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Liu F, Ye S, Zhao L, Niu Q. The role of IGF/IGF-1R signaling in the regulation of cancer stem cells. Clin Transl Oncol 2024; 26:2924-2934. [PMID: 38865036 DOI: 10.1007/s12094-024-03561-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/05/2024] [Indexed: 06/13/2024]
Abstract
Cancer stem cells (CSCs) are a group of tumor cells with high tumorigenic ability and self-renewal potential similar to those of normal stem cells. CSCs are the key "seeds" for tumor development, metastasis, and recurrence. A better insight into the key mechanisms underlying CSC survival improves the efficiency of cancer therapy via specific targeting of CSCs. Insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) signaling plays an important role in the maintenance of cancer stemness. However, the effect of IGF/IGF-1R signaling on stemness and CSCs and the underlying mechanisms are still controversial. Based on the similarity between CSCs and normal stem cells, this review discusses emerging data on the functions of IGF/IGF-1R signaling in normal stem cells and CSCs and dissects the underlying mechanisms by which IGF/IGF-1R signaling is involved in CSCs. On the other hand, this review highlighted the role of IGF/IGF-1R signaling blockade in multiple CSCs as a potential strategy to improve CSC-based therapy.
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Affiliation(s)
- Fengchao Liu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Susu Ye
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Liu Zhao
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qinghui Niu
- Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China
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Branco A, Rayabaram J, Miranda CC, Fernandes-Platzgummer A, Fernandes TG, Sajja S, da Silva CL, Vemuri MC. Advances in ex vivo expansion of hematopoietic stem and progenitor cells for clinical applications. Front Bioeng Biotechnol 2024; 12:1380950. [PMID: 38846805 PMCID: PMC11153805 DOI: 10.3389/fbioe.2024.1380950] [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: 02/02/2024] [Accepted: 04/25/2024] [Indexed: 06/09/2024] Open
Abstract
As caretakers of the hematopoietic system, hematopoietic stem cells assure a lifelong supply of differentiated populations that are responsible for critical bodily functions, including oxygen transport, immunological protection and coagulation. Due to the far-reaching influence of the hematopoietic system, hematological disorders typically have a significant impact on the lives of individuals, even becoming fatal. Hematopoietic cell transplantation was the first effective therapeutic avenue to treat such hematological diseases. Since then, key use and manipulation of hematopoietic stem cells for treatments has been aspired to fully take advantage of such an important cell population. Limited knowledge on hematopoietic stem cell behavior has motivated in-depth research into their biology. Efforts were able to uncover their native environment and characteristics during development and adult stages. Several signaling pathways at a cellular level have been mapped, providing insight into their machinery. Important dynamics of hematopoietic stem cell maintenance were begun to be understood with improved comprehension of their metabolism and progressive aging. These advances have provided a solid platform for the development of innovative strategies for the manipulation of hematopoietic stem cells. Specifically, expansion of the hematopoietic stem cell pool has triggered immense interest, gaining momentum. A wide range of approaches have sprouted, leading to a variety of expansion systems, from simpler small molecule-based strategies to complex biomimetic scaffolds. The recent approval of Omisirge, the first expanded hematopoietic stem and progenitor cell product, whose expansion platform is one of the earliest, is predictive of further successes that might arise soon. In order to guarantee the quality of these ex vivo manipulated cells, robust assays that measure cell function or potency need to be developed. Whether targeting hematopoietic engraftment, immunological differentiation potential or malignancy clearance, hematopoietic stem cells and their derivatives need efficient scaling of their therapeutic potency. In this review, we comprehensively view hematopoietic stem cells as therapeutic assets, going from fundamental to translational.
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Affiliation(s)
- André Branco
- Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Janakiram Rayabaram
- Protein and Cell Analysis, Biosciences Division, Invitrogen Bioservices, Thermo Fisher Scientific, Bangalore, India
| | - Cláudia C. Miranda
- Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- AccelBio, Collaborative Laboratory to Foster Translation and Drug Discovery, Cantanhede, Portugal
| | - Ana Fernandes-Platzgummer
- Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Tiago G. Fernandes
- Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Suchitra Sajja
- Protein and Cell Analysis, Biosciences Division, Invitrogen Bioservices, Thermo Fisher Scientific, Bangalore, India
| | - Cláudia L. da Silva
- Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
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Pastoors D, Havermans M, Mulet-Lazaro R, Brian D, Noort W, Grasel J, Hoogenboezem R, Smeenk L, Demmers JAA, Milsom MD, Enver T, Groen RWJ, Bindels E, Delwel R. Oncogene EVI1 drives acute myeloid leukemia via a targetable interaction with CTBP2. SCIENCE ADVANCES 2024; 10:eadk9076. [PMID: 38748792 PMCID: PMC11095456 DOI: 10.1126/sciadv.adk9076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 04/10/2024] [Indexed: 05/19/2024]
Abstract
Acute myeloid leukemia (AML) driven by the activation of EVI1 due to chromosome 3q26/MECOM rearrangements is incurable. Because transcription factors such as EVI1 are notoriously hard to target, insight into the mechanism by which EVI1 drives myeloid transformation could provide alternative avenues for therapy. Applying protein folding predictions combined with proteomics technologies, we demonstrate that interaction of EVI1 with CTBP1 and CTBP2 via a single PLDLS motif is indispensable for leukemic transformation. A 4× PLDLS repeat construct outcompetes binding of EVI1 to CTBP1 and CTBP2 and inhibits proliferation of 3q26/MECOM rearranged AML in vitro and in xenotransplant models. This proof-of-concept study opens the possibility to target one of the most incurable forms of AML with specific EVI1-CTBP inhibitors. This has important implications for other tumor types with aberrant expression of EVI1 and for cancers transformed by different CTBP-dependent oncogenic transcription factors.
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Affiliation(s)
- Dorien Pastoors
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Marije Havermans
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Roger Mulet-Lazaro
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Duncan Brian
- Stem Cell Group, UCL Cancer Institute, University College London, London, UK
| | - Willy Noort
- Department of Hematology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Cancer Center Amsterdam, Cancer biology and immunology, Amsterdam, Netherlands
| | - Julius Grasel
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany
- Division of Experimental Hematology, German Cancer Research Center, DKFZ69120 Heidelberg, Germany
| | - Remco Hoogenboezem
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Leonie Smeenk
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | | | - Michael D. Milsom
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany
- Division of Experimental Hematology, German Cancer Research Center, DKFZ69120 Heidelberg, Germany
| | - Tariq Enver
- Stem Cell Group, UCL Cancer Institute, University College London, London, UK
| | - Richard W. J. Groen
- Department of Hematology, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Cancer Center Amsterdam, Cancer biology and immunology, Amsterdam, Netherlands
| | - Eric Bindels
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Ruud Delwel
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
- Oncode Institute, Utrecht, Netherlands
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Zhou Y, Cai X, Zhang X, Dong Y, Pan X, Lai M, Zhang Y, Chen Y, Li X, Li X, Liu J, Zhang Y, Ma F. Mesenchymal stem/stromal cells from human pluripotent stem cell-derived brain organoid enhance the ex vivo expansion and maintenance of hematopoietic stem/progenitor cells. Stem Cell Res Ther 2024; 15:68. [PMID: 38443990 PMCID: PMC10916050 DOI: 10.1186/s13287-023-03624-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/22/2023] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) are of great therapeutic value due to their role in maintaining the function of hematopoietic stem/progenitor cells (HSPCs). MSCs derived from human pluripotent stem cells represent an ideal alternative because of their unlimited supply. However, the role of MSCs with neural crest origin derived from HPSCs on the maintenance of HSPCs has not been reported. METHODS Flow cytometric analysis, RNA sequencing and differentiation ability were applied to detect the characteristics of stromal cells from 3D human brain organoids. Human umbilical cord blood CD34+ (UCB-CD34+) cells were cultured in different coculture conditions composed of stromal cells and umbilical cord MSCs (UC-MSCs) with or without a cytokine cocktail. The hematopoietic stroma capacity of stromal cells was tested in vitro with the LTC-IC assay and in vivo by cotransplantation of cord blood nucleated cells and stroma cells into immunodeficient mice. RNA and proteomic sequencing were used to detect the role of MSCs on HSPCs. RESULTS The stromal cells, derived from both H1-hESCs and human induced pluripotent stem cells forebrain organoids, were capable of differentiating into the classical mesenchymal-derived cells (osteoblasts, chondrocytes, and adipocytes). These cells expressed MSC markers, thus named pluripotent stem cell-derived MSCs (pMSCs). The pMSCs showed neural crest origin with CD271 expression in the early stage. When human UCB-CD34+ HSPCs were cocultured on UC-MSCs or pMSCs, the latter resulted in robust expansion of UCB-CD34+ HSPCs in long-term culture and efficient maintenance of their transplantability. Comparison by RNA sequencing indicated that coculture of human UCB-CD34+ HSPCs with pMSCs provided an improved microenvironment for HSC maintenance. The pMSCs highly expressed the Wnt signaling inhibitors SFRP1 and SFRP2, indicating that they may help to modulate the cell cycle to promote the maintenance of UCB-CD34+ HSPCs by antagonizing Wnt activation. CONCLUSIONS A novel method for harvesting MSCs with neural crest origin from 3D human brain organoids under serum-free culture conditions was reported. We demonstrate that the pMSCs support human UCB-HSPC expansion in vitro in a long-term culture and the maintenance of their transplantable ability. RNA and proteomic sequencing indicated that pMSCs provided an improved microenvironment for HSC maintenance via mechanisms involving cell-cell contact and secreted factors and suppression of Wnt signaling. This represents a novel method for large-scale production of MSCs of neural crest origin and provides a potential approach for development of human hematopoietic stromal cell therapy for treatment of dyshematopoiesis.
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Affiliation(s)
- Ya Zhou
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Xinping Cai
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College(CAMS & PUMC), Tianjin, 300020, China
| | - Xiuxiu Zhang
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Yong Dong
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Xu Pan
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Mowen Lai
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Yimeng Zhang
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Yijin Chen
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Xiaohong Li
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Xia Li
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Jiaxin Liu
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China
| | - Yonggang Zhang
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China.
| | - Feng Ma
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Huacai Road 26, Chengdu, 610052, China.
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Thorin E, Labbé P, Lambert M, Mury P, Dagher O, Miquel G, Thorin-Trescases N. Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases. Can J Cardiol 2023; 39:1736-1756. [PMID: 37295611 DOI: 10.1016/j.cjca.2023.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/27/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open
Abstract
Despite the best pharmacologic tools available, cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality in developed countries. After 2 decades of research, new therapeutic targets, such as angiopoietin-like proteins (ANGPTLs), are emerging. ANGPTLs belong to a family of 8 members, from ANGPTL1 to ANGPTL8; they have structural homology with angiopoietins and are secreted in the circulation. ANGPTLs display a multitude of physiological and pathologic functions; they contribute to inflammation, angiogenesis, cell death, senescence, hematopoiesis, and play a role in repair, maintenance, and tissue homeostasis. ANGPTLs-particularly the triad ANGPTL3, 4, and 8-have an established role in lipid metabolism through the regulation of triacylglycerol trafficking according to the nutritional status. Some ANGPTLs also contribute to glucose metabolism. Therefore, dysregulation in ANGPTL expression associated with abnormal circulating levels are linked to a plethora of CVD and metabolic disorders including atherosclerosis, heart diseases, diabetes, but also obesity and cancers. Because ANGPTLs bind to different receptors according to the cell type, antagonists are therapeutically inadequate. Recently, direct inhibitors of ANGPTLs, mainly ANGPTL3, have been developed, and specific monoclonal antibodies and antisense oligonucleotides are currently being tested in clinical trials. The aim of the current review is to provide an up-to-date preclinical and clinical overview on the function of the 8 members of the ANGPTL family in the cardiovascular system, their contribution to CVD, and the therapeutic potential of manipulating some of them.
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Affiliation(s)
- Eric Thorin
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada.
| | - Pauline Labbé
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
| | - Mélanie Lambert
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada
| | - Pauline Mury
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada
| | - Olina Dagher
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada; Department of Cardiac Sciences, Libin Cardiovascular Institute, Calgary, Alberta, Canada
| | - Géraldine Miquel
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
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Kamil G, Karolina S, Aleksandra S, Filip B, Marta P, Artur B, Marcin M. Alterations in Stem Cell Populations in IGF-1 Deficient Pediatric Patients Subjected to Mecasermin (Increlex) Treatment. Stem Cell Rev Rep 2023; 19:392-405. [PMID: 36269524 PMCID: PMC9902328 DOI: 10.1007/s12015-022-10457-2] [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] [Accepted: 09/26/2022] [Indexed: 02/07/2023]
Abstract
Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies involving deficient patients with short stature, including Laron syndrome individuals. Noteworthy, despite disturbances in proper growth, elevated values for selected stem cell populations were found in IGF-1 deficient patients. Therefore, here we focused on investigating role of these cells-very small embryonic-like (VSEL) and hematopoietic stem cells (HSC), in the pathology. For the first time we performed long-term observation of these populations in response to rhIGF-1 (mecasermin) therapy. Enrolled pediatric subjects with IGF-1 deficiency syndrome were monitored for 4-5 years of rhIGF-1 treatment. Selected stem cells were analyzed in peripheral blood flow cytometrically, together with chemoattractant SDF-1 using immunoenzymatic method. Patients' data were collected for correlation of experimental results with clinical outcome. IGF-1 deficient patients were found to demonstrate initially higher levels of VSEL and HSC compared to healthy controls, with their gradual decrease in response to therapy. These changes were significantly associated with SDF-1 plasma levels. Correlations of VSEL and HSC were also reported in reference to growth-related parameters, and IGF-1 and IGFBP3 values. Noteworthy, rhIGF-1 was shown to efficiently induce development of Laron patients achieving at least proper rate of growth (compared to healthy group) in 80% of subjects. In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances.
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Affiliation(s)
- Grubczak Kamil
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Jerzego Waszyngtona 13, 15-269, Bialystok, Poland.
| | - Stożek Karolina
- Department of Pediatrics, Endocrinology and Diabetes With a Cardiology Unit, Medical University of Bialystok, Jerzego Waszyngtona 17, 15-275, Bialystok, Poland
| | - Starosz Aleksandra
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Jerzego Waszyngtona 13, 15-269, Bialystok, Poland
| | - Bossowski Filip
- Department of Pediatrics, Endocrinology and Diabetes With a Cardiology Unit, Medical University of Bialystok, Jerzego Waszyngtona 17, 15-275, Bialystok, Poland
| | - Pasławska Marta
- Department of Pediatrics, Endocrinology and Diabetes With a Cardiology Unit, Medical University of Bialystok, Jerzego Waszyngtona 17, 15-275, Bialystok, Poland
| | - Bossowski Artur
- Department of Pediatrics, Endocrinology and Diabetes With a Cardiology Unit, Medical University of Bialystok, Jerzego Waszyngtona 17, 15-275, Bialystok, Poland.
| | - Moniuszko Marcin
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Jerzego Waszyngtona 13, 15-269, Bialystok, Poland.,Department of Allergology and Internal Medicine, Medical University of Bialystok, Marii Sklodowskiej-Curie 24A, 15-276, Bialystok, Poland
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Ganuza M, Hall T, Myers J, Nevitt C, Sánchez-Lanzas R, Chabot A, Ding J, Kooienga E, Caprio C, Finkelstein D, Kang G, Obeng E, McKinney-Freeman S. Murine foetal liver supports limited detectable expansion of life-long haematopoietic progenitors. Nat Cell Biol 2022; 24:1475-1486. [PMID: 36202972 PMCID: PMC10026622 DOI: 10.1038/s41556-022-00999-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 08/22/2022] [Indexed: 11/09/2022]
Abstract
Current dogma asserts that the foetal liver (FL) is an expansion niche for recently specified haematopoietic stem cells (HSCs) during ontogeny. Indeed, between embryonic day of development (E)12.5 and E14.5, the number of transplantable HSCs in the murine FL expands from 50 to about 1,000. Here we used a non-invasive, multi-colour lineage tracing strategy to interrogate the embryonic expansion of murine haematopoietic progenitors destined to contribute to the adult HSC pool. Our data show that this pool of fated progenitors expands only two-fold during FL ontogeny. Although Histone2B-GFP retention in vivo experiments confirmed substantial proliferation of phenotypic FL-HSC between E12.5 and E14.5, paired-daughter cell assays revealed that many mid-gestation phenotypic FL-HSCs are biased to differentiate, rather than self-renew, relative to phenotypic neonatal and adult bone marrow HSCs. In total, these data support a model in which the FL-HSC pool fated to contribute to adult blood expands only modestly during ontogeny.
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Affiliation(s)
- Miguel Ganuza
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
| | - Trent Hall
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Jacquelyn Myers
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Chris Nevitt
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Raúl Sánchez-Lanzas
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Ashley Chabot
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Juan Ding
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Emilia Kooienga
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Claire Caprio
- Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - David Finkelstein
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Guolian Kang
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Esther Obeng
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
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8
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Zhang H, Cai B, Liu Y, Chong Y, Matsunaga A, Mori SF, Fang X, Kitamura E, Chang CS, Wang P, Cowell JK, Hu T. RHOA-regulated IGFBP2 promotes invasion and drives progression of BCR-ABL1 chronic myeloid leukemia. Haematologica 2022; 108:122-134. [PMID: 35833297 PMCID: PMC9827165 DOI: 10.3324/haematol.2022.280757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Indexed: 02/05/2023] Open
Abstract
The Philadelphia 9;22 chromosome translocation has two common isoforms that are preferentially associated with distinct subtypes of leukemia. The p210 variant is the hallmark of chronic myeloid leukemia (CML) whereas p190 is frequently associated with B-cell acute lymphoblastic leukemia. The only sequence difference between the two isoforms is the guanidine exchange factor domain. This guanidine exchange factor is reported to activate RHO family GTPases in response to diverse extracellular stimuli. It is not clear whether and, if so, how RHOA contributes to progression of p210 CML. Here we show that knockout of RHOA in the K562 and KU812, p210-expressing cell lines leads to suppression of leukemogenesis in animal models in vivo. RNA-sequencing analysis of the mock control and null cells demonstrated a distinct change in the gene expression profile as a result of RHOA deletion, with significant downregulation of genes involved in cell activation and cell adhesion. Cellular analysis revealed that RHOA knockout leads to impaired cell adhesion and migration and, most importantly, the homing ability of leukemia cells to the bone marrow, which may be responsible for the attenuated leukemia progression. We also identified IGFBP2 as an important downstream target of RHOA. Further mechanistic investigation showed that RHOA activation leads to relocation of the serum response factor (SRF) into the nucleus, where it directly activates IGFBP2. Knockout of IGFBP2 in CML cells suppressed cell adhesion/invasion, as well as leukemogenesis in vivo. This elevated IGFBP2 expression was confirmed in primary CML samples. Thus, we demonstrate one mechanism whereby the RHOA-SRF-IGFBP2 signaling axis contributes to the development of leukemia in cells expressing the p210 BCR-ABL1 fusion kinase.
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Affiliation(s)
- Hualei Zhang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China,Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - Baohuan Cai
- Georgia Cancer Center, Augusta University, Augusta, GA, USA,Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Liu
- Georgia Cancer Center, Augusta University, Augusta, GA, USA,Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yating Chong
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | | | | | - Xuexiu Fang
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - Eiko Kitamura
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | | | - Ping Wang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - John K. Cowell
- Georgia Cancer Center, Augusta University, Augusta, GA, USA,J. K. Cowell
| | - Tianxiang Hu
- Georgia Cancer Center, Augusta University, Augusta, GA, USA,T. Hu
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Mayer IM, Hoelbl-Kovacic A, Sexl V, Doma E. Isolation, Maintenance and Expansion of Adult Hematopoietic Stem/Progenitor Cells and Leukemic Stem Cells. Cancers (Basel) 2022; 14:1723. [PMID: 35406494 PMCID: PMC8996967 DOI: 10.3390/cancers14071723] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are rare, self-renewing cells that perch on top of the hematopoietic tree. The HSCs ensure the constant supply of mature blood cells in a tightly regulated process producing peripheral blood cells. Intense efforts are ongoing to optimize HSC engraftment as therapeutic strategy to treat patients suffering from hematopoietic diseases. Preclinical research paves the way by developing methods to maintain, manipulate and expand HSCs ex vivo to understand their regulation and molecular make-up. The generation of a sufficient number of transplantable HSCs is the Holy Grail for clinical therapy. Leukemia stem cells (LSCs) are characterized by their acquired stem cell characteristics and are responsible for disease initiation, progression, and relapse. We summarize efforts, that have been undertaken to increase the number of long-term (LT)-HSCs and to prevent differentiation towards committed progenitors in ex vivo culture. We provide an overview and compare methods currently available to isolate, maintain and enrich HSC subsets, progenitors and LSCs and discuss their individual advantages and drawbacks.
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Affiliation(s)
| | | | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; (I.M.M.); (A.H.-K.); (E.D.)
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10
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Park YS, Lee Y, Choi NY, Hwang HS, Rose-John S, Zenke M, Ko K. Enhancement of proliferation of human umbilical cord blood–derived CD34+ hematopoietic stem cells by a combination of hyper-interleukin-6 and small molecules. Biochem Biophys Rep 2022; 29:101214. [PMID: 35146134 PMCID: PMC8801758 DOI: 10.1016/j.bbrep.2022.101214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 11/05/2022] Open
Abstract
Umbilical cord blood (UCB) is an alternative source of allogeneic hematopoietic stem cells (HSCs) for transplantation to treat various hematological disorders. The major limitation to the use of UCB-derived HSCs (UCB–HSCs) in transplantation, however, is the low numbers of HSCs in a unit of cord blood. To overcome this limitation, various cytokines or small molecules have been used to expand UCB-HSCs ex vivo. In this study, we investigated a synergistic effect of the combination of HIL-6, SR1, and UM171 on UCB-HSC culture and found that this combination resulted in the highest number of CD34+ cells. These results suggest that the combination of SR1, UM171 and HIL-6 exerts a synergistic effect in the proliferation of HSCs from UCB and thus, SR1, UM171 and HIL-6 is the most suitable combination for obtaining HSCs from UCB for clinical transplantation.
Hyper IL-6 enhances the proliferation of both total nucleated cells and CD34+ cells. The combination of SR1 and UM171 with Hyper IL-6 led to increases in TNC and CD34+ cells number exvivo human cord blood HSCs. It potentially provides an optimization to achieving a successful strategy through exvivo expansion of HSCs for application.
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11
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Glaser DE, Curtis MB, Sariano PA, Rollins ZA, Shergill BS, Anand A, Deely AM, Shirure VS, Anderson L, Lowen JM, Ng NR, Weilbaecher K, Link DC, George SC. Organ-on-a-chip model of vascularized human bone marrow niches. Biomaterials 2022; 280:121245. [PMID: 34810038 PMCID: PMC10658812 DOI: 10.1016/j.biomaterials.2021.121245] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/01/2021] [Accepted: 11/08/2021] [Indexed: 12/12/2022]
Abstract
Bone marrow niches (endosteal and perivascular) play important roles in both normal bone marrow function and pathological processes such as cancer cell dormancy. Unraveling the mechanisms underlying these events in humans has been severely limited by models that cannot dissect dynamic events at the niche level. Utilizing microfluidic and stem cell technologies, we present a 3D in vitro model of human bone marrow that contains both the perivascular and endosteal niches, complete with dynamic, perfusable vascular networks. We demonstrate that our model can replicate in vivo bone marrow function, including maintenance and differentiation of CD34+ hematopoietic stem/progenitor cells, egress of neutrophils (CD66b+), and niche-specific responses to doxorubicin and granulocyte-colony stimulating factor. Our platform provides opportunities to accelerate current understanding of human bone marrow function and drug response with high spatial and temporal resolution.
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Affiliation(s)
- Drew E Glaser
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Matthew B Curtis
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Peter A Sariano
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Zachary A Rollins
- Department of Chemical Engineering, University of California, Davis, 1 Shields Ave, Bainer 3106, Davis, CA 95616, USA
| | - Bhupinder S Shergill
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Aravind Anand
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Alyssa M Deely
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Venktesh S Shirure
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Leif Anderson
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Jeremy M Lowen
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA
| | - Natalie R Ng
- Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Dr, Campus Box 1100, St Louis, MO 63130, USA
| | - Katherine Weilbaecher
- Department of Medicine, Washington University in St. Louis, 660 S Euclid Ave, Campus Box 8066, St. Louis, MO 63110, USA
| | - Daniel C Link
- Department of Medicine, Washington University in St. Louis, 660 S Euclid Ave, Campus Box 8066, St. Louis, MO 63110, USA
| | - Steven C George
- Department of Biomedical Engineering, University of California, Davis, 451 E Health Sciences Dr, GBSF 2303, Davis, CA 95616, USA.
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12
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Endothelial cell-derived angiopoietin-like protein 2 supports hematopoietic stem cell activities in bone marrow niches. Blood 2021; 139:1529-1540. [PMID: 34929029 PMCID: PMC9015010 DOI: 10.1182/blood.2021011644] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 12/11/2021] [Indexed: 11/20/2022] Open
Abstract
Endothelial cell-derived ANGPTL2 is important for the maintenance of HSC activities in bone marrow niches. ANGPTL2-mediated signaling pathways enhance PPARδ expression to transactivate G0s2 to sustain HSC activities. Bone marrow niche cells have been reported to fine-tune hematopoietic stem cell (HSC) stemness via direct interaction or secreted components. Nevertheless, how niche cells control HSC activities remains largely unknown. We previously showed that angiopoietin-like protein 2 (ANGPTL2) can support the ex vivo expansion of HSCs by binding to human leukocyte immunoglobulin-like receptor B2. However, how ANGPTL2 from specific niche cell types regulates HSC activities under physiological conditions is still not clear. Herein, we generated an Angptl2-flox/flox transgenic mouse line and conditionally deleted Angptl2 expression in several niche cells, including Cdh5+ or Tie2+ endothelial cells, Prx1+ mesenchymal stem cells, and Pf4+ megakaryocytes, to evaluate its role in the regulation of HSC fate. Interestingly, we demonstrated that only endothelial cell-derived ANGPTL2 and not ANGPTL2 from other niche cell types plays important roles in supporting repopulation capacity, quiescent status, and niche localization. Mechanistically, ANGPTL2 enhances peroxisome-proliferator-activated receptor D (PPARD) expression to transactivate G0s2 to sustain the perinuclear localization of nucleolin to prevent HSCs from entering the cell cycle. These findings reveal that endothelial cell-derived ANGPTL2 serves as a critical niche component to maintain HSC stemness, which may benefit the understanding of stem cell biology in bone marrow niches and the development of a unique strategy for the ex vivo expansion of HSCs.
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13
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Pellegrin S, Severn CE, Toye AM. Towards manufactured red blood cells for the treatment of inherited anemia. Haematologica 2021; 106:2304-2311. [PMID: 34042406 PMCID: PMC8409035 DOI: 10.3324/haematol.2020.268847] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Indexed: 11/21/2022] Open
Abstract
Patients with inherited anemia and hemoglobinopathies (such as sickle cell disease and β-thalassemia) are treated with red blood cell (RBC) transfusions to alleviate their symptoms. Some of these patients may have rare blood group types or go on to develop alloimmune reactions, which can make it difficult to source compatible blood in the donor population. Laboratory-grown RBC represent a particularly attractive alternative which could satisfy an unmet clinical need. The challenge, however, is to produce - from a limited number of stem cells - the 2x1012 RBC required for a standard adult therapeutic dose. Encouraging progress has been made in RBC production from adult stem cells under good manufacturing practice. In 2011, the Douay group conducted a successful proof-of-principle mini-transfusion of autologous manufactured RBC in a single volunteer. In the UK, a trial is planned to assess whether manufactured RBC are equivalent to RBC produced naturally in donors, by testing an allogeneic mini-dose of laboratory-grown manufactured RBC in multiple volunteers. This review discusses recent progress in the erythroid culture field as well as opportunities for further scaling up of manufactured RBC production for transfusion practice.
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Affiliation(s)
- Stephanie Pellegrin
- School of Biochemistry, Biomedical Sciences Building; National Institute for Health Research (NIHR) Blood and Transplant Research Unit in Red Blood Cell Products, University of Bristol.
| | - Charlotte E Severn
- School of Biochemistry, Biomedical Sciences Building; National Institute for Health Research (NIHR) Blood and Transplant Research Unit in Red Blood Cell Products, University of Bristol.
| | - Ashley M Toye
- School of Biochemistry, Biomedical Sciences Building; National Institute for Health Research (NIHR) Blood and Transplant Research Unit in Red Blood Cell Products, University of Bristol; Bristol Institute of Transfusion Sciences, NHSBT Filton. Bristol.
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14
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Fernandes SS, Limaye LS, Kale VP. Differentiated Cells Derived from Hematopoietic Stem Cells and Their Applications in Translational Medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1347:29-43. [PMID: 34114129 DOI: 10.1007/5584_2021_644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Hematopoietic stem cells (HSCs) and their development are one of the most widely studied model systems in mammals. In adults, HSCs are predominantly found in the bone marrow, from where they maintain homeostasis. Besides bone marrow and mobilized peripheral blood, cord blood is also being used as an alternate allogenic source of transplantable HSCs. HSCs from both autologous and allogenic sources are being applied for the treatment of various conditions like blood cancers, anemia, etc. HSCs can further differentiate to mature blood cells. Differentiation process of HSCs is being extensively studied so as to obtain a large number of pure populations of various differentiated cells in vitro so that they can be taken up for clinical trials. The ability to generate sufficient quantity of clinical-grade specialized blood cells in vitro would take the field of hematology a step ahead in translational medicine.
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Affiliation(s)
| | - Lalita S Limaye
- Stem Cell Lab, National Centre for Cell Science, Pune, India
| | - Vaijayanti P Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India.
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15
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Navaeian M, Asadian S, Ahmadpour Yazdi H, Gheibi N. ANGPTL8 roles in proliferation, metabolic diseases, hypothyroidism, polycystic ovary syndrome, and signaling pathways. Mol Biol Rep 2021; 48:3719-3731. [PMID: 33864588 DOI: 10.1007/s11033-021-06270-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 03/05/2021] [Indexed: 12/18/2022]
Abstract
A new and atypical member of the ANGPTL family is angiopoietin-like protein 8 (ANGPTL8). This newly discovered hormone is a drug target that can be used to treat diabetes and dyslipidemia. The protein, as a hepatocyte-derived circulating factor, can control the triglyceride level of plasma. ANGPTL8 is significantly associated with inflammation and metabolic syndrome consequences such as obesity, diabetes, hypothyroidism, and PCOS. ANGPTL8 gene has four exons encoding a 22/5 kDa weight of 198 amino acid polypeptides. A highly preserved ANGPTL8 gene among mammals exhibits the essential hormone functions of ANGPTL8. Nevertheless, the physiological function of this hormone in the body is poorly understood. Studies published in PubMed (2008-2020), Google Scholar (2004-2020), and Scopus (2004-2020) databases of clinical trials were reviewed. This analysis is aimed at collecting information on ANGPTL8. The emphasis of this review was on gathering information about the role of ANGPTL8 in the metabolism of glucose and lipids and cell proliferation. It addition to the different roles of ANGPTL8 in diabetes and lipid metabolism, this review emphasized on the protein role in signaling pathways. The study also proposes the signaling pathways that may be considered as a new target for treatment.
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Affiliation(s)
- Maryam Navaeian
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Samieh Asadian
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Hossein Ahmadpour Yazdi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Nematollah Gheibi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
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16
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Lu X. Structure and Function of Angiopoietin-like Protein 3 (ANGPTL3) in Atherosclerosis. Curr Med Chem 2020; 27:5159-5174. [PMID: 31223079 DOI: 10.2174/0929867326666190621120523] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 04/24/2019] [Accepted: 04/30/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Angiopoietin-Like Proteins (ANGPTLs) are structurally related to the angiopoietins. A total of eight ANGPTLs (from ANGPTL1 to ANGPTL8) have been identified so far. Most ANGPTLs possess multibiological functions on lipid metabolism, atherosclerosis, and cancer. Among them, ANGPTL3 has been shown to regulate the levels of Very Low-Density Lipoprotein (VLDL) made by the liver and play a crucial role in human lipoprotein metabolism. METHOD A systematic appraisal of ANGPTLs was conducted, focusing on the main features of ANGPTL3 that has a significant role in atherosclerosis. RESULTS Angiopoietins including ANGPTL3 are vascular growth factors that are highly specific for endothelial cells, perform a variety of other regulatory activities to influence inflammation, and have been shown to possess both pro-atherosclerotic and atheroprotective effects. CONCLUSION ANGPTL3 has been demonstrated as a promising target in the pharmacological management of atherosclerosis. However, many questions remain about its biological functions.
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Affiliation(s)
- Xinjie Lu
- The Mary and Garry Weston Molecular Immunology Laboratory, Thrombosis Research Institute, London SW3 6LR, England, United Kingdom
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17
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Morhayim J, Ghebes CA, Erkeland SJ, Ter Borg MND, Hoogenboezem RM, Bindels EMJ, van Alphen FPJ, Kassem M, van Wijnen AJ, Cornelissen JJ, van Leeuwen JP, van der Eerden BCJ, Voermans C, van de Peppel J, Braakman E. Identification of osteolineage cell-derived extracellular vesicle cargo implicated in hematopoietic support. FASEB J 2020; 34:5435-5452. [PMID: 32086861 PMCID: PMC7136136 DOI: 10.1096/fj.201902610r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/31/2020] [Accepted: 02/10/2020] [Indexed: 12/13/2022]
Abstract
Osteolineage cell‐derived extracellular vesicles (EVs) play a regulatory role in hematopoiesis and have been shown to promote the ex vivo expansion of human hematopoietic stem and progenitor cells (HSPCs). Here, we demonstrate that EVs from different human osteolineage sources do not have the same HSPC expansion promoting potential. Comparison of stimulatory and non‐stimulatory osteolineage EVs by next‐generation sequencing and mass spectrometry analyses revealed distinct microRNA and protein signatures identifying EV‐derived candidate regulators of ex vivo HSPC expansion. Accordingly, the treatment of umbilical cord blood‐derived CD34+ HSPCs with stimulatory EVs‐altered HSPC transcriptome, including genes with known roles in cell proliferation. An integrative bioinformatics approach, which connects the HSPC gene expression data with the candidate cargo in stimulatory EVs, delineated the potentially targeted biological functions and pathways during hematopoietic cell expansion and development. In conclusion, our study gives novel insights into the complex biological role of EVs in osteolineage cell‐HSPC crosstalk and promotes the utility of EVs and their cargo as therapeutic agents in regenerative medicine.
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Affiliation(s)
- Jess Morhayim
- Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | - Stefan J Erkeland
- Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Mariëtte N D Ter Borg
- Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Remco M Hoogenboezem
- Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Eric M J Bindels
- Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | - Moustapha Kassem
- Department of Endocrinology, Odense University Hospital, Odense, Denmark
| | | | - Jan J Cornelissen
- Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Johannes P van Leeuwen
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Bram C J van der Eerden
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | - Jeroen van de Peppel
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Eric Braakman
- Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
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18
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IGFBP2: integrative hub of developmental and oncogenic signaling network. Oncogene 2020; 39:2243-2257. [PMID: 31925333 DOI: 10.1038/s41388-020-1154-2] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 12/16/2019] [Accepted: 12/31/2019] [Indexed: 01/08/2023]
Abstract
Insulin-like growth factor (IGF) binding protein 2 (IGFBP2) was discovered and identified as an IGF system regulator, controlling the distribution, function, and activity of IGFs in the pericellular space. IGFBP2 is a developmentally regulated gene that is highly expressed in embryonic and fetal tissues and markedly decreases after birth. Studies over the last decades have shown that in solid tumors, IGFBP2 is upregulated and promotes several key oncogenic processes, such as epithelial-to-mesenchymal transition, cellular migration, invasion, angiogenesis, stemness, transcriptional activation, and epigenetic programming via signaling that is often independent of IGFs. Growing evidence indicates that aberrant expression of IGFBP2 in cancer acts as a hub of an oncogenic network, integrating multiple cancer signaling pathways and serving as a potential therapeutic target for cancer treatment.
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19
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Fibach E. Erythropoiesis In Vitro-A Research and Therapeutic Tool in Thalassemia. J Clin Med 2019; 8:jcm8122124. [PMID: 31810354 PMCID: PMC6947291 DOI: 10.3390/jcm8122124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 11/26/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022] Open
Abstract
Thalassemia (thal) is a hereditary chronic hemolytic anemia due to a partial or complete deficiency in the production of globin chains, in most cases, α or β, which compose, together with the iron-containing porphyrins (hemes), the hemoglobin molecules in red blood cells (RBC). The major clinical symptom of β-thal is severe chronic anemia—a decrease in RBC number and their hemoglobin content. In spite of the improvement in therapy, thal still severely affects the quality of life of the patients and their families and imposes a substantial financial burden on the community. These considerations position β-thal, among other hemoglobinopathies, as a major health and social problem that deserves increased efforts in research and its clinical application. These efforts are based on clinical studies, experiments in animal models and the use of erythroid cells grown in culture. The latter include immortal cell lines and cultures initiated by erythroid progenitor and stem cells derived from the blood and RBC producing (erythropoietic) sites of normal and thal donors, embryonic stem cells, and recently, "induced pluripotent stem cells" generated by manipulation of differentiated somatic cells. The present review summarizes the use of erythroid cultures, their technological aspects and their contribution to the research and its clinical application in thal. The former includes deciphering of the normal and pathological biology of the erythroid cell development, and the latter—their role in developing innovative therapeutics—drugs and methods of gene therapy, as well as providing an alternative source of RBC that may complement or substitute blood transfusions.
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Affiliation(s)
- Eitan Fibach
- The Hematology Department, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
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20
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Bari S, Chong P, Hwang WYK. Expansion of Haematopoietic Stem and Progenitor Cells: Paving the Way for Next-Generation Haematopoietic Stem Cell Transplantation. BLOOD CELL THERAPY 2019; 2:58-67. [PMID: 37588101 PMCID: PMC10427230 DOI: 10.31547/bct-2019-004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 09/18/2019] [Indexed: 08/18/2023]
Abstract
Haematopoietic stem cell transplantation (HSCT) is now an established practice with over 70,000 transplants performed annually, and over 1.5 million around the world so far. The practice of HSCT has improved over the years due to advances in conditioning regiments, preparatory practices for patients leading up to the transplant, graft versus host disease (GVHD) and infection prophylaxis, as well as a better selection of patients. However, in many instances, the stem cells supplied to the patient may not be adequate for optimal transplantation outcomes. This may be seen in a few areas including umbilical cord blood transplantation, inadequate bone marrow, peripheral blood stem cell harvest, or gene therapy. Growing and expanding HSCs in culture would provide an increase in cell numbers prior to stem cell infusion and accelerate haematopoietic recovery, resulting in improved outcomes. Several new technologies have emerged in recent years, which have facilitated the expansion of haematopoietic stem and progenitor cells (HSPCs) in culture with good outcomes in vitro, in vivo, and in clinical trials. In this review, we will outline some of the reasons for the expansion of HSPCs as well as the new technologies facilitating the advances in HSCT.
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Affiliation(s)
- Sudipto Bari
- National Cancer Centre Singapore
- Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore
| | | | - William Ying Khee Hwang
- National Cancer Centre Singapore
- Department of Haematology, Singapore General Hospital, Singapore
- Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore
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21
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Loukogeorgakis SP, Shangaris P, Bertin E, Franzin C, Piccoli M, Pozzobon M, Subramaniam S, Tedeschi A, Kim AG, Li H, Fachin CG, Dias AIBS, Stratigis JD, Ahn NJ, Thrasher AJ, Bonfanti P, Peranteau WH, David AL, Flake AW, De Coppi P. In Utero Transplantation of Expanded Autologous Amniotic Fluid Stem Cells Results in Long-Term Hematopoietic Engraftment. Stem Cells 2019; 37:1176-1188. [PMID: 31116895 PMCID: PMC6773206 DOI: 10.1002/stem.3039] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 12/06/2018] [Accepted: 12/23/2018] [Indexed: 12/20/2022]
Abstract
In utero transplantation (IUT) of hematopoietic stem cells (HSCs) has been proposed as a strategy for the prenatal treatment of congenital hematological diseases. However, levels of long‐term hematopoietic engraftment achieved in experimental IUT to date are subtherapeutic, likely due to host fetal HSCs outcompeting their bone marrow (BM)‐derived donor equivalents for space in the hematopoietic compartment. In the present study, we demonstrate that amniotic fluid stem cells (AFSCs; c‐Kit+/Lin−) have hematopoietic characteristics and, thanks to their fetal origin, favorable proliferation kinetics in vitro and in vivo, which are maintained when the cells are expanded. IUT of autologous/congenic freshly isolated or cultured AFSCs resulted in stable multilineage hematopoietic engraftment, far higher to that achieved with BM‐HSCs. Intravascular IUT of allogenic AFSCs was not successful as recently reported after intraperitoneal IUT. Herein, we demonstrated that this likely due to a failure of timely homing of donor cells to the host fetal thymus resulted in lack of tolerance induction and rejection. This study reveals that intravascular IUT leads to a remarkable hematopoietic engraftment of AFSCs in the setting of autologous/congenic IUT, and confirms the requirement for induction of central tolerance for allogenic IUT to be successful. Autologous, gene‐engineered, and in vitro expanded AFSCs could be used as a stem cell/gene therapy platform for the in utero treatment of inherited disorders of hematopoiesis. stem cells2019;37:1176–1188
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Affiliation(s)
- Stavros P Loukogeorgakis
- Stem Cells and Regenerative Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.,Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Panicos Shangaris
- Stem Cells and Regenerative Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.,Research Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London, London, United Kingdom
| | - Enrica Bertin
- Stem Cell and Regenerative Medicine Laboratory, Fondazione Instituto di Ricerca Pediatrica Città della Speranza, University of Padova, Padova, Italy
| | - Chiara Franzin
- Stem Cell and Regenerative Medicine Laboratory, Fondazione Instituto di Ricerca Pediatrica Città della Speranza, University of Padova, Padova, Italy
| | - Martina Piccoli
- Stem Cell and Regenerative Medicine Laboratory, Fondazione Instituto di Ricerca Pediatrica Città della Speranza, University of Padova, Padova, Italy.,Department of Women's and Children's Health, University of Padova, Padova, Italy
| | - Michela Pozzobon
- Stem Cell and Regenerative Medicine Laboratory, Fondazione Instituto di Ricerca Pediatrica Città della Speranza, University of Padova, Padova, Italy
| | - Sindhu Subramaniam
- Stem Cells and Regenerative Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Alfonso Tedeschi
- Stem Cells and Regenerative Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Aimee G Kim
- Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Haiying Li
- Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Camila G Fachin
- Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Federal University of São Paulo, São Paulo, Brazil.,Federal University of Paraná, Curitiba, Brazil
| | - Andre I B S Dias
- Stem Cells and Regenerative Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.,Federal University of São Paulo, São Paulo, Brazil.,Federal University of Paraná, Curitiba, Brazil
| | - John D Stratigis
- Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Nicholas J Ahn
- Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Adrian J Thrasher
- Molecular and Cellular Immunology Section, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Paola Bonfanti
- Stem Cells and Regenerative Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.,The Francis Crick Institute, London, United Kingdom
| | - William H Peranteau
- Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Anna L David
- Research Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London, London, United Kingdom
| | - Alan W Flake
- Center for Fetal Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Paolo De Coppi
- Stem Cells and Regenerative Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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22
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Turdiev A, Filiutovich O, Mirkin F, Byk G. A peptide fromTestudo horsfieldiitortoise spleen as a potential helper for reducing acute radiation syndrome. J Pept Sci 2019; 25:e3202. [DOI: 10.1002/psc.3202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 05/21/2019] [Accepted: 06/15/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Azim Turdiev
- Faculty of Life SciencesBar Ilan University Ramat Gan Israel
| | | | - Fiana Mirkin
- Department of ChemistryBar Ilan University Ramat Gan Israel
| | - Gerardo Byk
- Department of ChemistryBar Ilan University Ramat Gan Israel
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23
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Kadomatsu T, Oike Y. Roles of angiopoietin-like proteins in regulation of stem cell activity. J Biochem 2019; 165:309-315. [PMID: 30690458 DOI: 10.1093/jb/mvz005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 01/17/2019] [Indexed: 02/04/2023] Open
Abstract
Various types of stem cells reside in the body and self-renew throughout an organism's lifetime. Such self-renewal is essential for maintenance of tissue homeostasis and is co-ordinately regulated by stem cell-intrinsic signals and signals from stem cell niche. Angiopoietin is a niche-derived signalling molecule well known to contribute to maintenance of haematopoietic stem cells (HSCs). Angiopoietin-like proteins (ANGPTLs) are structurally similar to angiopoietin, and recent studies reveal that they function in angiogenesis, lipid and energy metabolism and regulation of inflammation. However, unlike angiopoietins, activities of ANGPTLs in stem cell maintenance have remained unclear. Recently, several studies have reported an association of ANGPTL signalling with stem cell maintenance. Here, we summarize those findings with a focus on HSCs, intestinal stem cells, neural stem cells and cancer stem cells and discuss mechanisms underlying ANGPTL-mediated stem cell maintenance.
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Affiliation(s)
- Tsuyoshi Kadomatsu
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan.,Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan
| | - Yuichi Oike
- Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan.,Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan.,Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), 1-7-1 Otemachi, Chiyoda-ku, Tokyo, Japan
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24
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Tajer P, Pike-Overzet K, Arias S, Havenga M, Staal FJT. Ex Vivo Expansion of Hematopoietic Stem Cells for Therapeutic Purposes: Lessons from Development and the Niche. Cells 2019; 8:cells8020169. [PMID: 30781676 PMCID: PMC6407064 DOI: 10.3390/cells8020169] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/08/2019] [Accepted: 02/13/2019] [Indexed: 12/21/2022] Open
Abstract
Expansion of hematopoietic stem cells (HSCs) for therapeutic purposes has been a “holy grail” in the field for many years. Ex vivo expansion of HSCs can help to overcome material shortage for transplantation purposes and genetic modification protocols. In this review, we summarize improved understanding in blood development, the effect of niche and conservative signaling pathways on HSCs in mice and humans, and also advances in ex vivo culturing protocols of human HSCs with cytokines or small molecule compounds. Different expansion protocols have been tested in clinical trials. However, an optimal condition for ex vivo expansion of human HSCs still has not been found yet. Translating and implementing new findings from basic research (for instance by using genetic modification of human HSCs) into clinical protocols is crucial to improve ex vivo expansion and eventually boost stem cell gene therapy.
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Affiliation(s)
- Parisa Tajer
- Department of Immunohematology and Blood Transfusion, L3-Q Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
- Department of Molecular Cell Biology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
| | - Karin Pike-Overzet
- Department of Immunohematology and Blood Transfusion, L3-Q Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
- Department of Molecular Cell Biology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
| | - Sagrario Arias
- Batavia Biosciences, Zernikedreef 16, 2333 CL Leiden, The Netherlands.
| | - Menzo Havenga
- Batavia Biosciences, Zernikedreef 16, 2333 CL Leiden, The Netherlands.
| | - Frank J T Staal
- Department of Immunohematology and Blood Transfusion, L3-Q Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
- Department of Molecular Cell Biology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
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25
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Meng X, Sun B, Xiao Z. Comparison in transcriptome and cytokine profiles of mesenchymal stem cells from human umbilical cord and cord blood. Gene 2019; 696:10-20. [PMID: 30769140 DOI: 10.1016/j.gene.2019.02.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 01/23/2019] [Accepted: 02/08/2019] [Indexed: 12/14/2022]
Abstract
Human umbilical cord (UC) and cord blood (CB) provide attractive sources of mesenchymal stem cells (MSCs) for cell therapy. Both UCMSCs and CBMSCs have been demonstrated to play prominent roles in clinical therapy. However, little is known about their functional differences in clinical application. Our transcriptome analysis uncovered high activity of insulin secretion related signaling pathways for CBMSCs and cell adhesion related signaling pathways for UCMSCs. Expression of a large number of immune related signaling pathways also showed the difference in both cells, implying their distinct immune modulatory functions. As the therapeutic effects of MSCs mainly dependent on the cytokines and growth factors produced by transplanted MSCs, we further compared the cytokine profiles of UCMSCs and CBMSCs using antibody array. By evaluating the expression of 106 cytokines, we found both MSCs abundantly secreted TSP-1, TSG-14, TIMP-1, IL-8, IL-6, CXCL1, GIF and IGFBP3. However, the expression of CCL2 in UCMSCs showed significantly higher than CBMSCs. IGFBP1 and IGFBP2 were secreted by CBMSCs with higher abundance than UCMSCs. Overall, these results suggest that UCMSCs and CBMSCs preserve different functional potentials, which have to be carefully considered before clinical treatment.
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Affiliation(s)
- Xianhui Meng
- State key laboratory of bioelectronics, School of biological science & medical engineering, Southeast University, Nanjing, 210096, China
| | - Bo Sun
- State key laboratory of bioelectronics, School of biological science & medical engineering, Southeast University, Nanjing, 210096, China.
| | - Zhongdang Xiao
- State key laboratory of bioelectronics, School of biological science & medical engineering, Southeast University, Nanjing, 210096, China.
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26
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Bone marrow MSCs in MDS: contribution towards dysfunctional hematopoiesis and potential targets for disease response to hypomethylating therapy. Leukemia 2018; 33:1487-1500. [PMID: 30575819 PMCID: PMC6756222 DOI: 10.1038/s41375-018-0310-y] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/15/2018] [Accepted: 10/16/2018] [Indexed: 01/13/2023]
Abstract
The study of myelodysplastic syndromes (MDS) in murine models has now indicated the possible involvement of the bone marrow microenvironment in the generation of dysplastic hematopoietic cells. However, there is scant work on patient samples and the role of hypomethylating agents on the bone marrow stromal cells of MDS patients is unclear. We show that human MDS-MSCs exhibit phenotypic, transcriptomic and epigenetic abnormalities. Stimuli provided by MDS-MSCs impaired the growth and function of healthy HSPCs, which is further sustained autonomously in HSPCs for significant periods of time resulting in a failure for active hematopoietic engraftment across primary and secondary transplant recipients (chimerism: 0.34–91% vs 2.78%, engraftment frequencies: at 0.06 ± 0.02 vs full engraftment for MDS-MSC vs healthy groups, respectively). Hypomethylation of MDS-MSCs improved overall engraftment in most of the MDS-MSC groups tested (2/7 with p < 0.01, 3/7 with p < 0.05 and 2/7 with no significant difference). MDS-MSCs that fail to respond to hypomethylating therapy are associated with patients with rapid adverse disease transformation and this further suggests that MDS-MSCs may be an integral part of disease progression and have prognostic value as well as potential as a therapeutic target.
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27
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Loh KP, Ho D, Chiu GNC, Leong DT, Pastorin G, Chow EKH. Clinical Applications of Carbon Nanomaterials in Diagnostics and Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2018; 30:e1802368. [PMID: 30133035 DOI: 10.1002/adma.201802368] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 05/28/2018] [Indexed: 06/08/2023]
Abstract
Nanomaterials have the potential to improve how patients are clinically treated and diagnosed. While there are a number of nanomaterials that can be used toward improved drug delivery and imaging, how these nanomaterials confer an advantage over other nanomaterials, as well as current clinical approaches is often application or disease specific. How the unique properties of carbon nanomaterials, such as nanodiamonds, carbon nanotubes, carbon nanofibers, graphene, and graphene oxides, make them promising nanomaterials for a wide range of clinical applications are discussed herein, including treating chemoresistant cancer, enhancing magnetic resonance imaging, and improving tissue regeneration and stem cell banking, among others. Additionally, the strategies for further improving drug delivery and imaging by carbon nanomaterials are reviewed, such as inducing endothelial leakiness as well as applying artificial intelligence toward designing optimal nanoparticle-based drug combination delivery. While the clinical application of carbon nanomaterials is still an emerging field of research, there is substantial preclinical evidence of the translational potential of carbon nanomaterials. Early clinically trial studies are highlighted, further supporting the use of carbon nanomaterials in clinical applications for both drug delivery and imaging.
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Affiliation(s)
- Kian Ping Loh
- Department of Chemistry and Centre for Advanced 2D Materials (CA2DM), National University of Singapore, Singapore, 117543, Singapore
| | - Dean Ho
- Department of Biomedical Engineering, National University of Singapore, Singapore, 117583, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
- Singapore Institute for Neurotechnology (SINAPSE), Singapore, 117456, Singapore
- Biomedical Institute for Global Health Research and Technology (BIGHEART), Singapore, 117599, Singapore
| | - Gigi Ngar Chee Chiu
- Department of Pharmacy, National University of Singapore, Singapore, 117543, Singapore
| | - David Tai Leong
- Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, 117585, Singapore
| | - Giorgia Pastorin
- Department of Pharmacy, National University of Singapore, Singapore, 117543, Singapore
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
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28
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Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, He L, Chen Y, Chen H, Luo W, Lu Z, Xie J, Churchill H, Xu Y, Zhou Z, Wu G, Yu C, John S, Hirayasu K, Nguyen N, Liu X, Huang F, Li L, Deng H, Tang H, Sadek AH, Zhang L, Huang T, Zou Y, Chen B, Zhu H, Arase H, Xia N, Jiang Y, Collins R, You MJ, Homsi J, Unni N, Lewis C, Chen GQ, Fu YX, Liao XC, An Z, Zheng J, Zhang N, Zhang CC. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature 2018; 562:605-609. [PMID: 30333625 PMCID: PMC6296374 DOI: 10.1038/s41586-018-0615-z] [Citation(s) in RCA: 205] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 08/15/2018] [Indexed: 12/18/2022]
Abstract
Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.
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MESH Headings
- Animals
- Apolipoproteins E/metabolism
- Arginase/metabolism
- CD4-Positive T-Lymphocytes/cytology
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/cytology
- CD8-Positive T-Lymphocytes/immunology
- Cell Movement
- Cell Proliferation
- Female
- Humans
- Immune Tolerance/immunology
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Male
- Membrane Glycoproteins
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, SCID
- Protein Binding
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
- Receptors, Cell Surface/deficiency
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Immunologic
- Receptors, Urokinase Plasminogen Activator/metabolism
- Signal Transduction
- Tumor Escape/drug effects
- Tumor Escape/immunology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Mi Deng
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xun Gui
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Jaehyup Kim
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Li Xie
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weina Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Zunling Li
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Taishan Immunology Program, Basic Medicine School, Binzhou Medical University, Yantai, China
| | - Licai He
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medical and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Yuanzhi Chen
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
- School of Public Health, Xiamen University, Xiamen, China
| | - Heyu Chen
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Weiguang Luo
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Immunology, Xiangya Medical School, Central South University, Changsha, China
| | - Zhigang Lu
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Institute of Biomedical Sciences and the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Jingjing Xie
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Taishan Immunology Program, Basic Medicine School, Binzhou Medical University, Yantai, China
| | - Hywyn Churchill
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yixiang Xu
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Zhan Zhou
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Guojin Wu
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Chenyi Yu
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
- Xiangya Medical School, Central South University, Changsha, China
| | - Samuel John
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kouyuki Hirayasu
- Department of Immunochemistry, Research Institute for Microbial Diseases and Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Nam Nguyen
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaoye Liu
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Fangfang Huang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Hematology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Leike Li
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Hui Deng
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Haidong Tang
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ali H Sadek
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lingbo Zhang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Xiangya Medical School, Central South University, Changsha, China
| | - Tao Huang
- Immune-Onc Therapeutics, Inc., Palo Alto, CA, USA
| | - Yizhou Zou
- Department of Immunology, Xiangya Medical School, Central South University, Changsha, China
| | - Benjamin Chen
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Hong Zhu
- Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Hisashi Arase
- Department of Immunochemistry, Research Institute for Microbial Diseases and Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Ningshao Xia
- School of Public Health, Xiamen University, Xiamen, China
| | - Youxing Jiang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Robert Collins
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - M James You
- Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jade Homsi
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nisha Unni
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Cheryl Lewis
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Guo-Qiang Chen
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang-Xin Fu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Zhiqiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
| | - Junke Zheng
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ningyan Zhang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
| | - Cheng Cheng Zhang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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29
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Hammerschmidt SI, Werth K, Rothe M, Galla M, Permanyer M, Patzer GE, Bubke A, Frenk DN, Selich A, Lange L, Schambach A, Bošnjak B, Förster R. CRISPR/Cas9 Immunoengineering of Hoxb8-Immortalized Progenitor Cells for Revealing CCR7-Mediated Dendritic Cell Signaling and Migration Mechanisms in vivo. Front Immunol 2018; 9:1949. [PMID: 30210501 PMCID: PMC6120996 DOI: 10.3389/fimmu.2018.01949] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 08/07/2018] [Indexed: 12/30/2022] Open
Abstract
To present antigens to cognate T cells, dendritic cells (DCs) exploit the chemokine receptor CCR7 to travel from peripheral tissue via afferent lymphatic vessels to directly enter draining lymph nodes through the floor of the subcapsular sinus. Here, we combined unlimited proliferative capacity of conditionally Hoxb8-immortalized hematopoietic progenitor cells with CRISPR/Cas9 technology to create a powerful experimental system to investigate DC migration and function. Hematopoietic progenitor cells from the bone marrow of Cas9-transgenic mice were conditionally immortalized by lentiviral transduction introducing a doxycycline-regulated form of the transcription factor Hoxb8 (Cas9-Hoxb8 cells). These cells could be stably cultured for weeks in the presence of doxycycline and puromycin, allowing us to introduce additional genetic modifications applying CRISPR/Cas9 technology. Importantly, modified Cas9-Hoxb8 cells retained their potential to differentiate in vitro into myeloid cells, and GM-CSF-differentiated Cas9-Hoxb8 cells showed the classical phenotype of GM-CSF-differentiated bone marrow-derived dendritic cells. Following intralymphatic delivery Cas9-Hoxb8 DCs entered the lymph node in a CCR7-dependent manner. Finally, we used two-photon microscopy and imaged Cas9-Hoxb8 DCs that expressed the genetic Ca2+ sensor GCaMP6S to visualize in real-time chemokine-induced Ca2+ signaling of lymph-derived DCs entering the LN parenchyma. Altogether, our study not only allows mechanistic insights in DC migration in vivo, but also provides a platform for the immunoengineering of DCs that, in combination with two-photon imaging, can be exploited to further dissect DC dynamics in vivo.
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Affiliation(s)
| | - Kathrin Werth
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Michael Rothe
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany
| | - Melanie Galla
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany
| | - Marc Permanyer
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | | | - Anja Bubke
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - David N. Frenk
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Anton Selich
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany
| | - Lucas Lange
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany
| | - Axel Schambach
- Institute of Experimental Hematology, REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany
| | - Berislav Bošnjak
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Reinhold Förster
- Institute of Immunology, Hannover Medical School, Hannover, Germany
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30
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Lidonnici MR, Ferrari G. Gene therapy and gene editing strategies for hemoglobinopathies. Blood Cells Mol Dis 2018; 70:87-101. [DOI: 10.1016/j.bcmd.2017.12.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 12/19/2017] [Accepted: 12/27/2017] [Indexed: 10/24/2022]
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31
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He J, Xu J, Yu X, Zhu H, Zeng Y, Fan D, Yi X. Overexpression of ANGPTL2 and LILRB2 as predictive and therapeutic biomarkers for metastasis and prognosis in colorectal cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:2281-2294. [PMID: 31938340 PMCID: PMC6958241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 03/24/2018] [Indexed: 06/10/2023]
Abstract
LILRB2 is an inhibitory receptor involved in immune cells. A variety of cancer cells have been observed to express LILRB2, which has been related to development of cancers. Recently, ANGPTL2 was found to be bound to LILRB2 as a high affinity ligand. Expression and function of LILRB2 and ANGPTL2 in colorectal cancer (CRC) remain unknown. To explore differential expression, 364 CRCs, 5 adenomas, and 205 normal samples for LILRB2 and 338 CRCs, 5 adenomas, and 232 normal samples for ANGPTL2 were studied in Oncomine and GEO databases. We noted that LILRB2 was significantly increased in CRC compared to adenoma and normal tissues. ANGPTL2 was higher in adenoma than normal tissues and further increased in CRC than adenoma. Copy number of LILRB2 and ANGPTL2 DNA was also more increased in CRC than in normal tissue. Furthermore, immunohistochemistry analysis of 155 pairs of primary CRC and normal tissues verified the positive rates of LILRB2 and ANGPTL2 were 87.10% (135/155) and 97.44% (151/155) in CRC, with almost no expression in normal tissues. LILRB2 and ANGPTL2 were significantly associated with tumor size, worse cell differentiation, lymph node metastasis, and advanced disease stage. Levels of ANGPTL2 were adversely related to survival of CRC patients, consistent with results in GEPIA (TCGA data) database. Moreover, a significant positive correlation was found between LILRB2 and ANGPTL2 in CRC. These findings suggest that ANGPTL2 and LILRB2 play an important role in CRC occurrence and progression. ANGPTL2 and LILRB2 could serve as novel biomarkers for treatment and prognosis of CRC.
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Affiliation(s)
- Jian He
- Department of Pathology, Tongji Hospital, Tongji University School of MedicineShanghai, P. R. China
| | - Jie Xu
- School of Public Health, Xinxiang Medical UniversityXinxiang, Henan Province, P. R. China
| | - Xiaoting Yu
- Department of Pathology, Tongji Hospital, Tongji University School of MedicineShanghai, P. R. China
| | - Hailong Zhu
- Department of Pathology, Tongji Hospital, Tongji University School of MedicineShanghai, P. R. China
| | - Yu Zeng
- Department of Pathology, Tongji Hospital, Tongji University School of MedicineShanghai, P. R. China
| | - Desheng Fan
- Department of Pathology, Tongji Hospital, Tongji University School of MedicineShanghai, P. R. China
| | - Xianghua Yi
- Department of Pathology, Tongji Hospital, Tongji University School of MedicineShanghai, P. R. China
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32
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ANGPTL8 reverses established adriamycin cardiomyopathy by stimulating adult cardiac progenitor cells. Oncotarget 2018; 7:80391-80403. [PMID: 27823982 PMCID: PMC5348328 DOI: 10.18632/oncotarget.13061] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 10/07/2016] [Indexed: 12/18/2022] Open
Abstract
Established adriamycin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50% in a year. It has been known that ANGPTLs has various functions in lipid metabolism, inflammation, cancer cell invasion, hematopoietic stem activity and diabetes. We hypothesized that ANGPTL8 is capable of maintaining heart function by stimulating adult cardiac progenitor cells to initiate myocardial regeneration. We employed UTMD to deliver piggybac transposon plasmids with the human ANGPTL8 gene to the liver of rats with adriamycin cardiomyopathy. After ANGPTL8 gene liver delivery, overexpression of transgenic human ANGPTL8 was found in rat liver cells and blood. UTMD- ANGPTL8 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Our results also showed that ANGPTL8 reversed established ADM cardiomyopathy. This was associated with activation of ISL-1 positive cardiac progenitor cells in the epicardium. A time-course experiment shown that ISL-1 cardiac progenitor cells proliferated and formed a niche in the epicardial layer and then migrated into sub-epicardium. The observed myocardial regeneration accompanying reversal of adriamycin cardiomyopathy was associated with upregulation of PirB expression on the cell membrane of cardiac muscle cells or progenitor cells stimulated by ANGPTL8.
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Chin CJ, Li S, Corselli M, Casero D, Zhu Y, He CB, Hardy R, Péault B, Crooks GM. Transcriptionally and Functionally Distinct Mesenchymal Subpopulations Are Generated from Human Pluripotent Stem Cells. Stem Cell Reports 2018; 10:436-446. [PMID: 29307583 PMCID: PMC5830911 DOI: 10.1016/j.stemcr.2017.12.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 02/06/2023] Open
Abstract
Various mesenchymal cell types have been identified as critical components of the hematopoietic stem/progenitor cell (HSPC) niche. Although several groups have described the generation of mesenchyme from human pluripotent stem cells (hPSCs), the capacity of such cells to support hematopoiesis has not been reported. Here, we demonstrate that distinct mesenchymal subpopulations co-emerge from mesoderm during hPSC differentiation. Despite co-expression of common mesenchymal markers (CD73, CD105, CD90, and PDGFRβ), a subset of cells defined as CD146hiCD73hi expressed genes associated with the HSPC niche and supported the maintenance of functional HSPCs ex vivo, while CD146loCD73lo cells supported differentiation. Stromal support of HSPCs was contact dependent and mediated in part through high JAG1 expression and low WNT signaling. Molecular profiling revealed significant transcriptional similarity between hPSC-derived CD146++ and primary human CD146++ perivascular cells. The derivation of functionally diverse types of mesenchyme from hPSCs opens potential avenues to model the HSPC niche and develop PSC-based therapies.
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Affiliation(s)
- Chee Jia Chin
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA
| | - Suwen Li
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA
| | | | - David Casero
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA
| | - Yuhua Zhu
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA
| | - Chong Bin He
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA
| | - Reef Hardy
- Department of Orthopedics, DGSOM, UCLA, Los Angeles, CA 90095, USA; Orthopedic Hospital Research Center, UCLA, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center (BSCRC), UCLA, Los Angeles, CA 90095, USA; Department of Medicine, University of Indiana, Indianapolis, IN 46202, USA
| | - Bruno Péault
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA; Department of Orthopedics, DGSOM, UCLA, Los Angeles, CA 90095, USA; Orthopedic Hospital Research Center, UCLA, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center (BSCRC), UCLA, Los Angeles, CA 90095, USA; Center for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Gay M Crooks
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA; Broad Stem Cell Research Center (BSCRC), UCLA, Los Angeles, CA 90095, USA; Department of Pediatrics, DGSOM, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA 90095, USA.
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34
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Rossmann MP, Orkin SH, Chute JP. Hematopoietic Stem Cell Biology. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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35
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Mehta RS, Olson A, Ponce DM, Shpall EJ. Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00107-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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36
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Costa MHG, de Soure AM, Cabral JMS, Ferreira FC, da Silva CL. Hematopoietic Niche - Exploring Biomimetic Cues to Improve the Functionality of Hematopoietic Stem/Progenitor Cells. Biotechnol J 2017; 13. [PMID: 29178199 DOI: 10.1002/biot.201700088] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 10/27/2017] [Indexed: 12/19/2022]
Abstract
The adult bone marrow (BM) niche is a complex entity where a homeostatic hematopoietic system is maintained through a dynamic crosstalk between different cellular and non-cellular players. Signaling mechanisms triggered by cell-cell, cell-extracellular matrix (ECM), cell-cytokine interactions, and local microenvironment parameters are involved in controlling quiescence, self-renewal, differentiation, and migration of hematopoietic stem/progenitor cells (HSPC). A promising strategy to more efficiently expand HSPC numbers and tune their properties ex vivo is to mimic the hematopoietic niche through integration of adjuvant stromal cells, soluble cues, and/or biomaterial-based approaches in HSPC culture systems. Particularly, mesenchymal stem/stromal cells (MSC), through their paracrine activity or direct contact with HSPC, are thought to be a relevant niche player, positioning HSPC-MSC co-culture as a valuable platform to support the ex vivo expansion of hematopoietic progenitors. To improve the clinical outcome of hematopoietic cell transplantation (HCT), namely when the available HSPC are present in a limited number such is the case of HSPC collected from umbilical cord blood (UCB), ex vivo expansion of HSPC is required without eliminating the long-term repopulating capacity of more primitive HSC. Here, we will focus on depicting the characteristics of co-culture systems, as well as other bioengineering approaches to improve the functionality of HSPC ex vivo.
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Affiliation(s)
- Marta H G Costa
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - António M de Soure
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Joaquim M S Cabral
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Frederico Castelo Ferreira
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Cláudia L da Silva
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
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37
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Adair JE, Kubek SP, Kiem HP. Hematopoietic Stem Cell Approaches to Cancer. Hematol Oncol Clin North Am 2017; 31:897-912. [DOI: 10.1016/j.hoc.2017.06.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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38
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Chen Q. The niche for hematopoietic stem cell expansion: a collaboration network. Cell Mol Immunol 2017; 14:865-867. [PMID: 28845045 PMCID: PMC5649112 DOI: 10.1038/cmi.2017.74] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 06/29/2017] [Indexed: 01/27/2023] Open
Affiliation(s)
- Qingfeng Chen
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- National Cancer Centre Singapore, Singapore 169610, Singapore
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
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39
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Kohlscheen S, Bonig H, Modlich U. Promises and Challenges in Hematopoietic Stem Cell Gene Therapy. Hum Gene Ther 2017; 28:782-799. [DOI: 10.1089/hum.2017.141] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Affiliation(s)
- Saskia Kohlscheen
- Research Group for Gene Modification in Stem Cells, Center for Cell and Gene Therapy Frankfurt, Paul-Ehrlich-Institute, Langen, Germany
| | - Halvard Bonig
- Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany
- German Red Cross Blood Service Baden-Württemberg-Hessen, Institute Frankfurt, Germany
- Department of Medicine/Division of Hematology, University of Washington, Seattle, Washington
| | - Ute Modlich
- Research Group for Gene Modification in Stem Cells, Center for Cell and Gene Therapy Frankfurt, Paul-Ehrlich-Institute, Langen, Germany
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40
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Severn CE, Toye AM. The challenge of growing enough reticulocytes for transfusion. ACTA ACUST UNITED AC 2017. [DOI: 10.1111/voxs.12374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- C. E. Severn
- School of Biochemistry; Biomedical Sciences Building; University Walk; University of Bristol; Bristol UK
- National Institute for Health Research (NIHR) Blood and Transplant Research Unit; University of Bristol; Bristol UK
| | - A. M. Toye
- School of Biochemistry; Biomedical Sciences Building; University Walk; University of Bristol; Bristol UK
- National Institute for Health Research (NIHR) Blood and Transplant Research Unit; University of Bristol; Bristol UK
- Bristol Institute of Transfusion Sciences; NHSBT Filton; Bristol UK
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41
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Garba A, Acar DD, Roukaerts IDM, Desmarets LMB, Devriendt B, Nauwynck HJ. Long-term culture and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized mesenchymal cells. Vet Immunol Immunopathol 2017; 191:44-50. [PMID: 28895865 DOI: 10.1016/j.vetimm.2017.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 07/24/2017] [Accepted: 08/03/2017] [Indexed: 12/01/2022]
Abstract
Mesenchymal cells are multipotent stromal cells with self-renewal, differentiation and immunomodulatory capabilities. We aimed to develop a co-culture model for differentiating hematopoietic cells on top of immortalized mesenchymal cells for studying interactions between hematopoietic and mesenchymal cells, useful for adequately exploring the therapeutic potential of mesenchymal cells. In this study, we investigated the survival, proliferation and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized porcine bone marrow mesenchymal cells for a period of five weeks. Directly after collection, primary porcine bone marrow mesenchymal cells adhered firmly to the bottom of the culture plates and showed a fibroblast-like appearance, one week after isolation. Upon immortalization, porcine bone marrow mesenchymal cells were continuously proliferating. They were positive for simian virus 40 (SV40) large T antigen and the mesenchymal cell markers CD44 and CD55. Isolated red bone marrow cells were added to these immortalized mesenchymal cells. Five weeks post-seeding, 92±6% of the red bone marrow hematopoietic cells were still alive and their number increased 3-fold during five weekly subpassages on top of the immortalized mesenchymal cells. The red bone marrow hematopoietic cells were originally small and round; later, the cells increased in size. Some of them became elongated, while others remained round. Tiny dendrites appeared attaching hematopoietic cells to the underlying immortalized mesenchymal cells. Furthermore, weekly differential-quick staining of the cells indicated the presence of monoblasts, monocytes, macrophages and lymphocytes in the co-cultures. At three weeks of co-culture, flow cytometry analysis showed an increased surface expression of CD172a, CD14, CD163, CD169, CD4 and CD8 up to 37±0.8%, 40±8%, 41±4%, 23±3% and 19±5% of the hematopoietic cells, respectively. In conclusion, continuous mesenchymal cell cultures were successfully established and characterized and they supported the proliferation of red bone marrow hematopoietic cells, which finally differentiated into monocytic cells and CD4+ and CD8+ cells.
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Affiliation(s)
- Abubakar Garba
- Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Delphine D Acar
- Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Inge D M Roukaerts
- Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Lowiese M B Desmarets
- Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Bert Devriendt
- Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium
| | - Hans J Nauwynck
- Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
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42
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Rödling L, Schwedhelm I, Kraus S, Bieback K, Hansmann J, Lee-Thedieck C. 3D models of the hematopoietic stem cell niche under steady-state and active conditions. Sci Rep 2017; 7:4625. [PMID: 28676663 PMCID: PMC5496931 DOI: 10.1038/s41598-017-04808-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 05/22/2017] [Indexed: 12/11/2022] Open
Abstract
Hematopoietic stem cells (HSCs) in the bone marrow are able to differentiate into all types of blood cells and supply the organism each day with billions of fresh cells. They are applied to cure hematological diseases such as leukemia. The clinical need for HSCs is high and there is a demand for being able to control and multiply HSCs in vitro. The hematopoietic system is highly proliferative and thus sensitive to anti-proliferative drugs such as chemotherapeutics. For many of these drugs suppression of the hematopoietic system is the dose-limiting toxicity. Therefore, biomimetic 3D models of the HSC niche that allow to control HSC behavior in vitro and to test drugs in a human setting are relevant for the clinics and pharmacology. Here, we describe a perfused 3D bone marrow analog that allows mimicking the HSC niche under steady-state and activated conditions that favor either HSC maintenance or differentiation, respectively, and allows for drug testing.
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Affiliation(s)
- Lisa Rödling
- Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Ivo Schwedhelm
- Institute for Tissue Engineering and Regenerative Medicine, University of Würzburg, 97070, Würzburg, Germany
| | - Saskia Kraus
- Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology Mannheim, Medical Faculty Mannheim, Heidelberg University; German Red Cross Blood Donor Service Baden-Württemberg-Hessen, 68167, Mannheim, Germany
| | - Jan Hansmann
- Institute for Tissue Engineering and Regenerative Medicine, University of Würzburg, 97070, Würzburg, Germany
| | - Cornelia Lee-Thedieck
- Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
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43
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van der Touw W, Chen HM, Pan PY, Chen SH. LILRB receptor-mediated regulation of myeloid cell maturation and function. Cancer Immunol Immunother 2017. [PMID: 28638976 DOI: 10.1007/s00262-017-2023-x] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The leukocyte immunoglobulin-like receptor (LILR) family comprises a set of paired immunomodulatory receptors expressed among human myeloid and lymphocyte cell populations. While six members of LILR subfamily A (LILRA) associate with membrane adaptors to signal via immunoreceptor tyrosine-based activating motifs (ITAM), LILR subfamily B (LILRB) members signal via multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). Ligand specificity of some LILR family members has been studied in detail, but new perspective into the immunoregulatory aspects of this receptor family in human myeloid cells has been limited. LILRB receptors and the murine ortholog, paired immunoglobulin-like receptor B (PIRB), have been shown to negatively regulate maturation pathways in myeloid cells including mast cells, neutrophils, dendritic cells, as well as B cells. Our laboratory further demonstrated in mouse models that PIRB regulated functional development of myeloid-derived suppressor cell and the formation of a tumor-permissive microenvironment. Based on observations from the literature and our own studies, our laboratory is focusing on how LILRs modulate immune homeostasis of human myeloid cells and how these pathways may be targeted in disease states. Integrity of this pathway in tumor microenvironments, for example, permits a myeloid phenotype that suppresses antitumor adaptive immunity. This review presents the evidence supporting a role of LILRs as myeloid cell regulators and ongoing efforts to understand the functional immunology surrounding this family.
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Affiliation(s)
- William van der Touw
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA
| | - Hui-Ming Chen
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA
- Immunotherapy Research Center, Houston Methodist Research institute, 6670 Bertner Ave, Houston, TX, 77030, USA
| | - Ping-Ying Pan
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA
- Immunotherapy Research Center, Houston Methodist Research institute, 6670 Bertner Ave, Houston, TX, 77030, USA
| | - Shu-Hsia Chen
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA.
- Immunotherapy Research Center, Houston Methodist Research institute, 6670 Bertner Ave, Houston, TX, 77030, USA.
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44
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Zhou W, Mahshid SS, Wang W, Vallée-Bélisle A, Zandstra PW, Sargent EH, Kelley SO. Steric Hindrance Assay for Secreted Factors in Stem Cell Culture. ACS Sens 2017; 2:495-500. [PMID: 28723184 DOI: 10.1021/acssensors.7b00136] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The ex vivo expansion of hematopoietic stem cells is significantly inhibited by secreted proteins that induce negative feedback loops. The ability to effectively monitor these factors is critical for their real-time regulation and control and, by extension, enhancing stem cell expansion. Here, we describe a novel monitoring strategy for the detection of soluble signaling factors in stem cell cultures using a DNA-based sensing mechanism on a chip-based nanostructured microelectrode platform. We combine DNA hybridization engineering with antibody-capturing chemistry in an amplified steric hindrance hybridization assay. This method enables the quantification of important secreted proteins, showcased by the detection of 10 pg·mL-1 level concentrations of three proteins in stem cell culture samples. This approach is the first universal nonsandwich technique that permits pg·mL-1 level quantification of small proteins in stem cell culture media without signal loss.
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Affiliation(s)
- Wendi Zhou
- Electrical
and Computer Engineering, University of Toronto, Toronto M5S 1A4 Canada
| | - Sahar S. Mahshid
- Leslie
Dan Faculty of Pharmacy, University of Toronto, Toronto M5S 3M2 Canada
| | - Weijia Wang
- Institute
of Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5S 3G9 Canada
| | | | - Peter W. Zandstra
- Institute
of Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5S 3G9 Canada
| | - Edward H. Sargent
- Electrical
and Computer Engineering, University of Toronto, Toronto M5S 1A4 Canada
| | - Shana O. Kelley
- Leslie
Dan Faculty of Pharmacy, University of Toronto, Toronto M5S 3M2 Canada
- Institute
of Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5S 3G9 Canada
- Department
of Biochemistry, University of Toronto, Toronto M5S 1A8 Canada
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45
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Alsheikh M, Abu-Khader A, Michalicka M, Pasha R, Pineault N. Impact of osteoblast maturation on their paracrine growth enhancing activity on cord blood progenitors. Eur J Haematol 2017; 98:542-552. [PMID: 28160325 DOI: 10.1111/ejh.12865] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2017] [Indexed: 01/05/2023]
Abstract
BACKGROUND Osteoblasts possess strong growth modulatory activity on haematopoietic stem cells and progenitors. We sought to characterise the growth and differentiation modulatory activities of human osteoblasts at distinct stages of maturation on cord blood (CB) progenitors in the context of osteoblast conditioned medium (OCM). METHODS OCM was produced from MSC-derived osteoblasts (M-OST) at distinct stages of maturation. The growth modulatory activities of the OCM were tested on CB CD34+ cells using different functional assays. RESULTS OCMs raised the growth of CB cells and expansion of CD34+ cells independently of the maturation status of M-OST. However, productions of immature CB cells including committed and multipotent progenitors were superior with OCM produced with immature osteoblasts. Osteogenic differentiation was accompanied by the upregulation of IGFBP-2, by several members of the Angpt-L family of growth factor, and by the Notch ligands Dll-1 and Dll-4. However, the growth activity of OCM and the in vivo engraftment properties of OCM-expanded CB cells were retained after IGFBP-2 neutralisation. Similarly, OCM-mediated expansion of CB myeloid progenitors was largely independent of Notch signalling. CONCLUSIONS These results demonstrate that immature osteoblasts possess greater regulatory activity over haematopoietic progenitors, and that this activity is not entirely dependent on Notch signalling.
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Affiliation(s)
- Manal Alsheikh
- Canadian Blood Services, Centre for Innovation, Ottawa, ON, Canada.,Biochemistry, Microbiology and Immunology Department, University of Ottawa, Ottawa, ON, Canada
| | - Ahmad Abu-Khader
- Canadian Blood Services, Centre for Innovation, Ottawa, ON, Canada
| | - Matthew Michalicka
- Canadian Blood Services, Centre for Innovation, Ottawa, ON, Canada.,Biochemistry, Microbiology and Immunology Department, University of Ottawa, Ottawa, ON, Canada
| | - Roya Pasha
- Canadian Blood Services, Centre for Innovation, Ottawa, ON, Canada
| | - Nicolas Pineault
- Canadian Blood Services, Centre for Innovation, Ottawa, ON, Canada.,Biochemistry, Microbiology and Immunology Department, University of Ottawa, Ottawa, ON, Canada
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46
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Yucel D, Kocabas F. Developments in Hematopoietic Stem Cell Expansion and Gene Editing Technologies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1079:103-125. [DOI: 10.1007/5584_2017_114] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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47
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Kiernan J, Damien P, Monaghan M, Shorr R, McIntyre L, Fergusson D, Tinmouth A, Allan D. Clinical Studies of Ex Vivo Expansion to Accelerate Engraftment After Umbilical Cord Blood Transplantation: A Systematic Review. Transfus Med Rev 2016; 31:173-182. [PMID: 28087163 DOI: 10.1016/j.tmrv.2016.12.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 11/30/2016] [Accepted: 12/20/2016] [Indexed: 01/04/2023]
Abstract
Cell dose limits greater use of umbilical cord blood (UCB) in hematopoietic cell transplantation. The clinical benefits of ex vivo expansion need clarity to understand its potential impact. A systematic search of studies addressing UCB ex vivo expansion was conducted. Fifteen clinical studies (349 transplanted patients) and 13 registered trials were identified. The co-infusion of an expanded unit and a second unmanipulated unit (8 studies), the fractional expansion of 12% to 60% of a single unit (5 studies), and the infusion of a single expanded unit (2 studies) were reported. More recently, published studies and 12 of 13 ongoing trials involve the use of novel small molecules in addition to traditional cytokine cocktails. Higher total cell number was closely associated with faster neutrophil engraftment. Compared with historical controls, neutrophil engraftment was significantly accelerated in more recent studies using small molecules or mesenchymal stromal cells (MSC) co-culture, and in some cases, platelet recovery was also statistically improved. Recent studies using nicotinamide and StemRegenin-1 reported long-term chimerism of the expanded unit. No significant improvement in survival or other transplant-related outcomes was demonstrated for any of the strategies. Ex vivo expansion of UCB can accelerate initial neutrophil engraftment after transplant. More recent studies suggest that long-term engraftment of ex vivo expanded cord blood units is achievable. Results of larger randomized controlled trials are needed to understand the impact on patient outcomes and health care costs.
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Affiliation(s)
- Jeffrey Kiernan
- Center for Transfusion Research, University of Ottawa, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Pauline Damien
- Center for Transfusion Research, University of Ottawa, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | | | - Risa Shorr
- Medical Library Services, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Lauralyn McIntyre
- Center for Transfusion Research, University of Ottawa, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Dean Fergusson
- Center for Transfusion Research, University of Ottawa, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Alan Tinmouth
- Center for Transfusion Research, University of Ottawa, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - David Allan
- Center for Transfusion Research, University of Ottawa, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
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48
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Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med 2016; 23:79-90. [PMID: 27941793 DOI: 10.1038/nm.4252] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 11/14/2016] [Indexed: 12/17/2022]
Abstract
New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.
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49
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Tarunina M, Hernandez D, Kronsteiner-Dobramysl B, Pratt P, Watson T, Hua P, Gullo F, van der Garde M, Zhang Y, Hook L, Choo Y, Watt SM. A Novel High-Throughput Screening Platform Reveals an Optimized Cytokine Formulation for Human Hematopoietic Progenitor Cell Expansion. Stem Cells Dev 2016; 25:1709-1720. [PMID: 27554619 DOI: 10.1089/scd.2016.0216] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The main limitations of hematopoietic cord blood (CB) transplantation, viz, low cell dosage and delayed reconstitution, can be overcome by ex vivo expansion. CB expansion under conventional culture causes rapid cell differentiation and depletion of hematopoietic stem and progenitor cells (HSPCs) responsible for engraftment. In this study, we use combinatorial cell culture technology (CombiCult®) to identify medium formulations that promote CD133+ CB HSPC proliferation while maintaining their phenotypic characteristics. We employed second-generation CombiCult screens that use electrospraying technology to encapsulate CB cells in alginate beads. Our results suggest that not only the combination but also the order of addition of individual components has a profound influence on expansion of specific HSPC populations. Top protocols identified by the CombiCult screen were used to culture human CD133+ CB HSPCs on nanofiber scaffolds and validate the expansion of the phenotypically defined CD34+CD38lo/-CD45RA-CD90+CD49f+ population of hematopoietic stem cells and their differentiation into defined progeny.
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Affiliation(s)
- Marina Tarunina
- 1 Plasticell Ltd. , Stevenage Bioscience Catalyst, Stevenage, United Kingdom
| | - Diana Hernandez
- 1 Plasticell Ltd. , Stevenage Bioscience Catalyst, Stevenage, United Kingdom
| | - Barbara Kronsteiner-Dobramysl
- 2 Stem Cell Research, Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford , Oxford, United Kingdom .,3 Stem Cell Research, NHS Blood and Transplant, Radcliffe Department of Medicine, John Radcliffe Hospital , Oxford, United Kingdom
| | - Philip Pratt
- 4 Department of Surgery and Cancer, Faculty of Medicine, Imperial College London , South Kensington, United Kingdom
| | - Thomas Watson
- 1 Plasticell Ltd. , Stevenage Bioscience Catalyst, Stevenage, United Kingdom
| | - Peng Hua
- 2 Stem Cell Research, Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford , Oxford, United Kingdom .,3 Stem Cell Research, NHS Blood and Transplant, Radcliffe Department of Medicine, John Radcliffe Hospital , Oxford, United Kingdom
| | - Francesca Gullo
- 2 Stem Cell Research, Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford , Oxford, United Kingdom .,3 Stem Cell Research, NHS Blood and Transplant, Radcliffe Department of Medicine, John Radcliffe Hospital , Oxford, United Kingdom
| | - Mark van der Garde
- 2 Stem Cell Research, Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford , Oxford, United Kingdom .,3 Stem Cell Research, NHS Blood and Transplant, Radcliffe Department of Medicine, John Radcliffe Hospital , Oxford, United Kingdom
| | - Youyi Zhang
- 2 Stem Cell Research, Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford , Oxford, United Kingdom .,3 Stem Cell Research, NHS Blood and Transplant, Radcliffe Department of Medicine, John Radcliffe Hospital , Oxford, United Kingdom
| | - Lilian Hook
- 1 Plasticell Ltd. , Stevenage Bioscience Catalyst, Stevenage, United Kingdom
| | - Yen Choo
- 1 Plasticell Ltd. , Stevenage Bioscience Catalyst, Stevenage, United Kingdom
| | - Suzanne M Watt
- 2 Stem Cell Research, Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford , Oxford, United Kingdom .,3 Stem Cell Research, NHS Blood and Transplant, Radcliffe Department of Medicine, John Radcliffe Hospital , Oxford, United Kingdom
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50
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Aryal B, Rotllan N, Araldi E, Ramírez CM, He S, Chousterman BG, Fenn AM, Wanschel A, Madrigal-Matute J, Warrier N, Martín-Ventura JL, Swirski FK, Suárez Y, Fernández-Hernando C. ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression. Nat Commun 2016; 7:12313. [PMID: 27460411 PMCID: PMC4974469 DOI: 10.1038/ncomms12313] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 06/21/2016] [Indexed: 12/27/2022] Open
Abstract
Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it's absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation. Angiopoietin-like 4 protein (ANGPTL4) is a regulator of lipoprotein metabolism whose role in atherosclerosis has been controversial. Here the authors show that ANGPTL4 deficiency in haematopoietic cells increases atherogenesis by promoting myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.
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Affiliation(s)
- Binod Aryal
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.,Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, New York 10016, USA
| | - Noemi Rotllan
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Elisa Araldi
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Cristina M Ramírez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Shun He
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Benjamin G Chousterman
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Ashley M Fenn
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Amarylis Wanschel
- Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, New York 10016, USA
| | - Julio Madrigal-Matute
- Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, New York 10016, USA
| | - Nikhil Warrier
- Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology and Cell Biology, New York University School of Medicine, New York, New York 10016, USA
| | - Jose L Martín-Ventura
- Vascular Research Lab, IIS-Fundación Jimenez-Díaz, Universidad Autónoma de Madrid, Madrid 28040, Spain
| | - Filip K Swirski
- Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
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