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1
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Balistreri CR. In reviewing the emerging biomarkers of human inflammatory bowel disease (IBD): Endothelial progenitor cells (EPC) and their vesicles as potential biomarkers of cardiovascular manifestations and targets for personalized treatments. Mech Ageing Dev 2024; 222:112006. [PMID: 39577473 DOI: 10.1016/j.mad.2024.112006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/15/2024] [Accepted: 11/19/2024] [Indexed: 11/24/2024]
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory and pathological conditions of the gastrointestinal tract, which include two main clinical subtypes: Crohn's disease (CD) and ulcerative colitis (UC). IBDs show an increase in their age-standardized global incidence rate worldwide, with no gender differences, although the age-standardized mortality rate has decreased over the years. Indeed, thanks to recent therapies with novel mechanisms of action, including those with biologics and small molecules, it has been possible to reduce the mortality rate of IBDs. However, a significant percentage of IBD patients remain refractory to these multiple advanced therapies. Therefore, another challenge of IBD research remains the development of novel therapies with novel agents or cells that could improve the quality of life and outcome of IBD patients. Furthermore, another aspect to be studied in IBDs is not only the high risk of progression not only to neoplastic transformation but also to the development of cardiovascular disease (CVD). Consequently, 25-40 % of IBD patients present with cardiovascular manifestations. Here, we propose that the altered number and functions of endothelial progenitor cells (EPCs) may represent one of the crucial mechanisms associated with incomplete/delayed healing of IBD and may offer the possibility of using them, as well as their vesicles and content, as novel biomarkers and potential candidates of cell therapy for IBD. The advantages and limitations are extensively described and discussed.
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Affiliation(s)
- Carmela Rita Balistreri
- Cellular, Molecular and Clinical Pathological Laboratory, Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Palermo 90134, Italy.
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2
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Jing Jia, Ma B, Zhao X. Fetal endothelial colony-forming cells: Possible targets for prevention of the fetal origins of adult diseases. Placenta 2024; 145:80-88. [PMID: 38100962 DOI: 10.1016/j.placenta.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 11/20/2023] [Accepted: 12/06/2023] [Indexed: 12/17/2023]
Abstract
Endothelial colony-forming cells (ECFCs), a subset of circulating and resident endothelial progenitor cells, are capable of self-renewal and de novo vessel formation, and are known key regulators of vascular integrity and homeostasis. Numerous studies have found that exposure to hostile environment during the fetal development exerts a profound influence on the level and function of ECFCs, which may be the underlying factor linking endothelial dysfunction to cardiovascular disease of the offspring in later life. Herein, we focus on the latest findings regarding the effects of pregnancy-related disorders on the frequency and function of fetal ECFCs. Subsequently, we discuss about placental ECFCs and put forward some details that should be paid attention to in the process of ECFC isolation and culture. Overall, the information presented in this review highlight the potential of ECFCs as a future biomarker or even therapeutic targets for the pregnancy-related adverse maternal and fetal outcomes.
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Affiliation(s)
- Jing Jia
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Baitao Ma
- Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xianlan Zhao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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3
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Suchy FP, Nishimura T, Seki S, Wilkinson AC, Higuchi M, Hsu I, Zhang J, Bhadury J, Nakauchi H. Streamlined and quantitative detection of chimerism using digital PCR. Sci Rep 2022; 12:10223. [PMID: 35715477 PMCID: PMC9206010 DOI: 10.1038/s41598-022-14467-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 06/07/2022] [Indexed: 12/28/2022] Open
Abstract
Animal chimeras are widely used for biomedical discoveries, from developmental biology to cancer research. However, the accurate quantitation of mixed cell types in chimeric and mosaic tissues is complicated by sample preparation bias, transgenic silencing, phenotypic similarity, and low-throughput analytical pipelines. Here, we have developed and characterized a droplet digital PCR single-nucleotide discrimination assay to detect chimerism among common albino and non-albino mouse strains. In addition, we validated that this assay is compatible with crude lysate from all solid organs, drastically streamlining sample preparation. This chimerism detection assay has many additional advantages over existing methods including its robust nature, minimal technical bias, and ability to report the total number of cells in a prepared sample. Moreover, the concepts discussed here are readily adapted to other genomic loci to accurately measure mixed cell populations in any tissue.
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Affiliation(s)
- Fabian P Suchy
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
| | - Toshiya Nishimura
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Shinsuke Seki
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Experimental Animal Division, Bioscience Education and Research Support Center, Akita University, Akita, 010-8543, Japan
| | - Adam C Wilkinson
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Maimi Higuchi
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Ian Hsu
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Jinyu Zhang
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Joydeep Bhadury
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Institute of Biomedicine, Sahlgrenska University Hospital, University of Gothenburg, 41345, Gothenburg, SE, Sweden
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
- Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
- Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
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4
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Stem C, Rodman C, Ramamurthy RM, George S, Meares D, Farland A, Atala A, Doering CB, Spencer HT, Porada CD, Almeida-Porada G. Investigating Optimal Autologous Cellular Platforms for Prenatal or Perinatal Factor VIII Delivery to Treat Hemophilia A. Front Cell Dev Biol 2021; 9:678117. [PMID: 34447745 PMCID: PMC8383113 DOI: 10.3389/fcell.2021.678117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 07/19/2021] [Indexed: 11/17/2022] Open
Abstract
Patients with the severe form of hemophilia A (HA) present with a severe phenotype, and can suffer from life-threatening, spontaneous hemorrhaging. While prophylactic FVIII infusions have revolutionized the clinical management of HA, this treatment is short-lived, expensive, and it is not available to many A patients worldwide. In the present study, we evaluated a panel of readily available cell types for their suitability as cellular vehicles to deliver long-lasting FVIII replacement following transduction with a retroviral vector encoding a B domain-deleted human F8 transgene. Given the immune hurdles that currently plague factor replacement therapy, we focused our investigation on cell types that we deemed to be most relevant to either prenatal or very early postnatal treatment and that could, ideally, be autologously derived. Our findings identify several promising candidates for use as cell-based FVIII delivery vehicles and lay the groundwork for future mechanistic studies to delineate bottlenecks to efficient production and secretion of FVIII following genetic-modification.
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Affiliation(s)
- Christopher Stem
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Christopher Rodman
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Ritu M. Ramamurthy
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Sunil George
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Diane Meares
- Special Hematology Laboratory, Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Andrew Farland
- Special Hematology Laboratory, Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Christopher B. Doering
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, United States
| | - H. Trent Spencer
- Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, United States
| | - Christopher D. Porada
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Graça Almeida-Porada
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
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5
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Orlando N, Babini G, Chiusolo P, Valentini CG, De Stefano V, Teofili L. Pre-Exposure to Defibrotide Prevents Endothelial Cell Activation by Lipopolysaccharide: An Ingenuity Pathway Analysis. Front Immunol 2020; 11:585519. [PMID: 33343567 PMCID: PMC7744778 DOI: 10.3389/fimmu.2020.585519] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/04/2020] [Indexed: 01/11/2023] Open
Abstract
Defibrotide (DFB) effects on different endothelial cell pathways have been investigated focusing on a limited number of genes or molecules. This study explored the modulation of the gene expression profile of steady-state or lipopolysaccharide (LPS)-activated endothelial cells, following the DFB exposure. Starting from differentially regulated gene expression datasets, we utilized the Ingenuity Pathway Analysis (IPA) to infer novel information about the activity of this drug. We found that effects elicited by LPS deeply differ depending on cells were exposed to DFB and LPS at the same time, or if the DFB priming occurs before the LPS exposure. Only in the second case, we observed a significant down-regulation of various pathways activated by LPS. In IPA, the pathways most affected by DFB were leukocyte migration and activation, vasculogenesis, and inflammatory response. Furthermore, the activity of DFB seemed to be associated with the modulation of six key genes, including matrix-metalloproteinases 2 and 9, thrombin receptor, sphingosine-kinase1, alpha subunit of collagen XVIII, and endothelial-protein C receptor. Overall, our findings support a role for DFB in a wide range of diseases associated with an exaggerated inflammatory response of endothelial cells.
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Affiliation(s)
- Nicoletta Orlando
- Department of Image, Radiation therapy, Oncology and Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Gabriele Babini
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Patrizia Chiusolo
- Department of Image, Radiation therapy, Oncology and Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Department of Radiological and Hematological Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Caterina Giovanna Valentini
- Department of Image, Radiation therapy, Oncology and Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Valerio De Stefano
- Department of Image, Radiation therapy, Oncology and Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Department of Radiological and Hematological Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luciana Teofili
- Department of Image, Radiation therapy, Oncology and Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.,Department of Radiological and Hematological Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
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6
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Morata Tarifa C, López Navas L, Azkona G, Sánchez Pernaute R. Chimeras for the twenty-first century. Crit Rev Biotechnol 2020; 40:283-291. [PMID: 32054356 DOI: 10.1080/07388551.2019.1679084] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Recent advances in stem cell biology and molecular engineering have improved and simplified the methodology employed to create experimental chimeras, highlighting their value in basic research and broadening the spectrum of potential applications. Experimental chimeras have been used for decades during the generation of murine genetic models, this being especially relevant in developmental and regeneration studies. Indeed, their value for the research and modeling of human diseases was recognized by the 2007 Nobel Prize to Mario Capecchi, Martin Evans, and Oliver Smithies. More recently, their potential application in regenerative medicine has generated a lot of interest, particularly the enticing possibility to generate human organs for transplantation in livestock animals. In this review, we provide an update on interspecific chimeric organogenesis, its possibilities, current limitations, alternatives, and ethical issues.
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Affiliation(s)
- Cynthia Morata Tarifa
- Preclinical Department, Andalusian Network for Advanced Therapies, Fundación Progreso y Salud, Sevilla, Spain
| | - Luis López Navas
- Preclinical Department, Andalusian Network for Advanced Therapies, Fundación Progreso y Salud, Sevilla, Spain
| | | | - Rosario Sánchez Pernaute
- Preclinical Department, Andalusian Network for Advanced Therapies, Fundación Progreso y Salud, Sevilla, Spain
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7
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Ungaro F, Tacconi C, Massimino L, Corsetto PA, Correale C, Fonteyne P, Piontini A, Garzarelli V, Calcaterra F, Della Bella S, Spinelli A, Carvello M, Rizzo AM, Vetrano S, Petti L, Fiorino G, Furfaro F, Mavilio D, Maddipati KR, Malesci A, Peyrin-Biroulet L, D'Alessio S, Danese S. MFSD2A Promotes Endothelial Generation of Inflammation-Resolving Lipid Mediators and Reduces Colitis in Mice. Gastroenterology 2017; 153:1363-1377.e6. [PMID: 28827082 DOI: 10.1053/j.gastro.2017.07.048] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 07/27/2017] [Accepted: 07/30/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Alterations in signaling pathways that regulate resolution of inflammation (resolving pathways) contribute to pathogenesis of ulcerative colitis (UC). The resolution process is regulated by lipid mediators, such as those derived from the ω-3 docosahexaenoic acid (DHA), whose esterified form is transported by the major facilitator superfamily domain containing 2A (MFSD2A) through the endothelium of brain, retina, and placenta. We investigated if and how MFSD2A regulates lipid metabolism of gut endothelial cells to promote resolution of intestinal inflammation. METHODS We performed lipidomic and functional analyses of MFSD2A in mucosal biopsies and primary human intestinal microvascular endothelial cells (HIMECs) isolated from surgical specimens from patients with active, resolving UC and healthy individuals without UC (controls). MFSD2A was knocked down in HIMECs with small hairpin RNAs or overexpressed from a lentiviral vector. Human circulating endothelial progenitor cells that overexpress MFSD2A were transferred to CD1 nude mice with dextran sodium sulfate-induced colitis, with or without oral administration of DHA. RESULTS Colonic biopsies from patients with UC had reduced levels of inflammation-resolving DHA-derived epoxy metabolites compared to healthy colon tissues or tissues with resolution of inflammation. Production of these metabolites by HIMECs required MFSD2A, which is required for DHA retention and metabolism in the gut vasculature. In mice with colitis, transplanted endothelial progenitor cells that overexpressed MFSD2A not only localized to the inflamed mucosa but also restored the ability of the endothelium to resolve intestinal inflammation, compared with mice with colitis that did not receive MFSD2A-overexpressing endothelial progenitors. CONCLUSIONS Levels of DHA-derived epoxides are lower in colon tissues from patients with UC than healthy and resolving mucosa. Production of these metabolites by gut endothelium requires MFSD2A; endothelial progenitor cells that overexpress MFSD2A reduce colitis in mice. This pathway might be induced to resolve intestinal inflammation in patients with colitis.
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Affiliation(s)
- Federica Ungaro
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
| | - Carlotta Tacconi
- Institute of Pharmaceutical Sciences, Pharmacogenomics, Swiss Federal Institute of Technology (ETH), Zurich, Switzerland
| | - Luca Massimino
- School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | | | - Carmen Correale
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Philippe Fonteyne
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Andrea Piontini
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
| | - Valeria Garzarelli
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Francesca Calcaterra
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Silvia Della Bella
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy; Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Michele Carvello
- Colon and Rectal Surgery Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Angela Maria Rizzo
- Departments of Pharmacology and Biomolecular Science, University of Milan, Milan, Italy
| | - Stefania Vetrano
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
| | - Luciana Petti
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Gionata Fiorino
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Federica Furfaro
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Domenico Mavilio
- Laboratory of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Krishna Rao Maddipati
- Department of Pathology, Lipdomics Core Facility, Wayne State University, Detroit, Michigan
| | - Alberto Malesci
- Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy; Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Institut National de la Santé et de la Recherche Médicale U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, France
| | - Silvia D'Alessio
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
| | - Silvio Danese
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy.
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Abstract
As chimeras transform from beasts of Greek mythology into tools of contemporary bioscience, secrets of developmental biology and evolutionary divergence are being revealed. Recent advances in stem cell biology and interspecies chimerism have generated new models with extensive basic and translational applications, including generation of transplantable, patient-specific organs.
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Affiliation(s)
- Fabian Suchy
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305
- Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan
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9
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Khoo CP, Roubelakis MG, Schrader JB, Tsaknakis G, Konietzny R, Kessler B, Harris AL, Watt SM. miR-193a-3p interaction with HMGB1 downregulates human endothelial cell proliferation and migration. Sci Rep 2017; 7:44137. [PMID: 28276476 PMCID: PMC5343468 DOI: 10.1038/srep44137] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 02/02/2017] [Indexed: 12/12/2022] Open
Abstract
Circulating endothelial colony forming cells (ECFCs) contribute to vascular repair where they are a target for therapy. Since ECFC proliferative potential is increased in cord versus peripheral blood and to define regulatory factors controlling this proliferation, we compared the miRNA profiles of cord blood and peripheral blood ECFC-derived cells. Of the top 25 differentially regulated miRNAs selected, 22 were more highly expressed in peripheral blood ECFC-derived cells. After validating candidate miRNAs by q-RT-PCR, we selected miR-193a-3p for further investigation. The miR-193a-3p mimic reduced cord blood ECFC-derived cell proliferation, migration and vascular tubule formation, while the miR-193a-3p inhibitor significantly enhanced these parameters in peripheral blood ECFC-derived cells. Using in silico miRNA target database analyses combined with proteome arrays and luciferase reporter assays of miR-193a-3p mimic treated cord blood ECFC-derived cells, we identified 2 novel miR-193a-3p targets, the high mobility group box-1 (HMGB1) and the hypoxia upregulated-1 (HYOU1) gene products. HMGB1 silencing in cord blood ECFC-derived cells confirmed its role in regulating vascular function. Thus, we show, for the first time, that miR-193a-3p negatively regulates human ECFC vasculo/angiogenesis and propose that antagonising miR-193a-3p in less proliferative and less angiogenic ECFC-derived cells will enhance their vasculo/angiogenic function.
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Affiliation(s)
- Cheen P. Khoo
- Stem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9BQ, UK
- Stem Cell Research, NHS Blood and Transplant, Oxford, OX3 9BQ, UK
| | - Maria G. Roubelakis
- Stem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9BQ, UK
- Stem Cell Research, NHS Blood and Transplant, Oxford, OX3 9BQ, UK
- Laboratory of Biology, National and Kapodistrian University of Athens Medical School, Athens 115 27, Greece
- Cell and Gene Therapy Laboratory, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, 11527, Greece
| | - Jack B. Schrader
- Stem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9BQ, UK
- Stem Cell Research, NHS Blood and Transplant, Oxford, OX3 9BQ, UK
- Department of Biology, University of York, York, YO10 5DD, UK
| | - Grigorios Tsaknakis
- Stem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9BQ, UK
- Stem Cell Research, NHS Blood and Transplant, Oxford, OX3 9BQ, UK
- Institute of Molecular Biology and Biotechnology, Foundation of Research & Technology, GR-70013 Heraklion, Crete
| | - Rebecca Konietzny
- Target Discovery Institute, NDM Research Building, Nuffield Department of Medicine, University of Oxford, OX3 7FZ, UK
| | - Benedikt Kessler
- Target Discovery Institute, NDM Research Building, Nuffield Department of Medicine, University of Oxford, OX3 7FZ, UK
| | - Adrian L. Harris
- The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
| | - Suzanne M. Watt
- Stem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9BQ, UK
- Stem Cell Research, NHS Blood and Transplant, Oxford, OX3 9BQ, UK
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10
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Circulating Bone Marrow-Derived CD45-/CD34+/CD133+/VEGF+ Endothelial Progenitor Cells in Adults with Crohn's Disease. Dig Dis Sci 2017; 62:633-638. [PMID: 27339637 DOI: 10.1007/s10620-016-4234-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 06/16/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Circulating endothelial progenitor cells (EPCs) are bone marrow-derived stem cells able to migrate to sites of damaged endothelium and differentiate into endothelial cells. Altered EPC level and function have been described in various inflammatory diseases and have been shown to augment vasculogenesis in murine models. Previous studies of EPC in the context of Crohn's disease (CD) have yielded conflicting results. AIM To determine whether the circulating levels of EPCs are changed in the context of CD. METHODS CD patients and healthy controls were recruited. Disease activity was assessed by CDAI. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by FACS analysis using anti-CD34, anti-VEGF receptor-2, anti-CD133, and anti-CD45 markers. RESULTS Eighty-three subjects, including 32 CD patients and 51 controls were recruited, including 19 (59.4 %) and 23 (45 %) males (p = 0.26), aged 34.8 ± 14.9 and 43.3 ± 18.5 years (p = 0.64), in cases and controls, respectively. Mean CDAI was 147 ± 97, disease duration was 12.7 ± 11.1 years, and 28 (87.5 %) were receiving biologics for a mean duration of 21.7 ± 16.8 months. The mean level of peripheral EPCs in CD patients was 0.050 ± 0.086 percent and 0.007 ± 0.013 % in controls (p < 0.01). There was no significant correlation between EPC levels and age (r = -0.13, p = 0.47), CDAI (r = -0.26, p = 0.15), disease duration (r = -0.04, p = 0.84), or duration of treatment with biologics (r = 0.004, p = 0.99). CONCLUSION EPCs are elevated in patients with CD. Further studies are needed to examine the function of EPCs and their possible role as a marker of disease severity or therapeutic response.
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11
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Dietrich C, Singh SR. Circulating Endothelial Progenitor Cells in Crohn's Disease: An EPiC in the Making? Dig Dis Sci 2017; 62:567-568. [PMID: 28078527 DOI: 10.1007/s10620-016-4445-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Catharine Dietrich
- Stem Cell Regulation and Animal Aging Section, Basic Research Laboratory, National Cancer Institute, NIH, Frederick, MD, 21702, USA
| | - Shree Ram Singh
- Stem Cell Regulation and Animal Aging Section, Basic Research Laboratory, National Cancer Institute, NIH, Frederick, MD, 21702, USA.
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12
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Ribeiro J, Caseiro AR, Pereira T, Armada-da-Silva PA, Pires I, Prada J, Amorim I, Leal Reis I, Amado S, Santos JD, Bompasso S, Raimondo S, Varejão ASP, Geuna S, Luís AL, Maurício AC. Evaluation of PVA biodegradable electric conductive membranes for nerve regeneration in axonotmesis injuries: the rat sciatic nerve animal model. J Biomed Mater Res A 2017; 105:1267-1280. [PMID: 28078802 DOI: 10.1002/jbm.a.35998] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 07/13/2016] [Accepted: 01/05/2017] [Indexed: 11/06/2022]
Abstract
The therapeutic effect of three polyvinyl alcohol (PVA) membranes loaded with electrically conductive materials - carbon nanotubes (PVA-CNTs) and polypyrrole (PVA-PPy) - were tested in vivo for neuro-muscular regeneration after an axonotmesis injury in the rat sciatic nerve. The membranes electrical conductivity measured was 1.5 ± 0.5 × 10-6 S/m, 579 ± 0.6 × 10-6 S/m, and 1837.5 ± 0.7 × 10-6 S/m, respectively. At week-12, a residual motor and nociceptive deficit were present in all treated groups, but at week-12, a better recovery to normal gait pattern of the PVA-CNTs and PVA-PPy treated groups was observed. Morphometrical analysis demonstrated that PVA-CNTs group presented higher myelin thickness and lower g-ratio. The tibialis anterior muscle, in the PVA-PPy and PVA-CNTs groups showed a 9% and 19% increase of average fiber size area and a 5% and 10% increase of the "minimal Feret's diameter," respectively. No inflammation, degeneration, fibrosis or necrosis were detected in lung, liver, kidneys, spleen, and regional lymph nodes and absence of carbon deposits was confirmed with Von Kossa and Masson-Fontana stains. In conclusion, the membranes of PVA-CNTs and PVA-PPy are biocompatible and have electrical conductivity. The higher electrical conductivity measured in PVA-CNTs membrane might be responsible for the positive results on maturation of myelinated fibers. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1267-1280, 2017.
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Affiliation(s)
- Jorge Ribeiro
- Departmento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal.,Sub-inidade de Cirurgia Experimental e Medicina Regenerativa, Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal.,UPVET, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal
| | - Ana Rita Caseiro
- Departmento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal.,Sub-inidade de Cirurgia Experimental e Medicina Regenerativa, Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal.,CEMUC, Departamento de Engenharia Metalúrgica e Materiais, Faculdade de Engenharia, Universidade do Porto, Rua Dr. Roberto Frias, Porto, 4200-465, Portugal
| | - Tiago Pereira
- Departmento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal.,Sub-inidade de Cirurgia Experimental e Medicina Regenerativa, Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal
| | - Paulo Alexandre Armada-da-Silva
- Faculdade de Motricidade Humana (FMH), Universidade de Lisboa (ULisboa), Estrada da Costa, 1499-002, Dafundo, Cruz Quebrada, Portugal.,CIPER-FMH: Centro Interdisciplinar de Estudo de Performance Humana, Faculdade de Motricidade Humana (FMH), Universidade de Lisboa (ULisboa), Estrada da Costa, 1499-002, Cruz Quebrada - Dafundo, Portugal
| | - Isabel Pires
- Departamento de Ciências Veterinárias, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801, Vila Real, Portugal.,CECAV, Centro de Ciência Animal e Veterinária, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, Vila Real, 5000-801, Portugal
| | - Justina Prada
- Departamento de Ciências Veterinárias, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801, Vila Real, Portugal.,CECAV, Centro de Ciência Animal e Veterinária, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, Vila Real, 5000-801, Portugal
| | - Irina Amorim
- Departmento de Patologia e de Imunologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal.,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Rua Dr. Roberto Frias s/n, 4200-465, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto (UP), Rua Alfredo Allen, Porto, 4200-135, Portugal
| | - Inês Leal Reis
- Departmento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal.,Sub-inidade de Cirurgia Experimental e Medicina Regenerativa, Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal
| | - Sandra Amado
- Instituto Politécnico de Leiria, UIS-IPL: Unidade de Investigação em Saúde da Escola Superior de Saúde de Leiria, Portugal.,CDrsp - Centre for Rapid and Sustainable Product Development, Rua de Portugal 2430-028, Marinha, Grande, Portugal
| | - José Domingos Santos
- CEMUC, Departamento de Engenharia Metalúrgica e Materiais, Faculdade de Engenharia, Universidade do Porto, Rua Dr. Roberto Frias, Porto, 4200-465, Portugal
| | - Simone Bompasso
- Department of Clinical and Biological Sciences, University of Turin, Turin, 10126, Italy.,Neuroscience Institute of the Cavalieri Ottolenghi Foundation (NICO), Azienda Ospedaliero-Universitaria San Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10043, Turin, Italy
| | - Stefania Raimondo
- Department of Clinical and Biological Sciences, University of Turin, Turin, 10126, Italy.,Neuroscience Institute of the Cavalieri Ottolenghi Foundation (NICO), Azienda Ospedaliero-Universitaria San Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10043, Turin, Italy
| | - Artur Severo Proença Varejão
- Departamento de Ciências Veterinárias, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801, Vila Real, Portugal.,CECAV, Centro de Ciência Animal e Veterinária, Universidade de Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, Vila Real, 5000-801, Portugal
| | - Stefano Geuna
- Department of Clinical and Biological Sciences, University of Turin, Turin, 10126, Italy.,Neuroscience Institute of the Cavalieri Ottolenghi Foundation (NICO), Azienda Ospedaliero-Universitaria San Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10043, Turin, Italy
| | - Ana Lúcia Luís
- Departmento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal.,Sub-inidade de Cirurgia Experimental e Medicina Regenerativa, Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal.,UPVET, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal
| | - Ana Colette Maurício
- Departmento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, Porto, 4050-313, Portugal.,Sub-inidade de Cirurgia Experimental e Medicina Regenerativa, Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, Porto, 4051-401, Portugal
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Patel J, Donovan P, Khosrotehrani K. Concise Review: Functional Definition of Endothelial Progenitor Cells: A Molecular Perspective. Stem Cells Transl Med 2016; 5:1302-1306. [PMID: 27381992 DOI: 10.5966/sctm.2016-0066] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 04/25/2016] [Indexed: 01/10/2023] Open
Abstract
: Since the discovery of endothelial progenitor cells (EPCs) almost 2 decades ago, there has been great hope in their use in treating chronic ischemic disease. Unfortunately, to date, many of the clinical trials using EPCs have been hampered by the lack of clear definition of this cell population. Attributes of a progenitor population are self-renewal and multipotentiality. Major progress has been achieved moving from a definition of EPCs based on a candidate cell surface molecule to a functional definition based essentially on self-renewal hierarchy of endothelial colony-forming cells (ECFCs). More recent work has seized on this functional characterization to associate gene expression signatures with the self-renewal capacity of ECFCs. In particular, Notch signaling driving the quiescence of progenitors has been shown to be central to progenitor self-renewal. This new molecular definition has tremendous translational consequences, because progenitors have been shown to display greater vasculogenic potential. Also, this molecular definition of EPC self-renewal allows assessment of the quality of presumed EPC preparations. This promises to be the initial stage in progressing EPCs further into mainstream clinical use. SIGNIFICANCE The development of a therapy using endothelial progenitor cells provides great hope for patients in treating cardiovascular diseases going forward. For continual development of this therapy toward the clinical, further understanding of the fundamental biology of these cells is required. This will enable a greater understanding of their stemness capacity and provide insight into their ability to differentiate and drive tissue regeneration when injected into a host.
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Affiliation(s)
- Jatin Patel
- University of Queensland Centre for Clinical Research, Herston, Queensland, Australia
| | - Prudence Donovan
- University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Kiarash Khosrotehrani
- University of Queensland Centre for Clinical Research, Herston, Queensland, Australia University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia
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14
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Tasev D, Koolwijk P, van Hinsbergh VWM. Therapeutic Potential of Human-Derived Endothelial Colony-Forming Cells in Animal Models. TISSUE ENGINEERING PART B-REVIEWS 2016; 22:371-382. [PMID: 27032435 DOI: 10.1089/ten.teb.2016.0050] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Tissue regeneration requires proper vascularization. In vivo studies identified that the endothelial colony-forming cells (ECFCs), a subtype of endothelial progenitor cells that can be isolated from umbilical cord or peripheral blood, represent a promising cell source for therapeutic neovascularization. ECFCs not only are able to initiate and facilitate neovascularization in diseased tissue but also can, by acting in a paracrine manner, contribute to the creation of favorable conditions for efficient and appropriate differentiation of tissue-resident stem or progenitor cells. This review outlines the progress in the field of in vivo regenerative and tissue engineering studies and surveys why, when, and how ECFCs can be used for tissue regeneration. RECENT FINDINGS Reviewed literature that regard human-derived ECFCs in xenogeneic animal models implicates that ECFCs should be considered as an endothelial cell source of preference for induction of neovascularization. Their neovascularization and regenerative potential is augmented in combination with other types of stem or progenitor cells. Biocompatible scaffolds prevascularized with ECFCs interconnect faster and better with the host vasculature. The physical incorporation of ECFCs in newly formed blood vessels grants prolonged release of trophic factors of interest, which also makes ECFCs an interesting cell source candidate for gene therapy and delivery of bioactive compounds in targeted area. SUMMARY ECFCs possess all biological features to be considered as a cell source of preference for tissue engineering and repair of blood supply. Investigation of regenerative potential of ECFCs in autologous settings in large animal models before clinical application is the next step to clearly outline the most efficient strategy for using ECFCs as treatment.
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Affiliation(s)
- Dimitar Tasev
- 1 Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam , Amsterdam, The Netherlands .,2 A-Skin Nederland BV , Amsterdam, The Netherlands
| | - Pieter Koolwijk
- 1 Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam , Amsterdam, The Netherlands
| | - Victor W M van Hinsbergh
- 1 Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam , Amsterdam, The Netherlands
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15
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Patel J, Wong HY, Wang W, Alexis J, Shafiee A, Stevenson AJ, Gabrielli B, Fisk NM, Khosrotehrani K. Self-Renewal and High Proliferative Colony Forming Capacity of Late-Outgrowth Endothelial Progenitors Is Regulated by Cyclin-Dependent Kinase Inhibitors Driven by Notch Signaling. Stem Cells 2016; 34:902-12. [PMID: 26732848 DOI: 10.1002/stem.2262] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 11/10/2015] [Accepted: 11/30/2015] [Indexed: 11/10/2022]
Abstract
Since the discovery of endothelial colony forming cells (ECFC), there has been significant interest in their therapeutic potential to treat vascular injuries. ECFC cultures display significant heterogeneity and a hierarchy among cells able to give rise to high proliferative versus low proliferative colonies. Here we aimed to define molecularly this in vitro hierarchy. Based on flow cytometry, CD34 expression levels distinguished two populations. Only CD34 + ECFC had the capacity to reproduce high proliferative potential (HPP) colonies on replating, whereas CD34- ECFCs formed only small clusters. CD34 + ECFCs were the only ones to self-renew in stringent single-cell cultures and gave rise to both CD34 + and CD34- cells. Upon replating, CD34 + ECFCs were always found at the centre of HPP colonies and were more likely in G0/1 phase of cell cycling. Functionally, CD34 + ECFC were superior at restoring perfusion and better engrafted when injected into ischemic hind limbs. Transcriptomic analysis identified cyclin-dependent kinase (CDK) cell cycle inhibiting genes (p16, p21, and p57), the Notch signaling pathway (dll1, dll4, hes1, and hey1), and the endothelial cytokine il33 as highly expressed in CD34 + ECFC. Blocking the Notch pathway using a γ-secretase inhibitor (DAPT) led to reduced expression of cell cycle inhibitors, increased cell proliferation followed by a loss of self-renewal, and HPP colony formation capacity reflecting progenitor exhaustion. Similarly shRNA knockdown of p57 strongly affected self-renewal of ECFC colonies. ECFC hierarchy is defined by Notch signalling driving cell cycle regulators, progenitor quiescence and self-renewal potential.
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Affiliation(s)
- Jatin Patel
- UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, Australia
| | - Ho Yi Wong
- UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, Australia
| | - Weili Wang
- UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, Australia
| | - Josue Alexis
- UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Abbas Shafiee
- UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, Australia
| | - Alexander J Stevenson
- UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Brian Gabrielli
- UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Nicholas M Fisk
- UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, Australia.,Centre for Advanced Prenatal Care, Royal Brisbane & Women's Hospital, Herston, Queensland, Australia
| | - Kiarash Khosrotehrani
- UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, Australia.,UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia
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16
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Markeson D, Pleat JM, Sharpe JR, Harris AL, Seifalian AM, Watt SM. Scarring, stem cells, scaffolds and skin repair. J Tissue Eng Regen Med 2015; 9:649-68. [PMID: 24668923 DOI: 10.1002/term.1841] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Revised: 08/09/2013] [Accepted: 09/16/2013] [Indexed: 01/19/2023]
Abstract
The treatment of full thickness skin loss, which can be extensive in the case of large burns, continues to represent a challenging clinical entity. This is due to an on-going inability to produce a suitable tissue engineered substrate that can satisfactorily replicate the epidermal and dermal in vivo niches to fulfil both aesthetic and functional demands. The current gold standard treatment of autologous skin grafting is inadequate because of poor textural durability, scarring and associated contracture, and because of a paucity of donor sites in larger burns. Tissue engineering has seen exponential growth in recent years with a number of 'off-the-shelf' dermal and epidermal substitutes now available. Each has its own limitations. In this review, we examine normal wound repair in relation to stem/progenitor cells that are intimately involved in this process within the dermal niche. Endothelial precursors, in particular, are examined closely and their phenotype, morphology and enrichment from multiple sources are described in an attempt to provide some clarity regarding the controversy surrounding their classification and role in vasculogenesis. We also review the role of the next generation of cellularized scaffolds and smart biomaterials that attempt to improve the revascularisation of artificial grafts, the rate of wound healing and the final cosmetic and functional outcome.
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Affiliation(s)
- Daniel Markeson
- Stem Cell Research Laboratory, NHS Blood and Transplant, Oxford, UK
- Department of Plastic and Reconstructive Surgery, Stoke Mandeville Hospital, Aylesbury, UK
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- University College London Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, Royal Free Hospital, London, UK
| | - Jonathon M Pleat
- Department of Plastic and Reconstructive Surgery, Stoke Mandeville Hospital, Aylesbury, UK
- Department of Plastic and Reconstructive Surgery, Frenchay Hospital, Bristol, UK
| | - Justin R Sharpe
- Blond McIndoe Research Foundation, Queen Victoria Hospital, East Grinstead, West Sussex, UK
| | - Adrian L Harris
- Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Alexander M Seifalian
- University College London Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, Royal Free Hospital, London, UK
| | - Suzanne M Watt
- Stem Cell Research Laboratory, NHS Blood and Transplant, Oxford, UK
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
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Flores AI, Gómez-Gómez GJ, Masedo-González &A, Martínez-Montiel MP. Stem cell therapy in inflammatory bowel disease: A promising therapeutic strategy? World J Stem Cells 2015; 7:343-351. [PMID: 25815119 PMCID: PMC4369491 DOI: 10.4252/wjsc.v7.i2.343] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/24/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and with immunoregulatory cells (regulatory T-lymphocytes and dendritic T-cells) opens up new expectations for their use in these diseases. The goal for stem cell-based therapy is to provide a permanent cure. To achieve this, it will be necessary to obtain a cellular product, original or genetically modified, that has a high migration capacity and homes into the intestine, has high survival after transplantation, regulates the immune reaction while not being visible to the patient’s immune system, and repairs the injured tissue.
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Liu Z, Li C, Huang M, Tong C, Zhang X, Wang L, Peng H, Lan P, Zhang P, Huang N, Peng J, Wu X, Luo Y, Qin H, Kang L, Wang J. Positive regulatory effects of perioperative probiotic treatment on postoperative liver complications after colorectal liver metastases surgery: a double-center and double-blind randomized clinical trial. BMC Gastroenterol 2015; 15:34. [PMID: 25881090 PMCID: PMC4374379 DOI: 10.1186/s12876-015-0260-z] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 02/27/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Colorectal liver metastases (CLM) occur frequently and postoperative intestinal infection is a common complication. Our previous study showed that probiotics could decrease the rate of infectious complications after colectomy for colorectal cancer. To determine the effects of the perioperative administration of probiotics on serum zonulin levels which is a marker of intestinal permeability and the subsequent impact on postoperative infectious complications in patients with CLM. METHODS 150 patients with CLM were randomly divided into control group (n = 68) and probiotics group (n = 66). Probiotics and placebo were given orally for 6 days preoperatively and 10 days postoperatively to control group and probiotics group respectively. We used the local resection for metastatic tumor ,while for large tumor, the segmental hepatectomy. Postoperative outcome were recorded. Furthermore, complications in patients with normal intestinal barrier function and the relation with serum zonulin were analyzed to evaluate the impact on the liver barrier dysfunction. RESULTS The incidence of infectious complications in the probiotics group was lower than control group. Analysis of CLM patients with normal postoperative intestinal barrier function paralleled with the serum zonulin level. And probiotics could also reduce the concentration of serum zonulin (P = 0.004) and plasma endotoxin (P < 0.001). CONCLUSION Perioperative probiotics treatment could reduce the serum zonulin level, the rate of postoperative septicemia and maintain the liver barrier in patients undergoing CLM surgery. we propose a new model about the regulation of probiotics to liver barrier via clinical regulatory pathway. We recommend the preoperative oral intake of probiotics combined with postoperative continued probiotics treatment in patients who undergo CLM surgery. TRIAL REGISTRATION ChiCTR-TRC- 12002841 . 2012/12/21.
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Affiliation(s)
- Zhihua Liu
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China. .,Department of Surgery, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Chao Li
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Meijin Huang
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Chao Tong
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Xingwei Zhang
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Lei Wang
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Hui Peng
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Ping Lan
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Peng Zhang
- Department of Surgery, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Nanqi Huang
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Junsheng Peng
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Xiaojian Wu
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Yanxing Luo
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Huanlong Qin
- Department of Surgery, Shanghai JiaoTong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Liang Kang
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
| | - Jianping Wang
- Gastrointestinal Institute of Sun Yat-sen University, Department of Colorectal Surgery, the Sixth Affiliated Hospital of Sun Yat-sen University (Guangdong Gastrointestinal Hospital), 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, People's Republic of China.
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Fomin ME, Togarrati PP, Muench MO. Progress and challenges in the development of a cell-based therapy for hemophilia A. J Thromb Haemost 2014; 12:1954-65. [PMID: 25297648 PMCID: PMC4388483 DOI: 10.1111/jth.12750] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Indexed: 12/11/2022]
Abstract
Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review, we discuss the possibilities, progress, and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific induced pluripotent stem cells.
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Affiliation(s)
- Marina E. Fomin
- Cell Therapy Core, Blood Systems Research Institute, San Francisco, CA
- Department of Laboratory Medicine, University of California, San Francisco, CA
| | - Padma Priya Togarrati
- Cell Therapy Core, Blood Systems Research Institute, San Francisco, CA
- Department of Laboratory Medicine, University of California, San Francisco, CA
| | - Marcus O. Muench
- Cell Therapy Core, Blood Systems Research Institute, San Francisco, CA
- Department of Laboratory Medicine, University of California, San Francisco, CA
- Liver Center, University of California, San Francisco, CA
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Almeida-Porada G, Soland M, Boura J, Porada CD. Regenerative medicine: prospects for the treatment of inflammatory bowel disease. Regen Med 2014; 8:631-44. [PMID: 23998755 DOI: 10.2217/rme.13.52] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
This article reviews the current understanding of the processes driving the development and progression of inflammatory bowel disease (IBD), discusses how the dynamic crosstalk between resident microorganisms, host cells and the immune system is required in order to maintain immune homeostasis, and considers innovative strategies that allow the modification or modulation of the intestinal microorganismal community as a potential approach for treating IBD. This article next rationalizes the use of cell-based regenerative medicine as treatment for IBD, discusses the obstacles hindering its success, summarizes some of the results of recent clinical trials employing these therapies, and discusses ongoing work to enhance mesenchymal stem/stromal cells, making them better suited to the task of repairing the damage within the IBD gut.
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Affiliation(s)
- Graça Almeida-Porada
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157-1083, USA.
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Ribeiro J, Gartner A, Pereira T, Gomes R, Lopes MA, Gonçalves C, Varejão A, Luís AL, Maurício AC. Perspectives of employing mesenchymal stem cells from the Wharton's jelly of the umbilical cord for peripheral nerve repair. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2014; 108:79-120. [PMID: 24083432 DOI: 10.1016/b978-0-12-410499-0.00004-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Mesenchymal stem cells (MSCs) from Wharton's jelly present high plasticity and low immunogenicity, turning them into a desirable form of cell therapy for the injured nervous system. Their isolation, expansion, and characterization have been performed from cryopreserved umbilical cord tissue. Great concern has been dedicated to the collection, preservation, and transport protocols of the umbilical cord after the parturition to the laboratory in order to obtain samples with higher number of viable MSCs without microbiological contamination. Different biomaterials like chitosan-silicate hybrid, collagen, PLGA90:10, poly(DL-lactide-ɛ-caprolactone), and poly(vinyl alcohol) loaded with electrical conductive materials, associated to MSCs have also been tested in the rat sciatic nerve in axonotmesis and neurotmesis lesions. The in vitro studies of the scaffolds included citocompatibility evaluation of the biomaterials used and cell characterization by imunocytochemistry, karyotype analysis, differentiation capacity into neuroglial-like cells, and flow cytometry. The regeneration process follow-up has been performed by functional analysis and the repaired nerves processed for stereological studies permitted the morphologic regeneration evaluation. The MSCs from Wharton's jelly delivered through tested biomaterials should be regarded a potentially valuable tool to improve clinical outcome especially after trauma to sensory nerves. In addition, these cells represent a noncontroversial source of primitive mesenchymal progenitor cells, which can be harvested after birth, cryogenically stored, thawed, and expanded for therapeutic uses. The importance of a longitudinal study concerning tissue engineering of the peripheral nerve, which includes a multidisciplinary team able to develop biomaterials associated to cell therapies, to perform preclinical trials concerning animal welfare and the appropriate animal model is here enhanced.
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Affiliation(s)
- Jorge Ribeiro
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Porto, Portugal; Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências e Tecnologias Agrárias e Agro-Alimentares (ICETA), Universidade do Porto (UP), Porto, Portugal
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Lanzoni G, Oikawa T, Wang Y, Cui CB, Carpino G, Cardinale V, Gerber D, Gabriel M, Dominguez-Bendala J, Furth ME, Gaudio E, Alvaro D, Inverardi L, Reid LM. Concise review: clinical programs of stem cell therapies for liver and pancreas. Stem Cells 2013; 31:2047-60. [PMID: 23873634 PMCID: PMC3812254 DOI: 10.1002/stem.1457] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Revised: 05/02/2013] [Accepted: 05/15/2013] [Indexed: 12/13/2022]
Abstract
Regenerative medicine is transitioning into clinical programs using stem/progenitor cell therapies for repair of damaged organs. We summarize those for liver and pancreas, organs that share endodermal stem cell populations, biliary tree stem cells (hBTSCs), located in peribiliary glands. They are precursors to hepatic stem/progenitors in canals of Hering and to committed progenitors in pancreatic duct glands. They give rise to maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis starting at the duodenum and ending with mature cells in the liver or pancreas. Clinical trials have been ongoing for years assessing effects of determined stem cells (fetal-liver-derived hepatic stem/progenitors) transplanted into the hepatic artery of patients with various liver diseases. Immunosuppression was not required. Control subjects, those given standard of care for a given condition, all died within a year or deteriorated in their liver functions. Subjects transplanted with 100-150 million hepatic stem/progenitor cells had improved liver functions and survival extending for several years. Full evaluations of safety and efficacy of transplants are still in progress. Determined stem cell therapies for diabetes using hBTSCs remain to be explored but are likely to occur following ongoing preclinical studies. In addition, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being used for patients with chronic liver conditions or with diabetes. MSCs have demonstrated significant effects through paracrine signaling of trophic and immunomodulatory factors, and there is limited evidence for inefficient lineage restriction into mature parenchymal or islet cells. HSCs' effects are primarily via modulation of immune mechanisms.
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Affiliation(s)
- Giacomo Lanzoni
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL. 33136
- Department of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy
| | - Tsunekazu Oikawa
- Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599
| | - Yunfang Wang
- The Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing, PR China, 100850
| | - Cai-Bin Cui
- Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, NC 27599
| | - Guido Carpino
- Department of Health Sciences, University of Rome “ForoItalico”, Rome, Italy
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy
| | - Vincenzo Cardinale
- Department of Scienze e Biotecnologie Medico-Chirurgiche, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy
| | - David Gerber
- Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, NC 27599
| | - Mara Gabriel
- MGabriel Consulting, 3621 Sweeten Creek Road, Chapel Hill, NC 27514
| | - Juan Dominguez-Bendala
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL. 33136
| | - Mark E. Furth
- Wake Forest Innovations, Wake Forest University School of Medicine, Winston-Salem, NC 27157
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy
| | - Domenico Alvaro
- Department of Scienze e Biotecnologie Medico-Chirurgiche, Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy
| | - Luca Inverardi
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL. 33136
| | - Lola M. Reid
- Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599
- Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC 27599
- Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599
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