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Cancedda R, Mastrogiacomo M. The Phoenix of stem cells: pluripotent cells in adult tissues and peripheral blood. Front Bioeng Biotechnol 2024; 12:1414156. [PMID: 39139297 PMCID: PMC11319133 DOI: 10.3389/fbioe.2024.1414156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 07/09/2024] [Indexed: 08/15/2024] Open
Abstract
Pluripotent stem cells are defined as cells that can generate cells of lineages from all three germ layers, ectoderm, mesoderm, and endoderm. On the contrary, unipotent and multipotent stem cells develop into one or more cell types respectively, but their differentiation is limited to the cells present in the tissue of origin or, at most, from the same germ layer. Multipotent and unipotent stem cells have been isolated from a variety of adult tissues, Instead, the presence in adult tissues of pluripotent stem cells is a very debated issue. In the early embryos, all cells are pluripotent. In mammalians, after birth, pluripotent cells are maintained in the bone-marrow and possibly in gonads. In fact, pluripotent cells were isolated from marrow aspirates and cord blood and from cultured bone-marrow stromal cells (MSCs). Only in few cases, pluripotent cells were isolated from other tissues. In addition to have the potential to differentiate toward lineages derived from all three germ layers, the isolated pluripotent cells shared other properties, including the expression of cell surface stage specific embryonic antigen (SSEA) and of transcription factors active in the early embryos, but they were variously described and named. However, it is likely that they are part of the same cell population and that observed diversities were the results of different isolation and expansion strategies. Adult pluripotent stem cells are quiescent and self-renew at very low rate. They are maintained in that state under the influence of the "niche" inside which they are located. Any tissue damage causes the release in the blood of inflammatory cytokines and molecules that activate the stem cells and their mobilization and homing in the injured tissue. The inflammatory response could also determine the dedifferentiation of mature cells and their reversion to a progenitor stage and at the same time stimulate the progenitors to proliferate and differentiate to replace the damaged cells. In this review we rate articles reporting isolation and characterization of tissue resident pluripotent cells. In the attempt to reconcile observations made by different authors, we propose a unifying picture that could represent a starting point for future experiments.
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Affiliation(s)
- Ranieri Cancedda
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
| | - Maddalena Mastrogiacomo
- Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università Degli Studi di Genova, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Summers BS, Thomas Broome S, Pang TWR, Mundell HD, Koh Belic N, Tom NC, Ng ML, Yap M, Sen MK, Sedaghat S, Weible MW, Castorina A, Lim CK, Lovelace MD, Brew BJ. A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease. Int J Tryptophan Res 2024; 17:11786469241248287. [PMID: 38757094 PMCID: PMC11097742 DOI: 10.1177/11786469241248287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 04/03/2024] [Indexed: 05/18/2024] Open
Abstract
Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.
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Affiliation(s)
- Benjamin Sebastian Summers
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Sarah Thomas Broome
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | | | - Hamish D Mundell
- Faculty of Medicine and Health, New South Wales Brain Tissue Resource Centre, School of Medical Sciences, Charles Perkins Centre, University of Sydney, NSW, Australia
| | - Naomi Koh Belic
- School of Life Sciences, University of Technology, Sydney, NSW, Australia
| | - Nicole C Tom
- Formerly of the Department of Physiology, University of Sydney, NSW, Australia
| | - Mei Li Ng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Maylin Yap
- Formerly of the Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Monokesh K Sen
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- School of Medicine, Western Sydney University, NSW, Australia
- Faculty of Medicine and Health, School of Medical Sciences, Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Sara Sedaghat
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Michael W Weible
- School of Environment and Science, Griffith University, Brisbane, QLD, Australia
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia
| | - Alessandro Castorina
- Faculty of Science, Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, University of Technology Sydney, NSW, Australia
| | - Chai K Lim
- Faculty of Medicine, Macquarie University, Sydney, NSW, Australia
| | - Michael D Lovelace
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
| | - Bruce J Brew
- Applied Neurosciences Program, Peter Duncan Neurosciences Research Unit, St. Vincent’s Centre for Applied Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, School of Clinical Medicine, UNSW Sydney, NSW, Australia
- Departments of Neurology and Immunology, St. Vincent’s Hospital, Sydney, NSW, Australia
- University of Notre Dame, Darlinghurst, Sydney, NSW, Australia
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Ahamad N, Singh BB. Calcium channels and their role in regenerative medicine. World J Stem Cells 2021; 13:260-280. [PMID: 33959218 PMCID: PMC8080543 DOI: 10.4252/wjsc.v13.i4.260] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/22/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cells hold indefinite self-renewable capability that can be differentiated into all desired cell types. Based on their plasticity potential, they are divided into totipotent (morula stage cells), pluripotent (embryonic stem cells), multipotent (hematopoietic stem cells, multipotent adult progenitor stem cells, and mesenchymal stem cells [MSCs]), and unipotent (progenitor cells that differentiate into a single lineage) cells. Though bone marrow is the primary source of multipotent stem cells in adults, other tissues such as adipose tissues, placenta, amniotic fluid, umbilical cord blood, periodontal ligament, and dental pulp also harbor stem cells that can be used for regenerative therapy. In addition, induced pluripotent stem cells also exhibit fundamental properties of self-renewal and differentiation into specialized cells, and thus could be another source for regenerative medicine. Several diseases including neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, virus infection (also coronavirus disease 2019) have limited success with conventional medicine, and stem cell transplantation is assumed to be the best therapy to treat these disorders. Importantly, MSCs, are by far the best for regenerative medicine due to their limited immune modulation and adequate tissue repair. Moreover, MSCs have the potential to migrate towards the damaged area, which is regulated by various factors and signaling processes. Recent studies have shown that extracellular calcium (Ca2+) promotes the proliferation of MSCs, and thus can assist in transplantation therapy. Ca2+ signaling is a highly adaptable intracellular signal that contains several components such as cell-surface receptors, Ca2+ channels/pumps/exchangers, Ca2+ buffers, and Ca2+ sensors, which together are essential for the appropriate functioning of stem cells and thus modulate their proliferative and regenerative capacity, which will be discussed in this review.
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Affiliation(s)
- Nassem Ahamad
- School of Dentistry, UT Health Science Center San Antonio, San Antonio, TX 78257, United States
| | - Brij B Singh
- School of Dentistry, UT Health Science Center San Antonio, San Antonio, TX 78257, United States
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Rossi F, Noren H, Jove R, Beljanski V, Grinnemo KH. Differences and similarities between cancer and somatic stem cells: therapeutic implications. Stem Cell Res Ther 2020; 11:489. [PMID: 33208173 PMCID: PMC7672862 DOI: 10.1186/s13287-020-02018-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 11/05/2020] [Indexed: 02/06/2023] Open
Abstract
Over the last decades, the cancer survival rate has increased due to personalized therapies, the discovery of targeted therapeutics and novel biological agents, and the application of palliative treatments. Despite these advances, tumor resistance to chemotherapy and radiation and rapid progression to metastatic disease are still seen in many patients. Evidence has shown that cancer stem cells (CSCs), a sub-population of cells that share many common characteristics with somatic stem cells (SSCs), contribute to this therapeutic failure. The most critical properties of CSCs are their self-renewal ability and their capacity for differentiation into heterogeneous populations of cancer cells. Although CSCs only constitute a low percentage of the total tumor mass, these cells can regrow the tumor mass on their own. Initially identified in leukemia, CSCs have subsequently been found in cancers of the breast, the colon, the pancreas, and the brain. Common genetic and phenotypic features found in both SSCs and CSCs, including upregulated signaling pathways such as Notch, Wnt, Hedgehog, and TGF-β. These pathways play fundamental roles in the development as well as in the control of cell survival and cell fate and are relevant to therapeutic targeting of CSCs. The differences in the expression of membrane proteins and exosome-delivered microRNAs between SSCs and CSCs are also important to specifically target the stem cells of the cancer. Further research efforts should be directed toward elucidation of the fundamental differences between SSCs and CSCs to improve existing therapies and generate new clinically relevant cancer treatments.
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Affiliation(s)
- Fiorella Rossi
- NSU Cell Therapy Institute, Nova Southeastern University, 3301 College Ave, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA
| | - Hunter Noren
- NSU Cell Therapy Institute, Nova Southeastern University, 3301 College Ave, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA
| | - Richard Jove
- NSU Cell Therapy Institute, Nova Southeastern University, 3301 College Ave, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA
| | - Vladimir Beljanski
- NSU Cell Therapy Institute, Nova Southeastern University, 3301 College Ave, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA.
| | - Karl-Henrik Grinnemo
- NSU Cell Therapy Institute, Nova Southeastern University, 3301 College Ave, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA. .,Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. .,Department of Surgical Sciences, Division of Cardiothoracic Surgery and Anaesthesiology, Uppsala University, Akademiska University Hospital, Akademiska sjukhuset, ingång 50, 4 tr, 751 85, Uppsala, Sweden.
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Ahangar P, Mills SJ, Smith LE, Strudwick XL, Ting AE, Vaes B, Cowin AJ. Human multipotent adult progenitor cell-conditioned medium improves wound healing through modulating inflammation and angiogenesis in mice. Stem Cell Res Ther 2020; 11:299. [PMID: 32680566 PMCID: PMC7368692 DOI: 10.1186/s13287-020-01819-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/15/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Stem cell therapies have been widely investigated for their healing effects. However, the translation of these therapies has been hampered by the requirement to deliver live allogeneic or autologous cells directly to the wound in a clinical setting. Multipotent adult progenitor cells (MAPC® cells) are a subpopulation of bone marrow-derived adherent stem cells that secrete a wide range of factors known to accelerate the wound healing process. The aim of this study was to determine the impact of MAPC cells secretome on healing outcomes without the presence of MAPC cells. METHODS The effect of MAPC-conditioned medium (MAPC-CM) on the capacity of keratinocytes, fibroblasts and endothelial cells to migrate and proliferate was determined in vitro using scratch wound closure and WST1 assay, respectively. The effect of MAPC-CM on collagen deposition and angiogenesis was also assessed using in vitro methods. Additionally, two excisional wounds were created on the dorsal surface of mice (n = 8/group) and 100 μL of 20× MAPC-CM were intradermally injected to the wound margins. Wound tissues were collected at 3, 7 and 14 days post-wounding and stained with H&E for microscopic analysis. Immunohistochemistry was performed to investigate inflammation, angiogenesis and collagen deposition in the wounds. RESULTS Skin fibroblasts, keratinocytes and endothelial cells treated with MAPC-CM all showed improved rates of scratch closure and increased cellular proliferation. Moreover, fibroblasts treated with MAPC-CM deposited more collagens I and III and endothelial cells treated with MAPC-CM showed increased capillary tube formation. Murine excisional wounds intradermally injected with MAPC-CM showed a significant reduction in the wound area and an increase in the rate of reepithelialisation. The results also showed that inflammatory cell infiltration was decreased while an increase in angiogenesis, as well as collagens I and III expressions, was observed. CONCLUSION These findings suggest that factors produced by MAPC cells can have an important effect on cutaneous wound healing by affecting skin cell proliferation and migration, balancing inflammation and improving the formation of extracellular matrix and angiogenesis. Development of stem cell-free therapy for the treatment of wounds may be a more clinically translatable approach for improving healing outcomes.
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Affiliation(s)
- Parinaz Ahangar
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Stuart J Mills
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Louise E Smith
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Xanthe L Strudwick
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia
| | | | - Bart Vaes
- ReGenesys BVBA, Bio-Incubator Leuven, Gaston Geenslaan 1, 3001, Heverlee, Belgium
| | - Allison J Cowin
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia. .,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia.
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Zhang J, Cui Y, Li X, Xiao Y, Liu L, Jia F, He J, Xie X, Parthasarathy S, Hao H, Fang N. 5F peptide promotes endothelial differentiation of bone marrow stem cells through activation of ERK1/2 signaling. Eur J Pharmacol 2020; 876:173051. [PMID: 32145325 DOI: 10.1016/j.ejphar.2020.173051] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 11/29/2022]
Abstract
Synthetic apolipoprotein A-I (apoA-I) mimetic peptide 5F exhibits anti-atherosclerotic ability with largely unknown mechanism(s). Bone marrow (BM)-derived endothelial progenitor cells (EPCs) play a critical role in vascular integrity and function. The objective of the present study was to evaluate the effect of 5F on endothelial differentiation of BM stem cells and related mechanisms. Murine BM multipotent adult progenitor cells (MAPCs) were induced to differentiate into endothelial cells in vitro with or without 5F. The expression of endothelial markers vWF, Flk-1 and CD31 was significantly increased in the cells treated with 5F with enhanced in vitro vascular tube formation and LDL uptake without significant changes on proliferation and stem cell maker Oct-4 expression. Phosphorylated ERK1/2, not Akt, was significantly increased in 5F-treated cells. Treatment of MAPCs with PD98059 or small interfering RNA against ERK2 substantially attenuated ERK1/2 phosphorylation, and effectively prevented 5F-induced enhancement of endothelial differentiation of MAPCs. In vivo studies revealed that 5F increased EPCs number in the BM in mice after acute hindlimb ischemia that was effectively prevented with PD98059 treatment. These data supported the conclusion that 5F promoted endothelial differentiation of MAPCs through activation of ERK1/2 signaling.
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Affiliation(s)
- Jia Zhang
- Department of Geriatrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, 200127, China; Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Yuqi Cui
- Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Xin Li
- Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Yuan Xiao
- Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Lingjuan Liu
- Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Fengpeng Jia
- Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jianfeng He
- Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Xiaoyun Xie
- Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Sampath Parthasarathy
- Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, USA
| | - Hong Hao
- Davis Heart & Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ningyuan Fang
- Department of Geriatrics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, 200127, China.
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Histone Arginine Methylation-Mediated Epigenetic Regulation of Discoidin Domain Receptor 2 Controls the Senescence of Human Bone Marrow Mesenchymal Stem Cells. Stem Cells Int 2019; 2019:7670316. [PMID: 31379950 PMCID: PMC6657615 DOI: 10.1155/2019/7670316] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 03/27/2019] [Accepted: 05/21/2019] [Indexed: 12/26/2022] Open
Abstract
The application of human bone marrow mesenchymal stem cells (hBM-MSCs) in cell-based clinical therapies is hindered by the limited number of cells remaining after the initial isolation process and by cellular senescence following in vitro expansion. Understanding the process of in vitro senescence in hBM-MSCs would enable the development of strategies to maintain their vitality after cell culture. Herein, we compared the gene expression profiles of human embryonic stem cells and human BM-MSCs from donors of different ages. We first found that the expression of discoidin domain receptor 2 (DDR2) in adult donor-derived hBM-MSCs was lower than it was in the young donor-derived hBM-MSCs. Moreover, in vitro cultured late-passage hBM-MSCs showed significant downregulation of DDR2 compared to their early-passage counterparts, and siRNA inhibition of DDR2 expression recapitulated features of senescence in early-passage hBM-MSCs. Further, we found through knockdown and overexpression approaches that coactivator-associated arginine methyltransferase 1 (CARM1) regulated the expression level of DDR2 and the senescence of hBM-MSCs. Finally, chromatin immunoprecipitation analysis confirmed direct binding of CARM1 to the DDR2 promoter region with a high level of H3R17 methylation in early-passage hBM-MSCs, and inhibition of CARM1-mediated histone arginine methylation decreased DDR2 expression and led to cellular senescence. Taken together, our findings suggest that DDR2 plays a major role in regulating the in vitro senescence of hBM-MSCs and that CARM1-mediated histone H3 methylation might be the upstream regulatory mechanism controlling this function of DDR2.
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Borlongan CV. Concise Review: Stem Cell Therapy for Stroke Patients: Are We There Yet? Stem Cells Transl Med 2019; 8:983-988. [PMID: 31099181 PMCID: PMC6708064 DOI: 10.1002/sctm.19-0076] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/03/2019] [Indexed: 12/14/2022] Open
Abstract
Four decades of preclinical research demonstrating survival, functional integration, and behavioral effects of transplanted stem cells in experimental stroke models have provided ample scientific basis for initiating limited clinical trials of stem cell therapy in stroke patients. Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. Two recently concluded stroke clinical trials on mesenchymal stem cells (MSCs) highlight the importance of strict adherence to the basic science findings of optimal transplant regimen of cell dose, timing, and route of delivery in enhancing the functional outcomes of cell therapy. Echoing the Stem Cell Therapeutics as an Emerging Paradigm for Stroke and Stroke Treatment Academic Industry Roundtable call for an NIH‐guided collaborative consortium of multiple laboratories in testing the safety and efficacy of stem cells and their derivatives, not just as stand‐alone but preferably in combination with approved thrombolytic or thrombectomy, may further increase the likelihood of successful fruition of translating stem cell therapy for stroke clinical application. The laboratory and clinical experience with MSC therapy for stroke may guide the future translational research on stem cell‐based regenerative medicine in neurological disorders. stem cells translational medicine2019;8:983&988
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Affiliation(s)
- Cesario V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida, USA
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Traumatic Brain Injury and Stem Cell: Pathophysiology and Update on Recent Treatment Modalities. Stem Cells Int 2017; 2017:6392592. [PMID: 28852409 PMCID: PMC5568618 DOI: 10.1155/2017/6392592] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 07/26/2017] [Indexed: 12/30/2022] Open
Abstract
Traumatic brain injury (TBI) is a complex condition that presents with a wide spectrum of clinical symptoms caused by an initial insult to the brain through an external mechanical force to the skull. In the United States alone, TBI accounts for more than 50,000 deaths per year and is one of the leading causes of mortality among young adults in the developed world. Pathophysiology of TBI is complex and consists of acute and delayed injury. In the acute phase, brain tissue destroyed upon impact includes neurons, glia, and endothelial cells, the latter of which makes up the blood-brain barrier. In the delayed phase, “toxins” released from damaged cells set off cascades in neighboring cells eventually leading to exacerbation of primary injury. As researches further explore pathophysiology and molecular mechanisms underlying this debilitating condition, numerous potential therapeutic strategies, especially those involving stem cells, are emerging to improve recovery and possibly reverse damage. In addition to elucidating the most recent advances in the understanding of TBI pathophysiology, this review explores two primary pathways currently under investigation and are thought to yield the most viable therapeutic approach for treatment of TBI: manipulation of endogenous neural cell response and administration of exogenous stem cell therapy.
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Martens A, Ordies S, Vanaudenaerde BM, Verleden SE, Vos R, Van Raemdonck DE, Verleden GM, Roobrouck VD, Claes S, Schols D, Verbeken E, Verfaillie CM, Neyrinck AP. Immunoregulatory effects of multipotent adult progenitor cells in a porcine ex vivo lung perfusion model. Stem Cell Res Ther 2017; 8:159. [PMID: 28676074 PMCID: PMC5497348 DOI: 10.1186/s13287-017-0603-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 05/19/2017] [Accepted: 06/05/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Primary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant. Previous research has indicated that MAPC cell therapy might attenuate this injury by its paracrine effects on the pro-/anti-inflammatory balance. This study aims to investigate the immunoregulatory capacities of MAPC cells in PGD when administered in the airways. METHODS Lungs of domestic pigs (n = 6/group) were subjected to 90 minutes of warm ischemia. Lungs were cold flushed, cannulated on ice and placed on EVLP for 6 hours. At the start of EVLP, 40 ml of an albumin-plasmalyte mixture was distributed in the airways (CONTR group). In the MAPC cell group, 150 million MAPC cells (ReGenesys/Athersys, Cleveland, OH, USA) were added to this mixture. At the end of EVLP, a physiological evaluation (pulmonary vascular resistance, lung compliance, PaO2/FiO2), wet-to-dry weight ratio (W/D) sampling and a multiplex analysis of bronchoalveolar lavage (BAL) (2 × 30 ml) was performed. RESULTS Pulmonary vascular resistance, lung compliance, PaO2/FiO2 and W/D were not statistically different at the end of EVLP between both groups. BAL neutrophilia was significantly reduced in the MAPC cell group. Moreover, there was a significant decrease in TNF-α, IL-1β and IFN-γ in the BAL, but not in IFN-α; whereas IL-4, IL-10 and IL-8 were below the detection limit. CONCLUSIONS Although no physiologic effect of MAPC cell distribution in the airways was detected during EVLP, we observed a reduction in pro-inflammatory cytokines and neutrophils in BAL in the MAPC cell group. This effect on the innate immune system might play an important role in critically modifying the process of PGD after transplantation. Further experiments will have to elucidate the immunoregulatory effect of MAPC cell administration on graft function after transplantation.
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Affiliation(s)
- An Martens
- Laboratory of Anesthesiology and Algology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven and University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Sofie Ordies
- Laboratory of Anesthesiology and Algology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven and University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Bart M. Vanaudenaerde
- Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium
- Laboratory of Pneumology, Department of Clinical and Experimental Medicine, Lung Transplant Unit, Katholieke Universiteit Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Stijn E. Verleden
- Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium
- Laboratory of Pneumology, Department of Clinical and Experimental Medicine, Lung Transplant Unit, Katholieke Universiteit Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Robin Vos
- Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium
- Laboratory of Pneumology, Department of Clinical and Experimental Medicine, Lung Transplant Unit, Katholieke Universiteit Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Dirk E. Van Raemdonck
- Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium
- Laboratory of Experimental Thoracic Surgery, Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Geert M. Verleden
- Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium
- Laboratory of Pneumology, Department of Clinical and Experimental Medicine, Lung Transplant Unit, Katholieke Universiteit Leuven and University Hospitals Leuven, Leuven, Belgium
| | | | - Sandra Claes
- Laboratory of Virology and Chemotherapy (Rega Institute), Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Dominique Schols
- Laboratory of Virology and Chemotherapy (Rega Institute), Department of Microbiology and Immunology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Eric Verbeken
- Department of Histopathology, University Hospitals Leuven, Leuven, Belgium
| | - Catherine M. Verfaillie
- Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven-University of Leuven, Leuven, Belgium
| | - Arne P. Neyrinck
- Laboratory of Anesthesiology and Algology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven and University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
- Leuven Lung Transplant Unit, Katholieke Universiteit Leuven, Leuven, Belgium
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11
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Cunha JPMCM, Leuckx G, Sterkendries P, Korf H, Bomfim-Ferreira G, Overbergh L, Vaes B, Heimberg H, Gysemans C, Mathieu C. Human multipotent adult progenitor cells enhance islet function and revascularisation when co-transplanted as a composite pellet in a mouse model of diabetes. Diabetologia 2017; 60:134-142. [PMID: 27704164 PMCID: PMC6518081 DOI: 10.1007/s00125-016-4120-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 09/06/2016] [Indexed: 12/28/2022]
Abstract
AIMS/HYPOTHESIS Hypoxia in the initial days after islet transplantation leads to considerable loss of islet mass and contributes to disappointing outcomes in the clinical setting. The aim of the present study was to investigate whether co-transplantation of human non-endothelial bone marrow-derived multipotent adult progenitor cells (MAPCs), which are non-immunogenic and can secrete angiogenic growth factors during the initial days after implantation, could improve islet engraftment and survival. METHODS Islets (150) were co-transplanted, with or without human MAPCs (2.5 × 105) as separate or composite pellets, under the kidney capsule of syngeneic alloxan-induced diabetic C57BL/6 mice. Blood glucose levels were frequently monitored and IPGTTs were carried out. Grafts and serum were harvested at 2 and 5 weeks after transplantation to assess outcome. RESULTS Human MAPCs produced high amounts of angiogenic growth factors, including vascular endothelial growth factor, in vitro and in vivo, as demonstrated by the induction of neo-angiogenesis in the chorioallantoic membrane assay. Islet-human MAPC co-transplantation as a composite pellet significantly improved the outcome of islet transplantation as measured by the initial glycaemic control, diabetes reversal rate, glucose tolerance and serum C-peptide concentration compared with the outcome following transplantation of islets alone. Histologically, a higher blood vessel area and density in addition to a higher vessel/islet ratio were detected in recipients of islet-human MAPC composites. CONCLUSIONS/INTERPRETATION The present data suggest that co-transplantation of mouse pancreatic islets with human MAPCs, which secrete high amounts of angiogenic growth factors, enhance islet graft revascularisation and subsequently improve islet graft function.
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Affiliation(s)
- João Paulo M C M Cunha
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
| | - Gunter Leuckx
- Beta cell neogenesis laboratory, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Hannelie Korf
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
| | - Gabriela Bomfim-Ferreira
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
| | - Lutgart Overbergh
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
| | | | - Harry Heimberg
- Beta cell neogenesis laboratory, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Conny Gysemans
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium.
| | - Chantal Mathieu
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
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12
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Plessers J, Dekimpe E, Van Woensel M, Roobrouck VD, Bullens DM, Pinxteren J, Verfaillie CM, Van Gool SW. Clinical-Grade Human Multipotent Adult Progenitor Cells Block CD8+ Cytotoxic T Lymphocytes. Stem Cells Transl Med 2016; 5:1607-1619. [PMID: 27465071 DOI: 10.5966/sctm.2016-0030] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 06/13/2016] [Indexed: 01/01/2023] Open
Abstract
: MultiStem cells are clinical-grade multipotent adult bone marrow-derived progenitor cells (MAPCs), with extensive replication potential and broader differentiation capacity compared with mesenchymal stem cells. Human MAPCs suppress T-cell proliferation induced by alloantigens and mutually interact with allogeneic natural killer cells. In this study, the interaction between MultiStem and CD8+ cytotoxic T lymphocytes (CTLs) was addressed for the first time. In an in vitro setting, the immunogenicity of MultiStem, the susceptibility of MultiStem toward CTL-mediated lysis, and its effects on CTL function were investigated. MultiStem was nonimmunogenic for alloreactive CTL induction and was-even after major histocompatibility complex class I upregulation-insensitive to alloantigen-specific CTL-mediated lysis. Furthermore, MultiStem reduced CTL proliferation and significantly decreased perforin expression during the T-cell activation phase. As a consequence, MultiStem dose-dependently impaired the induction of CTL function. These effects of MultiStem were mediated predominantly through contact-dependent mechanisms. Moreover, MultiStem cells considerably influenced the expression of T-cell activation markers CD25, CD69, and human leukocyte antigen-DR. The MultiStem-induced CD8-CD69+ T-cell population displayed a suppressive effect on the induction of CTL function during a subsequent mixed-lymphocyte culture. Finally, the killer activity of activated antigen-specific CTLs during their cytolytic effector phase was also diminished in the presence of MultiStem. This study confirms that these clinical-grade MAPCs are an immune-modulating population that inhibits CTL activation and effector responses and are, consequently, a highly valuable cell population for adoptive immunosuppressive therapy in diseases where damage is induced by CTLs. SIGNIFICANCE Because multipotent adult progenitor cells (MAPCs) are among the noteworthy adult mesenchymal stem cell populations for immune therapy and have the advantage over mesenchymal stem cells (MSCs) of large-scale manufacturing and banking potential and thus prompt availability, it is important to understand how MAPCs interact with immune cells to validate their widespread therapeutic applicability. Cytotoxic immune effector cells play a crucial role in immune homeostasis and in the pathogenesis of some autoimmune diseases. This study assessed for the first time the in vitro influence of a clinical-grade human MAPC product (MultiStem) on the cytotoxic function of CD8+ T cells (CTLs) by evaluating the immunogenicity of MAPCs and the susceptibility of MAPCs toward CTL-mediated lysis and by analyzing the mechanism of MAPC-mediated modulation of CTL functionality. These results may represent a highly relevant contribution to the current knowledge and, in combination with the results of future phase II/III trials using MultiStem, could lead to an intriguing continuation of stem cell-based research for immunotherapy.
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Affiliation(s)
- Jeroen Plessers
- Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium
| | - Emily Dekimpe
- Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium
| | - Matthias Van Woensel
- Research Group Experimental Neurosurgery and Neuroanatomy, Department of Neurosciences, KU Leuven-University of Leuven, Leuven, Belgium
| | - Valerie D Roobrouck
- Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven-University of Leuven, Leuven, Belgium
- ReGenesys, Heverlee, Belgium
| | - Dominique M Bullens
- Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium
- Clinical Department of Pediatrics, University Hospital UZ Leuven, Leuven, Belgium
| | | | - Catherine M Verfaillie
- Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven-University of Leuven, Leuven, Belgium
| | - Stefaan W Van Gool
- Department of Paediatrics, Uniklinik Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
- Immuno-Oncology Centre Cologne, Köln, Germany
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13
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LoGuidice A, Houlihan A, Deans R. Multipotent adult progenitor cells on an allograft scaffold facilitate the bone repair process. J Tissue Eng 2016; 7:2041731416656148. [PMID: 27493716 PMCID: PMC4959303 DOI: 10.1177/2041731416656148] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 06/02/2016] [Indexed: 01/08/2023] Open
Abstract
Multipotent adult progenitor cells are a recently described population of stem cells derived from the bone marrow stroma. Research has demonstrated the potential of multipotent adult progenitor cells for treating ischemic injury and cardiovascular repair; however, understanding of multipotent adult progenitor cells in orthopedic applications remains limited. In this study, we evaluate the osteogenic and angiogenic capacity of multipotent adult progenitor cells, both in vitro and loaded onto demineralized bone matrix in vivo, with comparison to mesenchymal stem cells, as the current standard. When compared to mesenchymal stem cells, multipotent adult progenitor cells exhibited a more robust angiogenic protein release profile in vitro and developed more extensive vasculature within 2 weeks in vivo. The establishment of this vascular network is critical to the ossification process, as it allows nutrient exchange and provides an influx of osteoprogenitor cells to the wound site. In vitro assays confirmed the multipotency of multipotent adult progenitor cells along mesodermal lineages and demonstrated the enhanced expression of alkaline phosphatase and production of calcium-containing mineral deposits by multipotent adult progenitor cells, necessary precursors for osteogenesis. In combination with a demineralized bone matrix scaffold, multipotent adult progenitor cells demonstrated enhanced revascularization and new bone formation in vivo in an orthotopic defect model when compared to mesenchymal stem cells on demineralized bone matrix or demineralized bone matrix–only control groups. The potent combination of angiogenic and osteogenic properties provided by multipotent adult progenitor cells appears to create a synergistic amplification of the bone healing process. Our results indicate that multipotent adult progenitor cells have the potential to better promote tissue regeneration and healing and to be a functional cell source for use in orthopedic applications.
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Burrows GG, Van't Hof W, Reddy AP, Wilmarth PA, David LL, Raber A, Bogaerts A, Timmerman L, Pinxteren J, Roobrouck VD, Deans RJ, Maziarz RT. Solution-Phase Crosstalk and Regulatory Interactions Between Multipotent Adult Progenitor Cells and Peripheral Blood Mononuclear Cells. Stem Cells Transl Med 2015; 4:1436-49. [PMID: 26494783 PMCID: PMC4675500 DOI: 10.5966/sctm.2014-0225] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 08/03/2015] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessed in clinical trials for acute graft versus host disease with demonstrated immunomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Anti-CD3/anti-CD28 (3/28) activation of T cells within the peripheral blood mononuclear cell (PBMC) compartment was performed in the presence or absence of MAPCs. Liquid chromatography-coupled tandem mass spectrometry was used to characterize the differential secretion of proteins, and transcriptional profiling was used to monitor mRNA expression changes in both cell populations. Overall, 239 secreted and/or ectodomain-shed proteins were detected in the secretomes of PBMCs and MAPCs. In addition, 3/28 activation of PBMCs induced differential expression of 2,925 genes, and 22% of these transcripts were differentially expressed on exposure to MAPCs in Transwell. MAPCs exposed to 3/28-activated PBMCs showed differential expression of 1,247 MAPC genes. Crosstalk was demonstrated by reciprocal transcriptional regulation. Secretome proteins and transcriptional signatures were used to predict molecular activities by which MAPCs could dampen local and systemic inflammatory responses. These data support the hypothesis that MAPCs block PBMC proliferation via cell cycle arrest coupled to metabolic stress in the form of tryptophan depletion, resulting in GCN2 kinase activation, downstream signaling, and inhibition of cyclin D1 translation. These data also provide a plausible explanation for the immune privilege reported with administration of donor MAPCs. Although most components of the major histocompatibility complex class II antigen presentation pathway were markedly transcriptionally upregulated, cell surface expression of human leukocyte antigen-DR is minimal on MAPCs exposed to 3/28-activated PBMCs. SIGNIFICANCE This study documents experiments quantifying solution-phase crosstalk between multipotent adult progenitor cells (MAPCs) and peripheral blood mononuclear cells. The secretome and transcriptional changes quantified suggest mechanisms by which MAPCs are hypothesized to provide both local and systemic immunoregulation of inflammation. The potential impact of these studies includes development of a robust experimental framework to be used for preclinical evaluation of the specific mechanisms by which beneficial effects are obtained after treatment of patients with MAPCs.
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Affiliation(s)
- Gregory G Burrows
- Center for Hematologic Malignancies, Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, USA
| | - Wouter Van't Hof
- Regenerative Medicine Program, Athersys Inc., Cleveland, Ohio, USA National Center for Regenerative Medicine, Cleveland, Ohio, USA
| | - Ashok P Reddy
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, USA
| | - Phillip A Wilmarth
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, USA
| | - Larry L David
- Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon, USA
| | - Amy Raber
- Regenerative Medicine Program, Athersys Inc., Cleveland, Ohio, USA
| | | | | | | | | | - Robert J Deans
- Regenerative Medicine Program, Athersys Inc., Cleveland, Ohio, USA National Center for Regenerative Medicine, Cleveland, Ohio, USA ReGenesys, Inc., Leuven, Belgium
| | - Richard T Maziarz
- Center for Hematologic Malignancies, Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA
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15
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Yu L, Weng Y, Shui X, Fang W, Zhang E, Pan J. Multipotent Adult Progenitor Cells from Bone Marrow Differentiate into Chondrocyte-Like Cells. J Arthroplasty 2015; 30:1273-6. [PMID: 25703771 DOI: 10.1016/j.arth.2015.01.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 01/27/2015] [Accepted: 01/28/2015] [Indexed: 02/01/2023] Open
Abstract
Cartilage tissue engineering has great potential for treating chondral and osteochondral injuries. Efficient seed cells are the key to cartilage tissue engineering. Multipotent adult progenitor cells (MAPCs) have greater differentiation ability than other bone-marrow stem cells, and thus may be candidate seed cells. We attempted to differentiate MAPCs into chondrocyte-like cells to evaluate their suitability as seed cells for cartilage tissue engineering. Toluidine blue and Alcian blue staining suggested that glycosaminoglycan was expressed in differentiated cells. Immunofluorostaining indicated that differentiated human MAPCs (hMAPCs) expressed collagen II. Based on these results, we concluded that bone-marrow-derived hMAPCs could differentiate into chondrocyte-like cells in vitro.
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Affiliation(s)
- Lele Yu
- Department of Orthopedics, The second Affiliated Hospital of Wenzhou Medical University, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, China
| | - Yimin Weng
- Department of Orthopedics, The second Affiliated Hospital of Wenzhou Medical University, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, China.
| | - Xiaolong Shui
- Department of Orthopedics, The second Affiliated Hospital of Wenzhou Medical University, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, China
| | - Wenlai Fang
- Department of Orthopedics, The second Affiliated Hospital of Wenzhou Medical University, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, China
| | - Erge Zhang
- Department of Orthopedics, The second Affiliated Hospital of Wenzhou Medical University, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, China
| | - Jun Pan
- Department of Orthopedics, The second Affiliated Hospital of Wenzhou Medical University, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, China
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16
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Abstract
Despite substantial clinical advances over the past 65 years, cardiovascular disease remains the leading cause of death in America. The past 15 years has witnessed major basic and translational interest in the use of stem and precursor cells as a therapeutic agent for chronically injured organs. Among the cell types under investigation, adult mesenchymal stem cells are widely studied, and in early stage, clinical studies show promise for repair and regeneration of cardiac tissues. The ability of mesenchymal stem cells to differentiate into mesoderm- and nonmesoderm-derived tissues, their immunomodulatory effects, their availability, and their key role in maintaining and replenishing endogenous stem cell niches have rendered them one of the most heavily investigated and clinically tested type of stem cell. Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials. Here, we review the biology of mesenchymal stem cells, their interaction with endogenous molecular and cellular pathways, and their modulation of immune responses. Additionally, we discuss factors that enhance their proliferative and regenerative ability and factors that may hinder their effectiveness in the clinical setting.
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Affiliation(s)
- Vasileios Karantalis
- From the University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, FL
| | - Joshua M Hare
- From the University of Miami Miller School of Medicine, Interdisciplinary Stem Cell Institute, FL.
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17
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18
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Shoshani O, Zipori D. Stress as a fundamental theme in cell plasticity. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1849:371-7. [PMID: 25038585 DOI: 10.1016/j.bbagrm.2014.07.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 07/08/2014] [Accepted: 07/09/2014] [Indexed: 01/16/2023]
Abstract
Over a decade of intensive investigation of the possible plasticity of mammalian cells has eventually substantiated that mammalian species are endowed with a remarkable capacity to change mature cell fates. We review below the evidence for the occurrence of processes such as dedifferentiation and transdifferentiation within mammalian tissues in vivo, and in cells removed from their protective microenvironment and seeded in culture under conditions poorly resembling their physiological state in situ. Overall, these studies point to one major conclusion: stressful conditions, whether due to in vivo tissue damage or otherwise to isolation of cells from their in vivo restrictive niches, lead to extreme fate changes. Some examples of dedifferentiation are discussed in detail showing that rare cells within the population tend to turn back into less mature ones due to severe cell damage. It is proposed that cell stress, mechanistically sensed by isolation from neighboring cells, leads to dedifferentiation, in an attempt to build a new stem cell reservoir for subsequent regeneration of the damaged tissue. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity.
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Affiliation(s)
- Ofer Shoshani
- Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA
| | - Dov Zipori
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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19
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Kozakowska M, Szade K, Dulak J, Jozkowicz A. Role of heme oxygenase-1 in postnatal differentiation of stem cells: a possible cross-talk with microRNAs. Antioxid Redox Signal 2014; 20:1827-50. [PMID: 24053682 PMCID: PMC3961774 DOI: 10.1089/ars.2013.5341] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
SIGNIFICANCE Heme oxygenase-1 (HO-1) converts heme to biliverdin, carbon monoxide, and ferrous ions, but its cellular functions are far beyond heme metabolism. HO-1 via heme removal and degradation products acts as a cytoprotective, anti-inflammatory, immunomodulatory, and proangiogenic protein, regulating also a cell cycle. Additionally, HO-1 can translocate to nucleus and regulate transcription factors, so it can also act independently of enzymatic function. RECENT ADVANCES Recently, a body of evidence has emerged indicating a role for HO-1 in postnatal differentiation of stem and progenitor cells. Maturation of satellite cells, skeletal myoblasts, adipocytes, and osteoclasts is inhibited by HO-1, whereas neurogenic differentiation and formation of cardiomyocytes perhaps can be enhanced. Moreover, HO-1 influences a lineage commitment in pluripotent stem cells and maturation of hematopoietic cells. It may play a role in development of osteoblasts, but descriptions of its exact effects are inconsistent. CRITICAL ISSUES In this review we discuss a role of HO-1 in cell differentiation, and possible HO-1-dependent signal transduction pathways. Among the potential mediators, we focused on microRNA (miRNA). These small, noncoding RNAs are critical for cell differentiation. Recently we have found that HO-1 not only influences expression of specific miRNAs but also regulates miRNA processing enzymes. FUTURE DIRECTIONS It seems that interplay between HO-1 and miRNAs may be important in regulating fates of stem and progenitor cells and needs further intensive studies.
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Affiliation(s)
- Magdalena Kozakowska
- 1 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Krakow, Poland
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20
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Ketkar-Atre A, Struys T, Soenen SJ, Lambrichts I, Verfaillie CM, De Cuyper M, Himmelreich U. Variability in contrast agent uptake by different but similar stem cell types. Int J Nanomedicine 2013; 8:4577-91. [PMID: 24399873 PMCID: PMC3876490 DOI: 10.2147/ijn.s51588] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The need to track and evaluate the fate of transplanted cells is an important issue in regenerative medicine. In order to accomplish this, pre-labelling cells with magnetic resonance imaging (MRI) contrast agents is a well-established method. Uptake of MRI contrast agents by non-phagocytic stem cells, and factors such as cell homeostasis or the adverse effects of contrast agents on cell biology have been extensively studied, but in the context of nanoparticle (NP)-specific parameters. Here, we have studied three different types of NPs (Endorem®, magnetoliposomes [MLs], and citrate coated C-200) to label relatively larger, mesenchymal stem cells (MSCs) and, much smaller yet faster proliferating, multipotent adult progenitor cells (MAPCs). Both cell types are similar, as they are isolated from bone marrow and have substantial regenerative potential, which make them interesting candidates for comparative experiments. Using NPs with different surface coatings and sizes, we found that differences in the proliferative and morphological characteristics of the cells used in the study are mainly responsible for the fate of endocytosed iron, intracellular iron concentration, and cytotoxic responses. The quantitative analysis, using high-resolution electron microscopy images, demonstrated a strong relationship between cell volume/surface, uptake, and cytotoxicity. Interestingly, uptake and toxicity trends are reversed if intracellular concentrations, and not amounts, are considered. This indicates that more attention should be paid to cellular parameters such as cell size and proliferation rate in comparative cell-labeling studies.
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Affiliation(s)
- Ashwini Ketkar-Atre
- Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Tom Struys
- Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, Katholieke Universiteit Leuven, Leuven, Belgium ; Lab of Histology, Biomedical Research Institute, Hasselt University, Campus Diepenbeek, Agoralaan, Diepenbeek, Belgium
| | - Stefaan J Soenen
- Lab for General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Ghent, Belgium
| | - Ivo Lambrichts
- Lab of Histology, Biomedical Research Institute, Hasselt University, Campus Diepenbeek, Agoralaan, Diepenbeek, Belgium
| | - Catherine M Verfaillie
- Interdepartmental Stem Cell Institute, O&N IV, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Marcel De Cuyper
- Laboratory of BioNanoColloids, Interdisciplinary Research Centre, Katholieke Universiteit Leuven, Kortrijk, Belgium
| | - Uwe Himmelreich
- Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, Katholieke Universiteit Leuven, Leuven, Belgium
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21
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Binas B, Verfaillie CM. Concise review: Bone marrow meets blastocyst: lessons from an unlikely encounter. Stem Cells 2013; 31:620-6. [PMID: 23169605 DOI: 10.1002/stem.1287] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 10/28/2012] [Indexed: 12/17/2022]
Abstract
This article discusses the implications of the recent discovery that rat bone marrow-derived multipotent adult progenitor cells (rMAPCs), a cell type with broad somatic differentiation potential but of uncertain lineage identity, are similar to rat blastocyst-derived extraembryonic endoderm precursor (rXENP) cells, which appear to represent the committed extraembryonic endoderm precursor of the blastocyst. It was found that under rMAPC culture conditions, rXENP cells can be homogeneously cultured and similar cells, named rat hypoblast stem cells (rHypoSCs), can be derived from rat blastocysts more rapidly and directly. The detailed comparison of rHypoSCs, rXENP cells, and rMAPCs revealed highly similar gene expression profiles and developmental potentials. The significance of these findings for embryology, stem cell biology, and medicine is discussed. Specifically, the results assign a lineage identity to rMAPCs, indicate that rMAPCs originated by environmental reprogramming, and imply that HypoSCs, XENP cells, and MAPCs possess lineage plasticity. The MAPC-HypoSC relation also strengthens the consistency of rat and mouse embryology and consequently the idea that HypoSCs represent the committed extraembryonic endoderm precursor of the blastocyst. On this basis, it is argued that the direct comparison of HypoSCs (now available in pure form) with embryonic stem cells will be highly useful for the understanding of pluripotency and plasticity. Finally, the new findings suggest an explanation for an obscure observation on stem cell-induced transplantation tolerance. Thus, the HypoSC/XENP/MAPC phenotype provides a unique but broadly instructive model with which to study stem cell plasticity, reprogramming, and transplantation tolerance, all central themes in regenerative medicine.
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Affiliation(s)
- Bert Binas
- Division of Molecular and Life Science, Hanyang University, Kyeonggi-do, South Korea.
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22
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Mesenchymal stem cells migration homing and tracking. Stem Cells Int 2013; 2013:130763. [PMID: 24194766 PMCID: PMC3806396 DOI: 10.1155/2013/130763] [Citation(s) in RCA: 300] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 07/08/2013] [Indexed: 02/06/2023] Open
Abstract
In this review, we discuss the migration and homing ability of mesenchymal stem cells (MSCs) and MSC-like cells and factors influencing this. We also discuss studies related to the mechanism of migration and homing and the approaches undertaken to enhance it. Finally, we describe the different methods available and frequently used to track and identify the injected cells in vivo.
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Hess DC, Sila CA, Furlan AJ, Wechsler LR, Switzer JA, Mays RW. A double-blind placebo-controlled clinical evaluation of MultiStem for the treatment of ischemic stroke. Int J Stroke 2013; 9:381-6. [PMID: 23692637 DOI: 10.1111/ijs.12065] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 11/10/2012] [Indexed: 12/16/2022]
Abstract
BACKGROUND There is growing interest in neurorestorative and reparative therapies after acute stroke. MultiStem is an allogeneic cell therapy treatment comprising a population of multipotent adherent bone marrow cells that has shown safety in clinical trials of myocardial infarction and graft vs. host disease, as well as preclinical evidence of activity in stroke and other neurological damage models. MultiStem is now being evaluated in a clinical trial in patients that have suffered an ischemic stroke, in which the product is administered intravenously 24-36 h after the ischemic event. METHODS The Phase 2 randomized, double-blind, placebo-controlled, multicenter dose-escalation trial will consist of three treatment cohorts, including a placebo group, and two treatment groups involving dose tiers of either 400 million or 1200 million cells per patient. Patients will be treated at 24-36 h after stroke. The two primary objectives are to determine the highest well-tolerated and safe single dose of MultiStem up to a maximum of 1200 million total cells in subjects with ischemic stroke and to determine the efficacy of MultiStem on functional outcome in subjects with stroke as measured by the modified Rankin Scale at 90 days. Patients will also be evaluated using the National Institutes of Health Stroke Scale and Barthel Index. The study will explore other aspects including, uniquely, the measurement of spleen size after stroke by magnetic resonance imaging or computed tomography imaging. CONCLUSIONS AND FUTURE DIRECTION If MultiStem is safe and there is a signal of efficacy, a late stage phase IIb-III trial is planned.
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Affiliation(s)
- David C Hess
- Department of Neurology, Georgia Health Sciences University, Augusta, GA, USA
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Boddy SL, Chen W, Romero-Guevara R, Kottam L, Bellantuono I, Rivolta MN. Inner ear progenitor cells can be generated in vitro from human bone marrow mesenchymal stem cells. Regen Med 2013; 7:757-67. [PMID: 23164077 DOI: 10.2217/rme.12.58] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM Mouse mesenchymal stem cells (MSCs) can generate sensory neurons and produce inner ear hair cell-like cells. An equivalent source from humans is highly desirable, given their potential application in patient-specific regenerative therapies for deafness. In this study, we explored the ability of human MSCs (hMSCs) to differentiate into otic lineages. MATERIALS & METHODS hMSCs were exposed to culture media conditioned by human fetal auditory stem cells. RESULTS Conditioned media induced the expression of otic progenitor markers PAX8, PAX2, GATA3 and SOX2. After 4 weeks, cells coexpressed ATOH1, MYO7A and POU4F3 (indicators of hair cell lineage) or neuronal markers NEUROG1, POU4F1 and NEFH. Inhibition of WNT signaling prevented differentiation into otic progenitors, while WNT activation partially phenocopied results seen with the conditioned media. CONCLUSION This study demonstrates that hMSCs can be driven to express key genes found in the otic lineages and thereby promotes their status as candidates for regenerative therapies for deafness.
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Affiliation(s)
- Sarah L Boddy
- Centre for Stem Cell Biology & Department of Biomedical Sciences, University of Sheffield, Alfred Denny Building, Western Bank, Sheffield S10 2TN, UK
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Singh SP, Tripathy NK, Nityanand S. Comparison of phenotypic markers and neural differentiation potential of multipotent adult progenitor cells and mesenchymal stem cells. World J Stem Cells 2013; 5:53-60. [PMID: 23671719 PMCID: PMC3648646 DOI: 10.4252/wjsc.v5.i2.53] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 12/20/2012] [Accepted: 02/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the phenotypic and neural differentiation potential of human bone marrow derived multipotent adult progenitor cells (MAPC) and mesenchymal stem cells (MSC).
METHODS: Cultures of MAPC and MSC were established in parallel from same samples of human bone marrow (n = 5). Both stem cell types were evaluated for expression of pluripotency markers including Oct-4 and Nanog by immunocytochemistry and reverse-transcription polymerase chain reaction (RT-PCR) and expression of standard mesenchymal markers including CD14, CD34, CD44, CD45, CD73, CD90, CD105 and human leukocyte antigen (HLA)-ABC by flow cytometry. After treatment with neural induction medium both MAPC and MSC were evaluated for expression of neural proteins [neuronal filament-200 (NF-200) and glial fibrillar acidic protein (GFAP)] by immunocytochemistry and Western blotting and neural genes [NF-200, GFAP, Tau, microtubule-associated protein (MAP)-1B, MAP-2, neuron-specific enolase (NSE) and oligodendrocyte-1 (Olig-1)] by quantitative real-time-PCR.
RESULTS: MAPC had small trigonal shaped while MSC had elongated spindle-shaped morphology. The MAPC expressed Oct-4 and Nanog both at gene and protein levels, whereas MSC were negative for these pluripotent markers. MAPC were negative for HLA-ABC while MSC had high expression of HLA-ABC. In addition, MAPC as compared to MSC had significantly lower expression of CD44 (36.56% ± 1.92% vs 98.23% ± 0.51%), CD73 (15.11% ± 2.24% vs 98.53% ± 2.22%) and CD105 (13.81% ± 3.82% vs 95.12% ± 5.65%) (P < 0.001, for all) MAPC cultures compared to MSC cultures treated with neural induction medium had significantly higher fold change expression of NF-200 (0.64), GFAP (0.52), Tau (0.59), MAP-2 (0.72), Olig-1 (0.18) and NSE (0.29) proteins (P < 0.01 for Olig-1 and P < 0.001 for rest) as well as higher fold change expression of genes of NF-200 (1.34), GFAP (1.12), Tau (1.08), MAP-1B (0.92), MAP-2 (1.14) and NSE (0.4) (P < 0.001 for all).
CONCLUSION: MAPC can be differentially characterized from MSC as Oct-4 and Nanog positive stem cells with no expression of HLA-ABC and low expression of mesenchymal markers CD44, CD73 and CD105 and when compared to MSC they possess greater predilection for differentiation into neuro-ectodermal lineage.
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Reading JL, Yang JHM, Sabbah S, Skowera A, Knight RR, Pinxteren J, Vaes B, Allsopp T, Ting AE, Busch S, Raber A, Deans R, Tree TIM. Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity. THE JOURNAL OF IMMUNOLOGY 2013; 190:4542-52. [DOI: 10.4049/jimmunol.1202710] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Ginis I, Weinreb M, Abramov N, Shinar D, Merchav S, Schwartz A, Shirvan M. Bone progenitors produced by direct osteogenic differentiation of the unprocessed bone marrow demonstrate high osteogenic potential in vitro and in vivo. Biores Open Access 2013; 1:69-78. [PMID: 23514783 PMCID: PMC3559218 DOI: 10.1089/biores.2012.9904] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Tissue-engineered bone grafts seeded with mesenchymal stem cells (MSCs) have been sought as a replacement for bone grafts currently used for bone repair. For production of osteogenic constructs, MSCs are isolated from bone marrow (BM) or other tissues, expanded in culture, then trypsinized, and seeded on a scaffold. Predifferentiation of seeded cells is often desired. We describe here bone progenitor cells (BPCs) obtained by direct osteogenic differentiation of unprocessed BM bypassing isolation of MSCs. Human BM aspirates were incubated for 2 weeks with a commonly used osteogenic medium (OM), except no fetal calf serum, serum substitutes, or growth factors were added, because responding stem and/or progenitor cells were present in the BM milieu. The adherent cells remaining after the culture medium and residual BM were washed out, expressed high levels of bone-specific alkaline phosphatase (ALP) on their surface, demonstrated high ALP activity, were capable of mineralization of the intercellular space, and expressed genes associated with osteogenesis. These parameters in BPCs were similar and even at higher levels compared to MSCs subjected to osteogenic differentiation for 2 weeks. The yield of BPCs per 1 mL BM was 0.71±0.39×10(6). In comparison, the yield of MSCs produced by adhesion of mononuclear cells derived from the same amount of BM and cultured in a commercial growth medium for 2 weeks was 0.3±0.17×10(6). When a scaffold was added to the BM-OM mixture, and the mixture was cultured in a simple rotational bioreactor; the resulting BPCs were obtained already seeded on the scaffold. BPCs seeded on scaffolds were capable of proliferation for at least 6 weeks, keeping high levels of ALP activity, expressing osteogenic genes, and mineralizing the scaffolds. Autologous rat BPCs seeded on various scaffolds were transplanted into critical-size calvarial defects. Six weeks after transplantation of polylactic acid/polyglycolic acid scaffolds, 76.1%±18.3% of the defects were filled with a new bone, compared to 37.9%±28.4% in the contralateral defects transplanted with the scaffolds without cells.
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Affiliation(s)
- Irene Ginis
- Teva Pharmaceutical Industries LTD , Petach Tikva, Israel
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Wolfs E, Struys T, Notelaers T, Roberts SJ, Sohni A, Bormans G, Van Laere K, Luyten FP, Gheysens O, Lambrichts I, Verfaillie CM, Deroose CM. 18F-FDG labeling of mesenchymal stem cells and multipotent adult progenitor cells for PET imaging: effects on ultrastructure and differentiation capacity. J Nucl Med 2013; 54:447-54. [PMID: 23353687 DOI: 10.2967/jnumed.112.108316] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
UNLABELLED Because of their extended differentiation capacity, stem cells have gained great interest in the field of regenerative medicine. For the development of therapeutic strategies, more knowledge on the in vivo fate of these cells has to be acquired. Therefore, stem cells can be labeled with radioactive tracer molecules such as (18)F-FDG, a positron-emitting glucose analog that is taken up and metabolically trapped by the cells. The aim of this study was to optimize the radioactive labeling of mesenchymal stem cells (MSCs) and multipotent adult progenitor cells (MAPCs) in vitro with (18)F-FDG and to investigate the potential radiotoxic effects of this labeling procedure with a range of techniques, including transmission electron microscopy (TEM). METHODS Mouse MSCs and rat MAPCs were used for (18)F-FDG uptake kinetics and tracer retention studies. Cell metabolic activity, proliferation, differentiation and ultrastructural changes after labeling were evaluated using an Alamar Blue reagent, doubling time calculations and quantitative TEM, respectively. Additionally, mice were injected with MSCs and MAPCs prelabeled with (18)F-FDG, and stem cell biodistribution was investigated using small-animal PET. RESULTS The optimal incubation period for (18)F-FDG uptake was 60 min. Significant early tracer washout was observed, with approximately 30%-40% of the tracer being retained inside the cells 3 h after labeling. Cell viability, proliferation, and differentiation capacity were not severely affected by (18)F-FDG labeling. No major changes at the ultrastructural level, considering mitochondrial length, lysosome size, the number of lysosomes, the number of vacuoles, and the average rough endoplasmic reticulum width, were observed with TEM. Small-animal PET experiments with radiolabeled MAPCs and MSCs injected intravenously in mice showed a predominant accumulation in the lungs and a substantial elution of (18)F-FDG from the cells. CONCLUSION MSCs and MAPCs can be successfully labeled with (18)F-FDG for molecular imaging purposes. The main cellular properties are not rigorously affected. TEM confirmed that the cells' ultrastructural properties are not influenced by (18)F-FDG labeling. Small-animal PET studies confirmed the intracellular location of the tracer and the possibility of imaging injected prelabeled stem cell types in vivo. Therefore, direct labeling of MSCs and MAPCs with (18)F-FDG is a suitable technique to noninvasively assess cell delivery and early retention with PET.
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Affiliation(s)
- Esther Wolfs
- Division of Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
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Ratajczak MZ, Mierzejewska K, Ratajczak J, Kucia M. CD133 Expression Strongly Correlates with the Phenotype of Very Small Embryonic-/Epiblast-Like Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 777:125-141. [PMID: 23161080 PMCID: PMC5565199 DOI: 10.1007/978-1-4614-5894-4_9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
CD133 antigen (prominin-1) is a useful cell surface marker of very small embryonic-like stem cells (VSELs). Antibodies against it, conjugated to paramagnetic beads or fluorochromes, are thus powerful biological tools for their isolation from human umbilical cord blood, mobilized peripheral blood, and bone marrow. VSELs are described with the following characteristics: (1) are slightly smaller than red blood cells; (2) display a distinct morphology, typified by a high nuclear/cytoplasmic ratio and an unorganized euchromatin; (3) become mobilized during stress situations into peripheral blood; (4) are enriched in the CD133(+)Lin(-)CD45(-) cell fraction in humans; and (5) express markers of pluripotent stem cells (e.g., Oct-4, Nanog, and stage-specific embryonic antigen-4). The most recent in vivo data from our and other laboratories demonstrated that human VSELs exhibit some characteristics of long-term repopulating hematopoietic stem cells and are at the top of the hierarchy in the mesenchymal lineage. However, still more labor is needed to characterize better at a molecular level these rare cells.
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Affiliation(s)
- Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, 40202 Rm. 107, Louisville, KY, USA,
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De Kock J, Najar M, Bolleyn J, Al Battah F, Rodrigues RM, Buyl K, Raicevic G, Govaere O, Branson S, Meganathan K, Gaspar JA, Roskams T, Sachinidis A, Lagneaux L, Vanhaecke T, Rogiers V. Mesoderm-derived stem cells: the link between the transcriptome and their differentiation potential. Stem Cells Dev 2012; 21:3309-23. [PMID: 22651824 DOI: 10.1089/scd.2011.0723] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Human adult stem cells (hASCs) have become an attractive source for autologous cell transplantation, tissue engineering, developmental biology, and the generation of human-based alternative in vitro models. Among the 3 germ cell layers, the mesoderm is the origin of today's most widely used and characterized hASC populations. A variety of isolated nonhematopoietic mesoderm-derived stem cell populations exist, and all of them show important differences in terms of function, efficacy, and differentiation potential both in vivo and in vitro. To better understand whether the intrinsic properties of these cells contribute to the overall differentiation potential of hASCs, we compared the global gene expression profiles of 4 mesoderm-derived stem cell populations: human adipose tissue-derived stromal cells, human bone marrow-derived stromal cells (hBMSCs), human (fore)skin-derived precursor cells (hSKPs), and human Wharton's jelly-derived mesenchymal stem cells (hWJs). Significant differences in gene expression profiles were detected between distinct stem cell types. hSKPs predominantly expressed genes involved in neurogenesis, skin, and bone development, whereas hWJs and, to some extent, hBMSCs showed an increased expression of genes involved in cardiovascular and liver development. Interestingly, the observed differential gene expression of distinct hASCs could be linked to existing differentiation data in which hASCs were differentiated toward specific cell types. As such, our data suggest that the intrinsic gene expression of the undifferentiated stem cells has an important impact on their overall differentiation potential as well as their application in stem cell-based research. Yet, the factors that define these intrinsic properties remain to be determined.
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Affiliation(s)
- Joery De Kock
- Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Burns JS, Safwat A, Grisendi G, Kassem M, Dominici M. Sarcomas as a mise en abyme of mesenchymal stem cells: exploiting interrelationships for cell mediated anticancer therapy. Cancer Lett 2012; 325:1-10. [PMID: 22659735 DOI: 10.1016/j.canlet.2012.05.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 05/22/2012] [Accepted: 05/24/2012] [Indexed: 12/24/2022]
Abstract
Mise en abyme meaning "placed into abyss or infinite recurrence" is an apt paradigm for the relentless growth of sarcoma cells. Its alternative meaning, "self-reflexive embedding" fits the central role attributed to cancer stem cells (CSCs). Diversely sourced and defined, mesenchymal stem cells (MSCs) may be the cells of sarcoma origin, evolve a CSC phenotype and/or contribute to tumor growth through inherent qualities for homing, neovascularization, paracrine cross-feeding, microvesicle secretion, cell fusion, entosis and immune modulation. Exploiting these qualities, MSC expressing modified forms of the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) are being developed to complement more conventional radiation and chemotherapy.
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Affiliation(s)
- Jorge S Burns
- Laboratory of Cell Biology and Advanced Cancer Therapies, Department of Oncology, Hematology and Respiratory Disease, University Hospital of Modena and Reggio Emilia, Modena, Italy.
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Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev 2012; 21:2724-52. [PMID: 22468918 DOI: 10.1089/scd.2011.0722] [Citation(s) in RCA: 600] [Impact Index Per Article: 46.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) comprise a heterogeneous population of cells with multilineage differentiation potential, the ability to modulate oxidative stress, and secrete various cytokines and growth factors that can have immunomodulatory, angiogenic, anti-inflammatory and anti-apoptotic effects. Recent data indicate that these paracrine factors may play a key role in MSC-mediated effects in modulating various acute and chronic pathological conditions. MSCs are found in virtually all organs of the body. Bone marrow-derived MSCs (BM-MSCs) were discovered first, and the bone marrow was considered the main source of MSCs for clinical application. Subsequently, MSCs have been isolated from various other sources with the adipose tissue, serving as one of the alternatives to bone marrow. Adipose tissue-derived MSCs (ASCs) can be more easily isolated; this approach is safer, and also, considerably larger amounts of ASCs can be obtained compared with the bone marrow. ASCs and BM-MSCs share many biological characteristics; however, there are some differences in their immunophenotype, differentiation potential, transcriptome, proteome, and immunomodulatory activity. Some of these differences may represent specific features of BM-MSCs and ASCs, while others are suggestive of the inherent heterogeneity of both BM-MSC and ASC populations. Still other differences may simply be related to different isolation and culture protocols. Most importantly, despite the minor differences between these MSC populations, ASCs seem to be as effective as BM-MSCs in clinical application, and, in some cases, may be better suited than BM-MSCs. In this review, we will examine in detail the ontology, biology, preclinical, and clinical application of BM-MSCs versus ASCs.
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Affiliation(s)
- Marius Strioga
- Department of Immunology, Center of Oncosurgery, Institute of Oncology, Vilnius University, Vilnius, Lithuania.
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Role of the blood service in cellular therapy. Biologicals 2011; 40:218-21. [PMID: 22063066 DOI: 10.1016/j.biologicals.2011.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Accepted: 10/18/2011] [Indexed: 11/21/2022] Open
Abstract
Cellular therapy is a novel form of medical or surgical treatment using cells in place of or in addition to traditional chemical drugs. The preparation of cellular products - called advanced therapy medicinal products - ATMP in Europe, requires compliance with good manufacturing practices (GMP). Based on long-term experience in blood component manufacturing, product traceability and hemovigilance, selected blood services may represent ideal settings for the development and experimental use of ATMP. International harmonization of the protocols and procedures for the preparation of ATMP is of paramount importance to facilitate the development of multicenter clinical trials with adequate sample size, which are urgently needed to determine the clinical efficacy of ATMP. This article describes European regulations on cellular therapy and summarizes the activities of the 'Franco Calori' Cell Factory, a GMP unit belonging to the department of regenerative medicine of a large public university hospital, which acquired a certification for the GMP production of ATMP in 2007 and developed nine experimental clinical protocols during 2003-2011.
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Otto WR, Wright NA. Mesenchymal stem cells: from experiment to clinic. FIBROGENESIS & TISSUE REPAIR 2011; 4:20. [PMID: 21902837 PMCID: PMC3182886 DOI: 10.1186/1755-1536-4-20] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Accepted: 09/08/2011] [Indexed: 02/07/2023]
Abstract
There is currently much interest in adult mesenchymal stem cells (MSCs) and their ability to differentiate into other cell types, and to partake in the anatomy and physiology of remote organs. It is now clear these cells may be purified from several organs in the body besides bone marrow. MSCs take part in wound healing by contributing to myofibroblast and possibly fibroblast populations, and may be involved in epithelial tissue regeneration in certain organs, although this remains more controversial. In this review, we examine the ability of MSCs to modulate liver, kidney, heart and intestinal repair, and we update their opposing qualities of being less immunogenic and therefore tolerated in a transplant situation, yet being able to contribute to xenograft models of human tumour formation in other contexts. However, such observations have not been replicated in the clinic. Recent studies showing the clinical safety of MSC in several pathologies are discussed. The possible opposing powers of MSC need careful understanding and control if their clinical potential is to be realised with long-term safety for patients.
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Affiliation(s)
- William R Otto
- Histopathology Laboratory, Cancer Research UK, London Research Institute, 44, Lincoln's Inn Fields, London WC2A 3LY, UK.
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