood transplantation. The graft was initially successful in both workers; autologous haematopoietic recovery was observed after donor/recipient mixed chimerism in one of them. Despite of all medical efforts available including haematopoietic stem cell transplantation, investigational drugs, skin graft, two workers died of multiple organ involvement and failure 83 and 211 days after the accident, respectively. Clinically as well as pathologically, the direct cause of death was deemed to be intractable gastrointestinal (GI) bleeding in one, and thoraco-abdominal compartment syndrome due to dermal fibrosis/sclerosis in the other. The third worker also developed bone marrow suppression but was treated with granulocyte colony-stimulating factor. He recovered without major complications and is now under periodical medical follow-up. These experiences suggest that treatment of bone marrow is not a limiting factor for saving the life of ARS victims severely exposed. Successful treatment of other organs such as lungs, skin, and GI tract is also essential. Furthermore, the whole-body dose may not always reflect the prognosis of ARS victims because of the nature of accidental exposure, heterogenous exposure.
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Affiliation(s)
- Makoto Akashi
- Faculty and Graduate School of Nursing, Tokyo Healthcare University, Tokyo, Japan
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Ferrara B, Pignatelli C, Cossutta M, Citro A, Courty J, Piemonti L. The Extracellular Matrix in Pancreatic Cancer: Description of a Complex Network and Promising Therapeutic Options. Cancers (Basel) 2021; 13:cancers13174442. [PMID: 34503252 PMCID: PMC8430646 DOI: 10.3390/cancers13174442] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 01/18/2023] Open
Abstract
The stroma is a relevant player in driving and supporting the progression of pancreatic ductal adenocarcinoma (PDAC), and a large body of evidence highlights its role in hindering the efficacy of current therapies. In fact, the dense extracellular matrix (ECM) characterizing this tumor acts as a natural physical barrier, impairing drug penetration. Consequently, all of the approaches combining stroma-targeting and anticancer therapy constitute an appealing option for improving drug penetration. Several strategies have been adopted in order to target the PDAC stroma, such as the depletion of ECM components and the targeting of cancer-associated fibroblasts (CAFs), which are responsible for the increased matrix deposition in cancer. Additionally, the leaky and collapsing blood vessels characterizing the tumor might be normalized, thus restoring blood perfusion and allowing drug penetration. Even though many stroma-targeting strategies have reported disappointing results in clinical trials, the ECM offers a wide range of potential therapeutic targets that are now being investigated. The dense ECM might be bypassed by implementing nanoparticle-based systems or by using mesenchymal stem cells as drug carriers. The present review aims to provide an overview of the principal mechanisms involved in the ECM remodeling and of new promising therapeutic strategies for PDAC.
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Affiliation(s)
- Benedetta Ferrara
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - Cataldo Pignatelli
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - Mélissande Cossutta
- INSERM U955, Immunorégulation et Biothérapie, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil, 94010 Créteil, France; (M.C.); (J.C.)
- AP-HP, Centre d’Investigation Clinique Biothérapie, Groupe Hospitalo-Universitaire Chenevier Mondor, 94010 Créteil, France
| | - Antonio Citro
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
| | - José Courty
- INSERM U955, Immunorégulation et Biothérapie, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil, 94010 Créteil, France; (M.C.); (J.C.)
- AP-HP, Centre d’Investigation Clinique Biothérapie, Groupe Hospitalo-Universitaire Chenevier Mondor, 94010 Créteil, France
| | - Lorenzo Piemonti
- Diabetes Research Institute (HSR-DRI), San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy; (B.F.); (C.P.); (A.C.)
- Correspondence:
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7
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The Potential of Mesenchymal Stromal Cells in Neuroblastoma Therapy for Delivery of Anti-Cancer Agents and Hematopoietic Recovery. J Pers Med 2021; 11:jpm11030161. [PMID: 33668854 PMCID: PMC7996318 DOI: 10.3390/jpm11030161] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma is one of the most common pediatric cancers and a major cause of cancer-related death in infancy. Conventional therapies including high-dose chemotherapy, stem cell transplantation, and immunotherapy approach a limit in the treatment of high-risk neuroblastoma and prevention of relapse. In the last two decades, research unraveled a potential use of mesenchymal stromal cells in tumor therapy, as tumor-selective delivery vehicles for therapeutic compounds and oncolytic viruses and by means of supporting hematopoietic stem cell transplantation. Based on pre-clinical and clinical advances in neuroblastoma and other malignancies, we assess both the strong potential and the associated risks of using mesenchymal stromal cells in the therapy for neuroblastoma. Furthermore, we examine feasibility and safety aspects and discuss future directions for harnessing the advantageous properties of mesenchymal stromal cells for the advancement of therapy success.
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8
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Song H, Park KH. Regulation and function of SOX9 during cartilage development and regeneration. Semin Cancer Biol 2020; 67:12-23. [PMID: 32380234 DOI: 10.1016/j.semcancer.2020.04.008] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 09/23/2019] [Accepted: 04/26/2020] [Indexed: 12/21/2022]
Abstract
Chondrogenesis is a highly coordinated event in embryo development, adult homeostasis, and repair of the vertebrate cartilage. Fate decisions and differentiation of chondrocytes accompany differential expression of genes critical for each step of chondrogenesis. SOX9 is a master transcription factor that participates in sequential events in chondrogenesis by regulating a series of downstream factors in a stage-specific manner. SOX9 either works alone or in combination with downstream SOX transcription factors, SOX5 and SOX6 as chondrogenic SOX Trio. SOX9 is reduced in the articular cartilage of patients with osteoarthritis while highly maintained during tumorigenesis of cartilage and bone. Gene therapy using viral and non-viral vectors accompanied by tissue engineering (scaffolds) is a promising tool to regenerate impaired cartilage. Delivery of SOX9 or chondrogenic SOX Trio into cells produces efficient therapeutic effects on chondrogenesis and this event is facilitated by scaffolds. Non-viral vector-guided delivery systems encapsulated or loaded in mechanically stable solid scaffolds are useful for the regeneration of articular cartilage. Here we review major milestones and most recent studies focusing on regulation and function of chondrogenic SOX Trio, during chondrogenesis and cartilage regeneration, and on the development of advanced technologies in gene delivery with tissue engineering to improve efficiency of cartilage repair process.
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Affiliation(s)
- Haengseok Song
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea
| | - Keun-Hong Park
- Department of Biomedical Science, CHA University, Seongnam, Republic of Korea.
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9
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Sadatpoor SO, Salehi Z, Rahban D, Salimi A. Manipulated Mesenchymal Stem Cells Applications in Neurodegenerative Diseases. Int J Stem Cells 2020; 13:24-45. [PMID: 32114741 PMCID: PMC7119211 DOI: 10.15283/ijsc19031] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 04/07/2019] [Accepted: 04/13/2019] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that have multilinear differentiation and self-renewal abilities. These cells are immune-privileged as they express no or low level of class-II major histocompatibility complex (MHC-II) and other costimulatory molecules. Having neuroprotective and regenerative properties, MSCs can be used to ameliorate several intractable neurodegenerative disorders by affecting both innate and adaptive immune systems. Several manipulations like pretreating MSCs with different conditions or agents, and using molecules derived from MSCs or genetically manipulating them, are the common and practical ways that can be used to strengthen MSCs survival and potency. Improved MSCs can have significantly enhanced impacts on diseases compared to MSCs not manipulated. In this review, we describe some of the most important manipulations that have been exerted on MSCs to improve their therapeutic functions and their applications in ameliorating three prevalent neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease.
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Affiliation(s)
- Seyyed omid Sadatpoor
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Zahra Salehi
- Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Dariush Rahban
- Department of Nanomedicine, School of Advanced Medical Technologies, Tehran University of Medical Science, Tehran, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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10
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Khalifa J, François S, Rancoule C, Riccobono D, Magné N, Drouet M, Chargari C. Gene therapy and cell therapy for the management of radiation damages to healthy tissues: Rationale and early results. Cancer Radiother 2019; 23:449-465. [PMID: 31400956 DOI: 10.1016/j.canrad.2019.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/06/2019] [Indexed: 12/14/2022]
Abstract
Nowadays, ionizing radiations have numerous applications, especially in medicine for diagnosis and therapy. Pharmacological radioprotection aims at increasing detoxification of free radicals. Radiomitigation aims at improving survival and proliferation of damaged cells. Both strategies are essential research area, as non-contained radiation can lead to harmful effects. Some advances allowing the comprehension of normal tissue injury mechanisms, and the discovery of related predictive biomarkers, have led to developing several highly promising radioprotector or radiomitigator drugs. Next to these drugs, a growing interest does exist for biotherapy in this field, including gene therapy and cell therapy through mesenchymal stem cells. In this review article, we provide an overview of the management of radiation damages to healthy tissues via gene or cell therapy in the context of radiotherapy. The early management aims at preventing the occurrence of these damages before exposure or just after exposure. The late management offers promises in the reversion of constituted late damages following irradiation.
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Affiliation(s)
- J Khalifa
- Départment de radiothérapie, institut Claudius-Regaud, institut universitaire du cancer de Toulouse - Oncopole, 1, avenue Irène-Joliot-Curie, 31100 Toulouse, France.
| | - S François
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - C Rancoule
- Département de radiothérapie, institut de cancérologie de la Loire Lucien-Neuwirth, 108 bis, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; Laboratoire de radiobiologie cellulaire et moléculaire, UMR 5822, institut de physique nucléaire de Lyon (IPNL), 69622 Villeurbanne, France; UMR 5822, CNRS, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université Lyon 1, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université de Lyon, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France
| | - D Riccobono
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - N Magné
- Département de radiothérapie, institut de cancérologie de la Loire Lucien-Neuwirth, 108 bis, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France; Laboratoire de radiobiologie cellulaire et moléculaire, UMR 5822, institut de physique nucléaire de Lyon (IPNL), 69622 Villeurbanne, France; UMR 5822, CNRS, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université Lyon 1, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France; UMR 5822, université de Lyon, domaine scientifique de la Doua, 4, rue Enrico-Fermi, 69622 Villeurbanne cedex, France
| | - M Drouet
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France
| | - C Chargari
- Institut de recherche biomédicale des armées, BP73, 91223 Brétigny-sur-Orge cedex, France; Service de santé des armées, école du Val-de-Grâce, 74, boulevard de Port-Royal, 75005 Paris, France; Département de radiothérapie, Gustave-Roussy Cancer Campus, 114, rue Édouard-Vailant, 94805 Villejuif, France
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11
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Golchin A, Farahany TZ, Khojasteh A, Soleimanifar F, Ardeshirylajimi A. The Clinical Trials of Mesenchymal Stem Cell Therapy in Skin Diseases: An Update and Concise Review. Curr Stem Cell Res Ther 2019; 14:22-33. [PMID: 30210006 DOI: 10.2174/1574888x13666180913123424] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 08/15/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022]
Abstract
The skin is one of the crucial body organs with anatomy and physiology linked to various disorders including congenital and acquired diseases. Nowadays, mesenchymal stem cell (MSCs)- based therapy has appeared as a promising therapeutic field, in which many see opportunities to cure the costliest and incurable diseases. However, one question to be asked is that if the use of MSCs in clinical trials studies and diseases treatment has improved. In this study, the clinical trials using MSCs in skin diseases were reviewed. A remarkable number of clinical trial studies are in progress in this field; however, only a few of them have led to tangible benefits for patients. The relevant papers and ongoing clinical trials that address MSC's therapeutic goals for various skin disorders were examined. This review can be very useful for both the dermatologists and basic skin researchers interested in contributing to stem cell-based therapeutic researches in the area of skin disorders.
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Affiliation(s)
- Ali Golchin
- Department of Tissue engineering and Applied Cell Sciences, Student Research Committee, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Z Farahany
- Department of Biology, School of Advanced Technologies in Medicine, Islamic Azad University Medical Branch of Tehran, Tehran, Iran
| | - Arash Khojasteh
- Department of Tissue engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Soleimanifar
- Dietary Supplements and Probiotic Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Abdolreza Ardeshirylajimi
- Department of Tissue engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Sher N, Ofir R. Placenta-Derived Adherent Stromal Cell Therapy for Hematopoietic Disorders: A Case Study of PLX-R18. Cell Transplant 2019; 27:140-150. [PMID: 29562777 PMCID: PMC6434483 DOI: 10.1177/0963689717727543] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The ephemeral placenta provides a noncontroversial source of young, healthy cells of both maternal and fetal origin from which cell therapy products can be manufactured. The 2 advantages of using live cells as therapeutic entities are: (a) in their environmental-responsive, multifactorial secretion profile and (b) in their activity as a “slow-release drug delivery system,” releasing secretions over a long time frame. A major difficulty in translating cell therapy to the clinic involves challenges of large-scale, robust manufacturing while maintaining product characteristics, identity, and efficacy. To address these concerns early on, Pluristem developed the PLacental eXpanded (PLX) platform, the first good manufacturing practice–approved, 3-dimensional bioreactor-based cell growth platform, to enable culture of mesenchymal-like adherent stromal cells harvested from the postpartum placenta. One of the products produced by Pluristem on this platform is PLX-R18, a product mainly comprising placental fetal cells, which is proven in vivo to alleviate radiation-induced lethality and to enhance hematopoietic cell counts after bone marrow (BM) failure. The identified mechanism of action of PLX-R18 cells is one of the cell-derived systemic pro-hematopoietic secretions, which upregulate endogenous secretions and subsequently rescue BM and peripheral blood cellularity, thereby boosting survival. PLX-R18 is therefore currently under study to treat both the hematopoietic syndrome of acute radiation (under the US Food and Drug Administration [FDA]’s Animal Rule) and the incomplete engraftment after BM transplantation (in a phase I study). In the future, they could potentially address additional hematological indications, such as aplastic anemia, myelodysplastic syndrome, primary graft failure, and acute or chronic graft versus host disease.
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Guo S, Zhen Y, Wang A. Transplantation of bone mesenchymal stem cells promotes angiogenesis and improves neurological function after traumatic brain injury in mouse. Neuropsychiatr Dis Treat 2017; 13:2757-2765. [PMID: 29158675 PMCID: PMC5683767 DOI: 10.2147/ndt.s141534] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Traumatic brain injury (TBI) has emerged as a leading cause of mortality and morbidity worldwide. Transplantation of bone mesenchymal stem cells (BMSCs) has emerged as a promising treatment for various central nervous system diseases. This study aims to evaluate the effect of BMSCs transplantation by intravenous injection on neurological function and angiogenesis of the TBI mice. C57BL/6 male mice were randomly divided into four groups: control, sham, TBI, and BMSC. Functional neurological evaluation was performed 1, 4, 7, 14, and 21 days after TBI using neurological severity scores. The impairment of learning and memory in mice was evaluated 14 days after TBI by Morris water maze experiment. Mice were sacrificed 14 days after TBI, and then brain sections were stained by terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling staining to assess brain neuronal apoptosis. Immunohistochemistry was conducted to evaluate caspase-3 activity and identify vascular distribution and microvessel density. Protein and mRNA levels of vascular endothelial growth factor (VEGF) and angiogenin-1 (Ang-1) in brain tissues were analyzed by Western blot and quantitative real-time polymerase chain reaction, respectively. BMSCs transplantation promoted recovery of neurological function, ameliorated impairment of learning and memory, attenuated neuronal apoptosis, and diminished caspase-3 activation in mice after TBI. Also, BMSCs transplantation upregulated expressions of VEGF and Ang-1 and promoted the formation of microvessels in brain tissues after TBI. Our study demonstrated the important role of BMSCs transplantation in TBI mouse and indicated that the underlying mechanism was through promoting angiogenesis and improving neurological function. This provides a novel and effective strategy for cell-based therapy in the treatment of TBI.
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Affiliation(s)
- Shewei Guo
- Department of Neurosurgery, The First Affiliated Hospital, Zhengzhou University, Henan, China
| | - Yingwei Zhen
- Department of Neurosurgery, The First Affiliated Hospital, Zhengzhou University, Henan, China
| | - Anran Wang
- Department of Neurosurgery, The First Affiliated Hospital, Zhengzhou University, Henan, China
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Raffaele M, Li Volti G, Barbagallo IA, Vanella L. Therapeutic Efficacy of Stem Cells Transplantation in Diabetes: Role of Heme Oxygenase. Front Cell Dev Biol 2016; 4:80. [PMID: 27547752 PMCID: PMC4974271 DOI: 10.3389/fcell.2016.00080] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 07/20/2016] [Indexed: 12/17/2022] Open
Abstract
The growing data obtained from in vivo studies and clinical trials demonstrated the benefit of adult stem cells transplantation in diabetes; although an important limit is represented by their survival after the transplant. To this regard, recent reports suggest that genetic manipulation of stem cells prior to transplantation can lead to enhanced survival and better engraftment. The following review proposes to stimulate interest in the role of heme oxygenase-1 over-expression on transplantation of stem cells in diabetes, focusing on the clinical potential of heme oxygenase protein and activity to restore tissue damage and/or to improve the immunomodulatory properties of transplanted stem cells.
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Affiliation(s)
- Marco Raffaele
- Department of Drug Science, University of Catania Catania, Italy
| | - Giovanni Li Volti
- Department Biomedical and Biotechnological Science, University of Catania Catania, Italy
| | | | - Luca Vanella
- Department of Drug Science, University of Catania Catania, Italy
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15
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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.
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16
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Almalki SG, Agrawal DK. Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation 2016; 92:41-51. [PMID: 27012163 DOI: 10.1016/j.diff.2016.02.005] [Citation(s) in RCA: 293] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 02/15/2016] [Accepted: 02/25/2016] [Indexed: 11/15/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells that represent a promising source for regenerative medicine. MSCs are capable of osteogenic, chondrogenic, adipogenic and myogenic differentiation. Efficacy of differentiated MSCs to regenerate cells in the injured tissues requires the ability to maintain the differentiation toward the desired cell fate. Since MSCs represent an attractive source for autologous transplantation, cellular and molecular signaling pathways and micro-environmental changes have been studied in order to understand the role of cytokines, chemokines, and transcription factors on the differentiation of MSCs. The differentiation of MSC into a mesenchymal lineage is genetically manipulated and promoted by specific transcription factors associated with a particular cell lineage. Recent studies have explored the integration of transcription factors, including Runx2, Sox9, PPARγ, MyoD, GATA4, and GATA6 in the differentiation of MSCs. Therefore, the overexpression of a single transcription factor in MSCs may promote trans-differentiation into specific cell lineage, which can be used for treatment of some diseases. In this review, we critically discussed and evaluated the role of transcription factors and related signaling pathways that affect the differentiation of MSCs toward adipocytes, chondrocytes, osteocytes, skeletal muscle cells, cardiomyocytes, and smooth muscle cells.
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Affiliation(s)
- Sami G Almalki
- Departments of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, USA
| | - Devendra K Agrawal
- Clinical and Translational Science, Creighton University School of Medicine, Omaha, NE, USA.
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Abstract
Acute radiation syndrome affects military personnel and civilians following the uncontrolled dispersal of radiation, such as that caused by detonation of nuclear devices and inappropriate medical treatments. Therefore, there is a growing need for medical interventions that facilitate the improved recovery of victims and patients. One promising approach may be cell therapy, which, when appropriately implemented, may facilitate recovery from whole body injuries. This editorial highlights the current knowledge regarding the use of mesenchymal stem cells for the treatment of acute radiation syndrome, the benefits and limitations of which are under investigation. Establishing successful therapies for acute radiation syndrome may require using such a therapeutic approach in addition to conventional approaches.
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Affiliation(s)
- Risaku Fukumoto
- Educational-Scientific Center, Faculty of Health Sciences, Medical University of Białystok, ul. Szpitalna 37, 15-295 Białystok, Poland
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Efficacy of Surgery Combined with Autologous Bone Marrow Stromal Cell Transplantation for Treatment of Intracerebral Hemorrhage. Stem Cells Int 2015; 2015:318269. [PMID: 26240570 PMCID: PMC4512614 DOI: 10.1155/2015/318269] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 12/30/2014] [Accepted: 01/13/2015] [Indexed: 12/29/2022] Open
Abstract
Bone marrow stromal cells (BMSCs) may differentiate into nerve cells under a certain condition; however, the clinical application for treating nervous system disease remains unclear. The aim is to assess the safety profile, feasibility, and effectiveness of surgery combined with autologous BMSCs transplantation for treating ICH. 206 ICH patients who had received surgical procedure were divided into transplantation (n = 110) or control group (n = 96). For transplantation group, BMSCs were injected into the perihemorrhage area in the base ganglia through an intracranial drainage tube 5.5 (3.01–6.89) days after surgery, followed by a second injection into the subarachnoid space through lumbar puncture 4 weeks later. Neurologic impairment and daily activities were assessed with National Institute Stroke Scale (NIHSS), Barthel index, and Rankin scale before transplantation and 6 months and 12 months after transplantation. Our results revealed that, compared with control group, NIHSS score and Rankin scale were both significantly decreased but Barthel index was increased in transplantation group after 6 months. Interestingly, no significant difference was observed between 12 months and 6 months. No transplantation-related adverse effects were investigated during follow-up assessments. Our findings suggest that surgery combined with autologous BMSCs transplantation is safe for treatment of ICH, providing short-term therapeutic benefits.
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Hematopoietic recovery of acute radiation syndrome by human superoxide dismutase-expressing umbilical cord mesenchymal stromal cells. Cytotherapy 2015; 17:403-17. [PMID: 25618561 DOI: 10.1016/j.jcyt.2014.11.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 11/15/2014] [Accepted: 11/23/2014] [Indexed: 01/10/2023]
Abstract
BACKGROUND AIMS Acute radiation syndrome (ARS) leads to pancytopenia and multi-organ failure. Transplantation of hematopoietic stem cells provides a curative option for radiation-induced aplasia, but this therapy is limited by donor availability. METHODS We examined an alternative therapeutic approach to ARS with the use of human extracellular superoxide dismutase (ECSOD)-modified umbilical cord mesenchymal stromal cells (UCMSCs). This treatment combines the unique regenerative role of UCMSCs with the anti-oxidative activity of ECSOD. RESULTS We demonstrated that systemically administered ECSOD-UCMSCs are able to protect mice from sub-lethal doses of radiation and improve survival by promoting multilineage hematopoietic recovery. The therapeutic effect of this treatment is related to the decrease in radiation-induced O(2)(-) and apoptosis. CONCLUSIONS Our data highlight the clinical potential of this two-pronged approach to the treatment of ARS, thereby serving as a rapid and effective first-line strategy to combat the hematopoietic failure resulting from a radiation accident, nuclear terrorism and other radiologic emergencies.
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Fan HC, Ho LI, Chi CS, Chen SJ, Peng GS, Chan TM, Lin SZ, Harn HJ. Polyglutamine (PolyQ) diseases: genetics to treatments. Cell Transplant 2015; 23:441-58. [PMID: 24816443 DOI: 10.3727/096368914x678454] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding a long polyQ tract in the respective proteins. To date, a total of nine polyQ disorders have been described: six spinocerebellar ataxias (SCA) types 1, 2, 6, 7, 17; Machado-Joseph disease (MJD/SCA3); Huntington's disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). PolyQ diseases are characterized by the pathological expansion of CAG trinucleotide repeat in the translated region of unrelated genes. The translated polyQ is aggregated in the degenerated neurons leading to the dysfunction and degeneration of specific neuronal subpopulations. Although animal models of polyQ disease for understanding human pathology and accessing disease-modifying therapies in neurodegenerative diseases are available, there is neither a cure nor prevention for these diseases, and only symptomatic treatments for polyQ diseases currently exist. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Cellular transplantation of stem cells may provide promising therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in polyQ diseases.
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Affiliation(s)
- Hueng-Chuen Fan
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Eaton EB, Varney TR. Mesenchymal stem cell therapy for acute radiation syndrome: innovative medical approaches in military medicine. Mil Med Res 2015; 2:2. [PMID: 25722881 PMCID: PMC4340678 DOI: 10.1186/s40779-014-0027-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 11/20/2014] [Indexed: 01/03/2023] Open
Abstract
After a radiological or nuclear event, acute radiation syndrome (ARS) will present complex medical challenges that could involve the treatment of hundreds to thousands of patients. Current medical doctrine is based on limited clinical data and remains inadequate. Efforts to develop medical innovations that address ARS complications are unlikely to be generated by industry because of market uncertainties specific to this type of injury. A prospective strategy could be the integration of cellular therapy to meet the medical demands of ARS. The most clinically advanced cellular therapy to date is the administration of mesenchymal stem cells (MSCs). Results of currently published investigations describing MSC safety and efficacy in a variety of injury and disease models demonstrate the unique qualities of this reparative cell population in adapting to the specific requirements of the damaged tissue in which the cells integrate. This report puts forward a rationale for the further evaluation of MSC therapy to address the current unmet medical needs of ARS. We propose that the exploration of this novel therapy for the treatment of the multivariate complications of ARS could be of invaluable benefit to military medicine.
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Affiliation(s)
- Erik B Eaton
- United States Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland, 21010 US
| | - Timothy R Varney
- United States Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland, 21010 US
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22
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Lee DK, Yi T, Park KE, Lee HJ, Cho YK, Lee SJ, Lee J, Park JH, Lee MY, Song SU, Kwon SW. Non-invasive characterization of the adipogenic differentiation of human bone marrow-derived mesenchymal stromal cells by HS-SPME/GC-MS. Sci Rep 2014; 4:6550. [PMID: 25298091 PMCID: PMC4190506 DOI: 10.1038/srep06550] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 08/11/2014] [Indexed: 01/10/2023] Open
Abstract
A non-invasive method to characterize human mesenchymal stromal cells during adipogenic differentiation was developed for the first time. Seven fatty acid methyl esters (FAMEs), including methyl laurate, methyl myristate, methyl palmitate, methyl linoleate, methyl oleate, methyl elaidate and methyl stearate, were used for characterizing adipogenic differentiation using headspace solid-phase microextraction (HS-SPME) which is a very simple and non-invasive method for the extraction of volatile compounds. Glassware was used for culturing mesenchymal stromal cells rather than the common plasticware to minimize contamination by volatile impurities. The optimal SPME fiber was selected by comparing diverse fibers containing two pure liquid polymers (PDMS and PA) and two porous solids (PDMS/DVB and CAR/PDMS). Using optimized procedures, we discovered that seven FAMEs were only detected in adipogenic differentiated mesenchymal stromal cells and not in the mesenchymal stromal cells before differentiation. These data could support the quality control of clinical mesenchymal stromal cell culture in the pharmaceutical industry in addition to the development of many clinical applications using mesenchymal stromal cells.
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Affiliation(s)
- Dong-Kyu Lee
- 1] College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea [2]
| | - TacGhee Yi
- 1] Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon 400-712, Republic of Korea [2]
| | - Kyung-Eun Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea
| | - Hyun-Joo Lee
- Drug Development Program, Department of Medicine, Inha University School of Medicine, Incheon 400-712, Republic of Korea
| | - Yun-Kyoung Cho
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon 400-712, Republic of Korea
| | - Seul Ji Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea
| | - Jeongmi Lee
- School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
| | - Jeong Hill Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea
| | - Mi-Young Lee
- Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency Incheon 403-711, Republic of Korea
| | - Sun U Song
- Translational Research Center and Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon 400-712, Republic of Korea
| | - Sung Won Kwon
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea
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23
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Goodrich AD, Varain NM, Jeanblanc CM, Colon DM, Kim J, Zanjani ED, Hematti P. Influence of a dual-injection regimen, plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model. Cytotherapy 2014; 16:1280-93. [PMID: 25108653 PMCID: PMC4131210 DOI: 10.1016/j.jcyt.2014.05.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 05/19/2014] [Accepted: 05/27/2014] [Indexed: 01/01/2023]
Abstract
BACKGROUND AIMS Inadequate engraftment of hematopoietic stem cells (HSCs) after in utero HSC transplantation (IUHSCT) remains a major obstacle for the prenatal correction of numerous hereditary disorders. HSCs express CXCR4 receptors that allow homing and engraftment in response to stromal-derived factor 1 (SDF-1) ligand present in the bone marrow stromal niche. Plerixafor, a mobilization drug, works through the interruption of the CXCR4-SDF-1 axis. METHODS We used the fetal sheep large-animal model to test our hypotheses that (i) by administering plerixafor in utero before performing IUHSCT to release fetal HSCs and thus vacating recipient HSC niches, (ii) by using human mesenchymal stromal/stem cells (MSCs) to immunomodulate and humanize the fetal BM niches and (iii) by increasing the CXCR4(+) fraction of CD34(+) HSCs, we could improve engraftment. Human cord blood-derived CD34(+) cells and human bone marrow-derived MSCs were used for these studies. RESULTS When MSCs were transplanted 1 week before CD34(+) cells with plerixafor treatment, we observed 2.80% donor hematopoietic engraftment. Combination of this regimen with additional CD34(+) cells at the time of MSC infusion increased engraftment levels to 8.77%. Next, increasing the fraction of CXCR4(+) cells in the CD34(+) population albeit transplanting at a late gestation age was not beneficial. Our results show engraftment of both lymphoid and myeloid lineages. CONCLUSIONS Prior MSC and HSC cotransplantation followed by manipulation of the CXCR4-SDF-1 axis in IUHSCT provides an innovative conceptual approach for conferring competitive advantage to donor HSCs. Our novel approach could provide a clinically relevant approach for enhancing engraftment early in the fetus.
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Affiliation(s)
- A Daisy Goodrich
- Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA
| | - Nicole M Varain
- Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA
| | - Christine M Jeanblanc
- Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA
| | - Donna M Colon
- Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA
| | - Jaehyup Kim
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Esmail D Zanjani
- Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA
| | - Peiman Hematti
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA; Carbone Cancer Center, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
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24
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D'Souza S, Murata H, Jose MV, Askarova S, Yantsen Y, Andersen JD, Edington CDJ, Clafshenkel WP, Koepsel RR, Russell AJ. Engineering of cell membranes with a bisphosphonate-containing polymer using ATRP synthesis for bone targeting. Biomaterials 2014; 35:9447-58. [PMID: 25150889 DOI: 10.1016/j.biomaterials.2014.07.041] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 07/23/2014] [Indexed: 01/14/2023]
Abstract
The field of polymer-based membrane engineering has expanded since we first demonstrated the reaction of N-hydroxysuccinimide ester-terminated polymers with cells and tissues almost two decades ago. One remaining obstacle, especially for conjugation of polymers to cells, has been that exquisite control over polymer structure and functionality has not been used to influence the behavior of cells. Herein, we describe a multifunctional atom transfer radical polymerization initiator and its use to synthesize water-soluble polymers that are modified with bisphosphonate side chains and then covalently bound to the surface of live cells. The polymers contained between 1.7 and 3.1 bisphosphonates per chain and were shown to bind to hydroxyapatite crystals with kinetics similar to free bisphosphonate binding. We engineered the membranes of both HL-60 cells and mesenchymal stem cells in order to impart polymer-guided bone adhesion properties on the cells. Covalent coupling of the polymer to the non-adherent HL-60 cell line or mesenchymal stem cells was non-toxic by proliferation assays and enhanced the binding of these cells to bone.
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Affiliation(s)
- Sonia D'Souza
- The Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, USA
| | - Hironobu Murata
- The Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, USA
| | - Moncy V Jose
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Pittsburgh, PA 15219, USA; PolyOne Technology & Innovation Center, 11650 Lake Side Crossing Court, St Louis, MO 63146, USA
| | - Sholpan Askarova
- Department for Bioengineering, Cell Technologies, and Cell Therapy, Center for Life Sciences, Nazarbayev University, 53 Kabanbay Batyr Ave, Astana 010000, Kazakhstan
| | - Yuliya Yantsen
- Department for Bioengineering, Cell Technologies, and Cell Therapy, Center for Life Sciences, Nazarbayev University, 53 Kabanbay Batyr Ave, Astana 010000, Kazakhstan
| | - Jill D Andersen
- The Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, USA
| | - Collin D J Edington
- The Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, USA
| | - William P Clafshenkel
- The Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, USA
| | - Richard R Koepsel
- The Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, USA
| | - Alan J Russell
- The Institute for Complex Engineered Systems, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA 15213, USA. alanrussell+@cmu.edu
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25
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Gottipamula S, Ashwin KM, Muttigi MS, Kannan S, Kolkundkar U, Seetharam RN. Isolation, expansion and characterization of bone marrow-derived mesenchymal stromal cells in serum-free conditions. Cell Tissue Res 2014; 356:123-35. [PMID: 24448665 DOI: 10.1007/s00441-013-1783-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 12/10/2013] [Indexed: 12/16/2022]
Abstract
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) heralded a new beginning for regenerative medicine and generated tremendous interest as the most promising source for therapeutic application. Most cell therapies require stringent regulatory compliance and prefer the use of serum-free media (SFM) or xeno-free media (XFM) for the MSC production process, starting from the isolation onwards. Here, we report on serum-free isolation and expansion of MSCs and compare them with cells grown in conventional fetal bovine serum (FBS)-containing media as a control. The isolation, proliferation and morphology analysis demonstrated significant differences between MSCs cultured in various SFM/XFM in addition to their difference with FBS controls. BD Mosaic™ Mesenchymal Stem Cell Serum-Free media (BD-SFM) and Mesencult-XF (MSX) supported the isolation, sequential passaging, tri-lineage differentiation potential and acceptable surface marker expression profile of BM-MSCs. Further, MSCs cultured in SFM showed higher immune suppression and hypo-immunogenicity properties, making them an ideal candidate for allogeneic cell therapy. Although cells cultured in control media have a significantly higher proliferation rate, BM-MSCs cultured in BD-SFM or MSX media are the preferred choice to meet regulatory requirements as they do not contain bovine serum. While BM-MSCs cultured in BD-SFM and MSX media adhered to all MSC characteristics, in the case of few parameters, the performance of cells cultured in BD-SFM was superior to that of MSX media. Pre-clinical safety and efficiency studies are required before qualifying SFM or XFM media-derived MSCs for therapeutic applications.
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Affiliation(s)
- Sanjay Gottipamula
- Stempeutics Research Pvt. Ltd, Shirdi Sai Baba Cancer Hospital, Manipal, India
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26
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Valim V, Amorin B, Pezzi A, Aparecida Lima da Silva M, Paula Alegretti A, Silla L. Optimization of the Cultivation of Donor Mesenchymal Stromal Cells for Clinical Use in Cellular Therapy. ACTA ACUST UNITED AC 2014. [DOI: 10.4236/cellbio.2014.31003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Chapel A, Francois S, Douay L, Benderitter M, Voswinkel J. New insights for pelvic radiation disease treatment: Multipotent stromal cell is a promise mainstay treatment for the restoration of abdominopelvic severe chronic damages induced by radiotherapy. World J Stem Cells 2013; 5:106-111. [PMID: 24179599 PMCID: PMC3812515 DOI: 10.4252/wjsc.v5.i4.106] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 05/22/2013] [Accepted: 08/29/2013] [Indexed: 02/06/2023] Open
Abstract
Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded severity as radiotherapy affects not only the targeted tumor cells but also the surrounding healthy tissues. The late adverse effects of pelvic radiotherapy concern 5% to 10% of them, which could be life threatening. However, a clear medical consensus concerning the clinical management of such healthy tissue sequelae does not exist. Although no pharmacologic interventions have yet been proven to efficiently mitigate radiotherapy severe side effects, few preclinical researches show the potential of combined and sequential pharmacological treatments to prevent the onset of tissue damage. Our group has demonstrated in preclinical animal models that systemic mesenchymal stromal cell (MSC) injection is a promising approach for the medical management of gastrointestinal disorder after irradiation. We have shown that MSCs migrate to damaged tissues and restore gut functions after irradiation. We carefully studied side effects of stem cell injection for further application in patients. We have shown that clinical status of four patients suffering from severe pelvic side effects resulting from an over-dosage was improved following MSC injection in a compationnal situation.
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Lin P, Correa D, Kean TJ, Awadallah A, Dennis JE, Caplan AI. Serial transplantation and long-term engraftment of intra-arterially delivered clonally derived mesenchymal stem cells to injured bone marrow. Mol Ther 2013; 22:160-8. [PMID: 24067545 DOI: 10.1038/mt.2013.221] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 09/15/2013] [Indexed: 12/24/2022] Open
Abstract
It has been hypothesized that mesenchymal stem cells (MSCs) home to sites of injury. Nevertheless, efficient delivery of MSCs to target organs and description of their ultimate fate remain major challenges. We provide evidence that intra-arterially (IA) injected MSCs selectively engraft from the circulation as perivascular cells in the bone marrow (BM) after a localized radiation injury. Luciferase-expressing MSCs, derived from a conditionally immortalized clone (BMC-9) representing a pure population of cells, were arterially delivered into mice irradiated in one leg. Cell distribution was measured by bioluminescent imaging and final destination assessed by luciferase immunolocalization. IA injections resulted in engraftment only in the irradiated leg where cells localize and proliferate abluminal to the BM vasculature, a phenomenon not replicated with intravenous injections or with IA injections of kidney cells harvested from the same donor used for MSCs. Furthermore, MSCs harvested from the engrafted marrow and serially transplanted retain the ability to selectively engraft at sites of injury. This study demonstrates that MSCs can serially engraft at sites of injury from the circulation, that they reside in the perivascular space, and that arterial delivery is more efficient than venous delivery for cell engraftment.
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Affiliation(s)
- Paul Lin
- 1] Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA [2] Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Diego Correa
- Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, Ohio, USA
| | - Thomas J Kean
- Benaroya Research Institute, Seattle, Washington, USA
| | - Amad Awadallah
- Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, Ohio, USA
| | | | - Arnold I Caplan
- Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, Ohio, USA
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MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation. Stem Cells Int 2013; 2013:732742. [PMID: 24000286 PMCID: PMC3755386 DOI: 10.1155/2013/732742] [Citation(s) in RCA: 309] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 06/27/2013] [Accepted: 07/01/2013] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the "first-pass" accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.
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Chapel A, Francois S, Douay L, Benderitter M, Voswinkel J. Fifteen years of preclinical and clinical experiences about biotherapy treatment of lesions induced by accidental irradiation and radiotherapy. World J Stem Cells 2013; 5:68-72. [PMID: 23951388 PMCID: PMC3744132 DOI: 10.4252/wjsc.v5.i3.68] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 05/06/2013] [Accepted: 05/10/2013] [Indexed: 02/06/2023] Open
Abstract
High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is therefore crucial. Because developments in cell therapy have brought some hope for the treatment of tissues damages induced by irradiation, the Institute for Radiation and Nuclear Safety contributed to establish the clinical guidelines for the management of accidentally irradiated victims and to provide the best supportive care to patients all over the world. In the past 15 years, we contributed to develop and test cell therapy for protection against radiation side effects in several animal models, and we proposed mechanisms to explain the benefit brought by this new therapeutic approach. We established the proof of concept that mesenchymal stem cells (MSCs) migrate to damaged tissues in the nonobese diabetic/severe combined immunodeficiency immunotolerant mice model and in non-human primate after radiation exposure. We showed that the intravenous injection of MSCs sustains hematopoiesis after total body irradiation, improves wound healing after radiodermatitis and protects gut function from irradiation damages. Thanks to a tight collaboration with clinicians from several French hospitals, we report successful treatments of therapeutic/accidental radiation damages in several victims with MSC infusions for hematopoiesis correction, radio-induced burns, gastrointestinal disorders and protection homeostatic functions of gut management after radio-therapy.
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31
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Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol 2013; 91:32-9. [PMID: 23295415 PMCID: PMC3540326 DOI: 10.1038/icb.2012.64] [Citation(s) in RCA: 163] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Somatic, also termed adult, stem cells are highly attractive biomedical cell candidates because of their extensive replication potential and functional multilineage differentiation capacity. They can be used for drug and toxicity screenings in preclinical studies, as in vitro model to study differentiation or for regenerative medicine to aid in the repair of tissues or replace tissues that are lost upon disease, injury or ageing. Multipotent adult progenitor cells (MAPCs) and mesenchymal stem cells (MSCs) are two types of adult stem cells derived from bone marrow that are currently being used clinically for tissue regeneration and for their immunomodulatory and trophic effects. This review will give an overview of the phenotypic and functional differences between human MAPCs and MSCs, with a strong emphasis on their immunological characteristics. Finally, we will discuss the clinical studies in which MSCs and MAPCs are already used.
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Third party cord blood transplant boosts autologous hematopoiesis in a case of persistent bone marrow aplasia after double transplant failure for B-thalassemia major. Mediterr J Hematol Infect Dis 2013; 5:e2013029. [PMID: 23667727 PMCID: PMC3647713 DOI: 10.4084/mjhid.2013.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 04/04/2013] [Indexed: 11/30/2022] Open
Abstract
A 9-year-old female received an allogeneic stem cell transplant (SCT) from an ABO-incompatible HLA-matched sibling for β-thalassemia major, without achieving a complete donor chimerism. Subsequently, the patient received five donor lymphocyte infusions, without increasing donor chimerism, and autologous SCT. Due to the persistent bone marrow aplasia, the patient received a second allogeneic SCT from the same donor without obtaining any engrafment. After the double transplant failure, we performed an unrelated transplant from a full-matched umbilical cord blood (UCBT) without administering any neither conditioning regimen nor GVHD prophylaxis. Forty days after UCBT, trilinear engraftment was documented. Surprisingly, the hematopoietic reconstitution was related to the re-expansion of the autologous (beta-thalassemic) hematopoietic stem cell, as documented by chimerism studies. At present, 30 months after UCBT, there is stable hematopoietic autologous reconstitution. This is the first description of the restoration of autologous hematopoiesis obtained with UCBT in a thalassemia-major patient after a double transplant failure.
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Gottipamula S, Muttigi MS, Chaansa S, Ashwin KM, Priya N, Kolkundkar U, SundarRaj S, Majumdar AS, Seetharam RN. Large-scale expansion of pre-isolated bone marrow mesenchymal stromal cells in serum-free conditions. J Tissue Eng Regen Med 2013; 10:108-19. [PMID: 23495227 DOI: 10.1002/term.1713] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Revised: 12/02/2012] [Accepted: 01/04/2013] [Indexed: 12/30/2022]
Abstract
The regenerative potential of mesenchymal stromal or stem cells (MSCs) has generated tremendous interest for treating various degenerative diseases. Regulatory preference is to use a culture medium that is devoid of bovine components for stem cell expansion intended for therapeutic applications. However, a clear choice an alternative to fetal bovine serum (FBS) has not yet emerged. We have screened five different commercially available serum-free media (SFM) for their ability to support the growth and expansion of pre-isolated undifferentiated bone marrow-derived MSCs (BM-MSCs) and compared the results with cells grown in standard FBS-containing medium as control. In addition, based on initial screening results, BD Mosaic™ Mesenchymal Stem Cell Serum-free (BD-SFM) medium was evaluated in large-scale cultures for the performance and culture characteristics of BM-MSCs. Of the five different serum-free media, BD-SFM enhanced BM-MSCs growth and expansion in Cell STACK (CS), but the cell yield per CS-10 was less when compared to the control medium. The characteristics of MSCs were measured in terms of population doubling time (PDT), cell yield and expression of MSC-specific markers. Significant differences were observed between BD-SFM and control medium in terms of population doublings (PDs), cell yield, CFU-F and morphological features, whereas surface phenotype and differentiation potentials were comparable. The BD-SFM-cultured MSCs were also found to retain the differentiation potential, immune-privileged status and immunosuppressive properties inherent to MSCs. Our results suggest that BD-SFM supports large-scale expansion of BM-MSCs for therapeutic use.
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Affiliation(s)
- Sanjay Gottipamula
- Stempeutics Research Pvt. Ltd, Shirdi Sai Baba Cancer Hospital, Manipal, India
| | | | - S Chaansa
- Stempeutics Research Pvt. Ltd, Shirdi Sai Baba Cancer Hospital, Manipal, India
| | - K M Ashwin
- Stempeutics Research Pvt. Ltd, Shirdi Sai Baba Cancer Hospital, Manipal, India
| | - Nancy Priya
- Stempeutics Research Pvt. Ltd, Akshay Tech Park, Bangalore, India
| | | | - Swathi SundarRaj
- Stempeutics Research Pvt. Ltd, Akshay Tech Park, Bangalore, India
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Shim S, Lee SB, Lee JG, Jang WS, Lee SJ, Park S, Lee SS. Mitigating effects of hUCB-MSCs on the hematopoietic syndrome resulting from total body irradiation. Exp Hematol 2013; 41:346-53.e2. [PMID: 23333483 DOI: 10.1016/j.exphem.2013.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 12/26/2012] [Accepted: 01/04/2013] [Indexed: 12/20/2022]
Abstract
This study evaluated the clinical and pathologic effects of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in the recovery from total body irradiation by comparing it with the effects of granulocyte-colony stimulating factor (G-CSF), an efficacious drug in the treatment of acute bone marrow radiation syndrome. BALB/c mice were treated with G-CSF or hUCB-MSCs after they were irradiated with 7 Gy cobalt-60 γ-rays. Circulating blood counts, histopathologic changes in the bone marrow, and plasma level of Flt-3L and transforming growth factor (TGF-β1) were monitored in the postirradiation period. Hematologic analysis revealed that the peripheral leukocyte counts were markedly increased in the hUCB-MSCs-treated group, whereas G-CSF-treated mice did not recover significantly. Moreover, differential counts showed that hUCB-MSC treatment has regenerative effects on white blood cells, lymphocytes, and monocytes compared with the irradiated group. Treatment with hUCB-MSCs or G-CSF significantly increased immunoreactivity of Ki-67 until 3 weeks after total body irradiation. However, at 3 weeks, the number of Ki-67 immunoreactive cells significantly increased in the hUCB-MSCs-treated group compared with the G-CSF-treated group. Furthermore, hUCB-MSC treatment significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGF-β1, whereas G-CSF treatment failed to decrease the plasma Flt-3L levels at 2 weeks after irradiation. Based on the differences in circulating blood cell reconstitution and cell density of bone marrow, the authors suggest that MSC treatment is superior to G-CSF treatment for hematopoietic reconstitution following sublethal dose radiation exposure.
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Affiliation(s)
- Sehwan Shim
- National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
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35
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Mouiseddine M, François S, Souidi M, Chapel A. Intravenous human mesenchymal stem cells transplantation in NOD/SCID mice preserve liver integrity of irradiation damage. Methods Mol Biol 2012; 826:179-88. [PMID: 22167649 DOI: 10.1007/978-1-61779-468-1_15] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This work was initiated in an effort to evaluate the potential therapeutic contribution of the infusion of mesenchymal stem cells (MSC) for the correction of liver injuries. We subjected NOD-SCID mice to a 10.5-Gy abdominal irradiation and we tested the biological and histological markers of liver injury in the absence and after infusion of expanded human MSC. Irradiation alone induced a significant elevation of the ALT and AST. Apoptosis in the endothelial layer of vessels was observed. When MSC were infused in mice, a significant decrease of transaminases was measured, and a total disappearance of apoptotic cells. MSC were not found in liver. To explain the protection of liver without MSC engraftment, we hypothesize an indirect action of MSC on the liver via the intestinal tract. Pelvic or total body irradiation induces intestinal absorption defects leading to an alteration of the enterohepatic recirculation of bile acids. This alteration induces an increase in Deoxy Cholic Acid (DCA) which is hepatoxic. In this study, we confirm these results. DCA concentration increased approximately twofold after irradiation but stayed to the baseline level after MSC injection. We propose from our observations that, following irradiation, MSC infusion indirectly corrected liver dysfunction by preventing gut damage. This explanation would be consistent with the absence of MSC engraftment in liver. These results evidenced that MSC treatment of a target organ may have an effect on distant tissues. This observation comes in support to the interest for the use of MSC for cellular therapy in multiple pathologies proposed in the recent years.
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36
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Isolation of the stromal-vascular fraction of mouse bone marrow markedly enhances the yield of clonogenic stromal progenitors. Blood 2012; 119:e86-95. [PMID: 22262767 DOI: 10.1182/blood-2011-08-372334] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The low incidence of CFU-F significantly complicates the isolation of homogeneous populations of mouse bone marrow stromal cells (BMSCs), a common problem being contamination with hematopoietic cells. Taking advantage of burgeoning evidence demonstrating the perivascular location of stromal cell stem/progenitors, we hypothesized that a potential reason for the low yield of mouse BMSCs is the flushing of the marrow used to remove single-cell suspensions and the consequent destruction of the marrow vasculature, which may adversely affect recovery of BMSCs physically associated with the abluminal surface of blood vessels. Herein, we describe a simple methodology based on preparation and enzymatic disaggregation of intact marrow plugs, which yields distinct populations of both stromal and endothelial cells. The recovery of CFU-F obtained by pooling the product of each digestion (1631.8 + 199) reproducibly exceeds that obtained using the standard BM flushing technique (14.32 + 1.9) by at least 2 orders of magnitude (P < .001; N = 8) with an accompanying 113.95-fold enrichment of CFU-F frequency when plated at low oxygen (5%). Purified BMSC populations devoid of hematopoietic contamination are readily obtained by FACS at P0 and from freshly prepared single-cell suspensions. Furthermore, this population demonstrates robust multilineage differentiation using standard in vivo and in vitro bioassays.
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37
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Hao L, Sun H, Wang J, Wang T, Wang M, Zou Z. Mesenchymal stromal cells for cell therapy: besides supporting hematopoiesis. Int J Hematol 2012; 95:34-46. [PMID: 22183780 DOI: 10.1007/s12185-011-0991-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2011] [Revised: 12/06/2011] [Accepted: 12/07/2011] [Indexed: 02/07/2023]
Abstract
Mesenchymal stromal cells (MSC) have attracted the attention of scientists and clinicians due to their self-renewal, capacity for multipotent differentiation, and immunomodulatory properties. Some essential problems remain to be solved before the clinical application of MSC. Platelet lysate (PL) has recently been used as a substitute for FBS in MSC amplification in vitro to achieve clinically applicable numbers of MSC. In addition to promising trials in regenerative medicine, such as in the treatment of major bone defects and myocardial infarction, MSC have shown therapeutic effect other than direct hematopoiesis support in hematopoietic reconstruction. It has been confirmed that MSC promote hematopoietic cell engraftment and immune recovery after allogeneic hematopoietic stem cell transplantation, probably through the provision of cytokines, matrix proteins, and cell-to-cell contacts. Their suppressive effects on immune cells, including T cells, B cells, NK cells and DC cells, suggest MSCs as a novel therapy for GVHD and other autoimmune disorders. These cells thus present as promising candidates for cellular therapy in the fields of regenerative medicine, allogeneic hematopoietic stem cell transplantation, and autoimmune disorders.
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Affiliation(s)
- Lei Hao
- Department of Internal Medicine, No. 324 Hospital of PLA, Chongqing 400020, China
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38
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Chen FM, Zhao YM, Jin Y, Shi S. Prospects for translational regenerative medicine. Biotechnol Adv 2011; 30:658-72. [PMID: 22138411 DOI: 10.1016/j.biotechadv.2011.11.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Revised: 11/12/2011] [Accepted: 11/15/2011] [Indexed: 02/06/2023]
Abstract
Translational medicine is an evolutional concept that encompasses the rapid translation of basic research for use in clinical disease diagnosis, prevention and treatment. It follows the idea "from bench to bedside and back", and hence relies on cooperation between laboratory research and clinical care. In the past decade, translational medicine has received unprecedented attention from scientists and clinicians and its fundamental principles have penetrated throughout biomedicine, offering a sign post that guides modern medical research toward a patient-centered focus. Translational regenerative medicine is still in its infancy, and significant basic research investment has not yet achieved satisfactory clinical outcomes for patients. In particular, there are many challenges associated with the use of cell- and tissue-based products for clinical therapies. This review summarizes the transformation and global progress in translational medicine over the past decade. The current obstacles and opportunities in translational regenerative medicine are outlined in the context of stem cell therapy and tissue engineering for the safe and effective regeneration of functional tissue. This review highlights the requirement for multi-disciplinary and inter-disciplinary cooperation to ensure the development of the best possible regenerative therapies within the shortest timeframe possible for the greatest patient benefit.
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Affiliation(s)
- Fa-Ming Chen
- Department of Periodontology & Oral Medicine, School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
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Chang YK, Chen MH, Chiang YH, Chen YF, Ma WH, Tseng CY, Soong BW, Ho JH, Lee OK. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci 2011; 18:54. [PMID: 21824437 PMCID: PMC3174876 DOI: 10.1186/1423-0127-18-54] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2011] [Accepted: 08/08/2011] [Indexed: 12/14/2022] Open
Abstract
Background Spinocerebellar ataxia (SCA) refers to a disease entity in which polyglutamine aggregates are over-produced in Purkinje cells (PCs) of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions. So far there is no effective neuroprotective treatment for this debilitating disease although numerous efforts have been made. Mesenchymal stem cells (MSCs) possess multi-lineage differentiation potentials as well as immuno-modulatory properties, and are theoretically good candidates for SCA treatment. The purpose of this study is to investigate whether transplantation of human MSCs (hMSCs) can rescue cerebellar PCs and ameliorate motor function deterioration in SCA in a pre-clinical animal model. Method Transgenic mice bearing poly-glutamine mutation in ataxin-2 gene (C57BL/6J SCA2 transgenic mice) were serially transplanted with hMSCs intravenously or intracranially before and after the onset of motor function loss. Motor function of mice was evaluated by an accelerating protocol of rotarod test every 8 weeks. Immunohistochemical stain of whole brain sections was adopted to demonstrate the neuroprotective effect of hMSC transplantation on cerebellar PCs and engraftment of hMSCs into mice brain. Results Intravenous transplantation of hMSCs effectively improved rotarod performance of SCA2 transgenic mice and delayed the onset of motor function deterioration; while intracranial transplantation failed to achieve such neuroprotective effect. Immunohistochemistry revealed that intravenous transplantation was more effective in the preservation of the survival of cerebellar PCs and engraftment of hMSCs than intracranial injection, which was compatible to rotarod performance of transplanted mice. Conclusion Intravenous transplantation of hMSCs can indeed delay the onset as well as improve the motor function of SCA2 transgenic mice. The results of this preclinical study strongly support further exploration of the feasibility to transplant hMSCs for SCA patients.
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Affiliation(s)
- You-Kang Chang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
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40
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Horwitz EM, Maziarz RT, Kebriaei P. MSCs in hematopoietic cell transplantation. Biol Blood Marrow Transplant 2011; 17:S21-9. [PMID: 21195306 DOI: 10.1016/j.bbmt.2010.11.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Edwin M Horwitz
- Division of Oncology/Blood and Marrow Transplantation, The Children's Hospital of Philadelphia, and The University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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41
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Hilfiker A, Kasper C, Hass R, Haverich A. Mesenchymal stem cells and progenitor cells in connective tissue engineering and regenerative medicine: is there a future for transplantation? Langenbecks Arch Surg 2011; 396:489-497. [PMID: 21373941 DOI: 10.1007/s00423-011-0762-2] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Accepted: 02/21/2011] [Indexed: 12/14/2022]
Abstract
PURPOSE Transplantation surgery suffers from a shortage of donor organs worldwide. Cell injection and tissue engineering (TE), thus emerge as alternative therapy options. The purpose of this article is to review the progress of TE technology, focusing on mesenchymal stem cells (MSC) as a cell source for artificial functional tissue. RESULTS MSC from many different sources can be minimally invasively harvested: peripheral blood, fat tissue, bone marrow, amniotic fluid, cord blood. In comparison to embryonic stem cells (ESC), there are no ethical concerns; MSC can be extracted from autologous or allogenic tissue and cause an immune modulatory effect by suppressing the graft-versus-host reaction (GvHD). Furthermore, MSC do not develop into teratomas when transplanted, a consequence observed with ESC and iPS cells. CONCLUSION MSC as multipotent cells are capable of differentiating into mesodermal and non-mesodermal lineages. However, further studies must be performed to elucidate the differentiation capacity of MSC from different sources, and to understand the involved pathways and processes. Already, MSC have been successfully applied in clinical trials, e.g., to heal large bone defects, cartilage lesions, spinal cord injuries, cardiovascular diseases, hematological pathologies, osteogenesis imperfecta, and GvHD. A detailed understanding of the behavior and homing of MSC is desirable to enlarge the clinical application spectrum of MSC towards the in vitro generation of functional tissue for implantation, for example, resilient cartilage, contractile myocardial replacement tissue, and bioartificial heart valves.
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Affiliation(s)
- Andres Hilfiker
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
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Roux S, Leotot J, Chevallier N, Bierling P, Rouard H. [Mesenchymal stromal cells: Biological properties and clinical prospects]. Transfus Clin Biol 2011; 18:1-12. [PMID: 21367635 DOI: 10.1016/j.tracli.2011.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 01/14/2011] [Indexed: 10/18/2022]
Abstract
Mesenchymal stromal cells are defined as non-hematopoietic progenitors characterised by their adherence to plastic in culture, their expression of non-specific markers and their differentiation potential into cells of mesodermic lineage. Resident in numerous tissues, mesenchymal stromal cells are now available from several sources, including both adult and foetal tissues. After their administration, mesenchymal stromal cells preferentially migrate to injured tissues. Mesenchymal stromal cells have therapeutic effects in numerous animal models of tissue injury by a mechanism not yet clearly understood. Mechanisms likely involved in repair can be the production of paracrine, anti-inflammatory and anti-apoptotic factors, as well as cell replacement by their differentiation potential. Mesenchymal stromal cells possess immunosuppressive properties on both innate and adaptative immunity in vitro and in animal models of autoimmunity. Currently their immunosuppressive properties allow testing of mesenchymal stromal cells in allogenic context, although this use requires further investigations. Mesenchymal stromal cells can be isolated and expanded in vitro in clinical grade conditions. They represent a promising candidate for the cellular therapy of diseases, such as acute myocardial infarction, diabetes, graft versus host disease or neurodegenerative diseases. Critical points including the standardization of production and long term toxicity have to be resolved before their large scale use in clinical conditions.
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Affiliation(s)
- S Roux
- EA3952, université Paris-Est Créteil Val-de-Marne, 61, avenue du Général-de-Gaulle, 94010 Créteil cedex, France.
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Majore I, Moretti P, Stahl F, Hass R, Kasper C. Growth and differentiation properties of mesenchymal stromal cell populations derived from whole human umbilical cord. Stem Cell Rev Rep 2011; 7:17-31. [PMID: 20596801 DOI: 10.1007/s12015-010-9165-y] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Up to 2.8 × 10(7) fibroblast-like cells displaying an abundant presence of mesenchymal stem cell (MSC) markers CD73, CD90, CD105 and a low level of HLA-I expression can be isolated from one whole human umbilical cord (UC) using a simple and highly reproducible explant culture approach. Cells derived from whole UC, similar to cells collected from separate compartments of UC, display a distinct chondrogenic and adipogenic potential. Therefore they are potential candidates for cartilage and adipose tissue engineering. Cell differentiation along the osteogenic pathway is, however, less efficient, even after the addition of 1.25-dihydroxyvitamin D3, a potent osteoinductive substance. Isolated cells are highly proliferative, tolerate cryopreservation with an average survival rate of about 75% and after thawing can be propagated further, at least over 20 population doublings before their proliferative activity begins to decline. More importantly, they synthesize numerous trophic factors including neurotrophins and factors which facilitate angiogenesis and hematopoiesis. In conclusion, cells isolated from whole UC satisfies all requirements essential for the generation of stem cell banks containing permanently available cell material for applications in the field of regenerative medicine. Nevertheless, further studies are needed to improve and adjust the methods which are already employed for adult MSC expansion and differentiation to specific properties and requirements of the primitive stem cells collected from UC. So, our data verify that the choice of individual parameters for cell propagation, such as duration of cell expansion and cell seeding density, has a substantial impact on the quality of UC-derived cell populations.
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Affiliation(s)
- Ingrida Majore
- Institute of Technical Chemistry, Leibniz University of Hannover, Callinstraße 5, Hannover 30167, Germany.
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Abstract
PURPOSE OF REVIEW Multipotent mesenchymal stromal cells (MSCs) are rare cells resident in bone marrow and other organs capable of differentiating into mesodermal lineage tissues. MSCs possess immunomodulatory properties and have extensive capacity for ex-vivo expansion. Early clinical studies demonstrated safety and feasibility of infusing autologous MSCs and suggested a role in enhancing engraftment after hematopoietic cell transplant (HCT). Subsequent pilot studies using allogeneic MSCs showed safety but presented contradictory results regarding efficacy in treating graft-versus-host disease (GVHD). RECENT FINDINGS Larger, phase II allogeneic MSC infusion studies, including cells obtained from haploidentical and third-party donors, showed efficacy in GVHD treatment; however, recent randomized, placebo-controlled studies failed to corroborate these results. New investigations include MSC infusions in umbilical cord blood transplantation, MSC therapy for tissue regeneration/repair, harvest and use of MSCs from adipose tissue and cell-tracking/imaging studies using radionuclides, gene and fluorescent dye-labeled MSCs. SUMMARY MSCs remain the subject of intense investigation in HCT because of their differentiation potential and immunomodulatory properties. Whereas infusions of autologous, allogeneic and third-party donor MSCs are well tolerated, further research is needed to clarify the optimal methods for harvesting and expansion, optimal timing of administration and efficacy in the setting of HCT.
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Tolar J, Le Blanc K, Keating A, Blazar BR. Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 2011; 28:1446-55. [PMID: 20597105 DOI: 10.1002/stem.459] [Citation(s) in RCA: 296] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Mesenchymal stromal cells or mesenchymal stem cells (MSCs) have captured considerable scientific and public interest because of their potential to limit physical and immune injury, to produce bioactive molecules and to regenerate tissues. MSCs are phenotypically heterogeneous and distinct subpopulations within MSC cultures are presumed to contribute to tissue repair and the modulation of allogeneic immune responses. As the first example of efficacy, clinical trials for prevention and treatment of graft-versus-host disease after hematopoietic cell transplantation show that MSCs can effectively treat human disease. The view of the mechanisms whereby MSCs function as immunomodulatory and reparative cells has evolved simultaneously. Initially, donor MSCs were thought to replace damaged cells in injured tissues of the recipient. More recently, however, it has become increasingly clear that even transient MSC engraftment may exert favorable effects through the secretion of cytokines and other paracrine factors, which engage and recruit recipient cells in productive tissue repair. Thus, an important reason to investigate MSCs in mechanistic preclinical models and in clinical trials with well-defined end points and controls is to better understand the therapeutic potential of these multifunctional cells. Here, we review the controversies and recent insights into MSC biology, the regulation of alloresponses by MSCs in preclinical models, as well as clinical experience with MSC infusions (Table 1) and the challenges of manufacturing a ready supply of highly defined transplantable MSCs.
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Affiliation(s)
- Jakub Tolar
- Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
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Abstract
Mesenchymal stem cells (MSCs) are multipotent cells that are being clinically explored as a new therapeutic for treating a variety of immune-mediated diseases. First heralded as a regenerative therapy for skeletal tissue repair, MSCs have recently been shown to modulate endogenous tissue and immune cells. Preclinical studies of the mechanism of action suggest that the therapeutic effects afforded by MSC transplantation are short-lived and related to dynamic, paracrine interactions between MSCs and host cells. Therefore, representations of MSCs as drug-loaded particles may allow for pharmacokinetic models to predict the therapeutic activity of MSC transplants as a function of drug delivery mode. By integrating principles of MSC biology, therapy, and engineering, the field is armed to usher in the next generation of stem cell therapeutics.
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Affiliation(s)
- Biju Parekkadan
- Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Shriners Hospital for Children, and Harvard Medical School, Boston, Massachusetts 02114, USA.
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Hu KX, Sun QY, Guo M, Ai HS. The radiation protection and therapy effects of mesenchymal stem cells in mice with acute radiation injury. Br J Radiol 2010; 83:52-8. [PMID: 20139249 DOI: 10.1259/bjr/61042310] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The aim of this study was to investigate the effects and mechanisms of mesenchymal stem cells (MSCs) on haematopoietic reconstitution in reducing bone marrow cell apoptosis effects in irradiated mice, and to research the safe and effective dosage of MSCs in mice with total body irradiation (TBI). After BALB/c mice were irradiated with 5.5 Gy cobalt-60 gamma-rays, the following were observed: peripheral blood cell count, apoptosis rate, cell cycle, colony-forming unit-granulocyte macrophage (CFU-GM) and colony-forming unit-fibroblast (CFU-F) counts of bone marrow cells and pathological changes in the medulla. The survival of mice infused with three doses of MSCs after 8.0 Gy or 10 Gy TBI was examined. The blood cells recovered rapidly in the MSC groups. The apoptotic ratio of bone marrow cells in the control group was higher at 24 h after radiation. A lower ratio of G0/G1 cell cycle phases and a higher ratio of G2/M and S phases, as well as a greater number of haematopoietic islands and megalokaryocytes in the bone marrow, were observed in the MSC-treated groups. MSCs induced recovery of CFU-GM and CFU-GM and improved the survival of mice after 8 Gy TBI, but 1.5 x 10(8) kg(-1) of MSCs increased mortality. These results indicate that MSCs protected and treated irradiated mice by inducing haematopoiesis and reducing apoptosis. MSCs may be a succedaneous or intensive method of haematopoietic stem cell transplantation under certain radiation dosages, and could provide a valuable strategy for acute radiation syndrome.
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Affiliation(s)
- K X Hu
- Department of Haematology and Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
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G-CSF increases mesenchymal precursor cell numbers in the bone marrow via an indirect mechanism involving osteoclast-mediated bone resorption. Stem Cell Res 2010; 5:65-75. [PMID: 20537607 DOI: 10.1016/j.scr.2010.04.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Revised: 04/13/2010] [Accepted: 04/14/2010] [Indexed: 01/07/2023] Open
Abstract
During the course of studies to investigate whether MPC circulate in response to G-CSF, the agent most frequently used to induce mobilization of hematopoietic progenitors, we observed that while G-CSF failed to increase the number of MPC in circulation (assayed in vitro as fibroblast colony-forming cells, CFU-F), G-CSF administration nevertheless resulted in a time-dependent increase in the absolute number of CFU-F within the BM, peaking at Day 7. Treatment of BM cells from G-CSF-treated mice with hydroxyurea did not alter CFU-F numbers, suggesting that the increase in their numbers in response to G-CSF administration is not due to proliferation of existing CFU-F. Given previous studies demonstrating that G-CSF potently induces bone turnover in mice, we hypothesized that the increase in CFU-F may be triggered by the bone resorption that occurs following G-CSF administration. In accord with this hypothesis, administration of an inhibitor of osteoclast differentiation, osteoprotegerin (OPG), prevented the increase of CFU-F numbers induced by G-CSF. In conclusion, these data indicate that the cytokine treatment routinely used to mobilize hematopoietic stem cells could provide a readily applicable method to induce in vivo expansion of MPC for clinical applications.
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Effects of high-dose chemotherapy on bone marrow multipotent mesenchymal stromal cells isolated from lymphoma patients. Exp Hematol 2010; 38:292-300.e4. [DOI: 10.1016/j.exphem.2010.01.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2009] [Revised: 01/26/2010] [Accepted: 01/29/2010] [Indexed: 02/08/2023]
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Cellules souches mésenchymateuses et immunomodulation : vers de nouvelles stratégies immunosuppressives pour le traitement des maladies auto-immunes ? Rev Med Interne 2009; 30:287-99. [DOI: 10.1016/j.revmed.2008.08.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2008] [Revised: 08/27/2008] [Accepted: 08/29/2008] [Indexed: 12/29/2022]
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