Publications
90 results found
Athanasiou D, Edgar LT, Jafarnejad M, et al., 2017, The passive biomechanics of human pelvic collecting lymphatic vessels, PLOS One, Vol: 12, ISSN: 1932-6203
The lymphatic system has a major significance in the metastatic pathways in women’s cancers. Lymphatic pumping depends on both extrinsic and intrinsic mechanisms, and the mechanical behavior of lymphatic vessels regulates the function of the system. However, data on the mechanical properties and function of human lymphatics are lacking. Our aim is to characterize, for the first time, the passive biomechanical behavior of human collecting lymphatic vessels removed at pelvic lymph node dissection during primary debulking surgeries for epithelial ovarian cancer. Isolated vessels were cannulated and then pressurized at varying levels of applied axial stretch in a calcium-free Krebs buffer. Pressurized vessels were then imaged using multi-photon microscopy for collagen-elastin structural composition and fiber orientation. Both pressure-diameter and force-elongation responses were highly nonlinear, and axial stretching of the vessel served to decrease diameter at constant pressure. Pressure-diameter behavior for the human vessels is very similar to data from rat mesenteric vessels, though the human vessels were approximately 10× larger than those from rats. Multiphoton microscopy revealed the vessels to be composed of an inner layer of elastin with an outer layer of aligned collagen fibers. This is the first study that successfully described the passive biomechanical response and composition of human lymphatic vessels in patients with ovarian cancer. Future work should expand on this knowledge base with investigations of vessels from other anatomical locations, contractile behavior, and the implications on metastatic cell transport.
Duarte D, Hawkins ED, Akinduro O, et al., 2017, BONE MARROW ECOLOGICAL COLLAPSE IN ACUTE MYELOID LEUKEMIA IS MEDIATED BY REMODELING OF ENDOSTEAL VESSELS, 22nd Congress of the European-Hematology-Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 360-360, ISSN: 0390-6078
Secklehner J, Lo Celso C, Carlin LM, 2017, Intravital microscopy in historic and contemporary immunology, IMMUNOLOGY AND CELL BIOLOGY, Vol: 95, Pages: 506-513, ISSN: 0818-9641
Lo Celso C, 2017, Revealing the inner workings of human HSC adhesion, BLOOD, Vol: 129, Pages: 921-922, ISSN: 0006-4971
Beerman I, Luis TC, Singbrant S, et al., 2017, The evolving view of the hematopoietic stem cell niche, Experimental Hematology, Vol: 50, Pages: 22-26, ISSN: 0301-472X
Hematopoietic stem cells (HSCs) reside in specialized microenvironments known as niches. The niche is essential to support HSC function and to maintain a correct balance between self-renewal and differentiation. Recent advances in defining different mesenchymal and endothelial bone marrow cell populations, as well as hematopoietic stem and progenitor cells, greatly enhanced our understanding of these niches and of the molecular mechanisms by which they regulate HSC function. In addition to the role in maintaining HSC homeostasis, the niche has also been implicated in the pathogenesis of blood disorders including hematological malignancies. Characterizing the extrinsic regulators and the cellular context in which the niches interact with HSCs will be crucial to define new strategies to enhance blood regeneration. Furthermore, a better understanding of the role of the niche in leukemia development will open new possibilities for the treatment of these disorders by using therapies aiming to target the leukemic niche specifically. To update on recent findings on this topic, the International Society for Experimental Hematology (ISEH) organized a webinar, presented by Prof. Sean J. Morrison and Dr. Simón Méndez-Ferrer and moderated by Dr. Cristina Lo Celso, entitled "The evolving view of the hematopoietic stem cell niche," which we summarize here.
Lo Celso C, Hawkins ED, Duarte D, et al., 2016, Intravital Microscopy Reveals Fundamental Differences in the Interaction of Stem Cells and T Acute Lymphoblastic Leukaemia with the Bone Marrow Microenvironment, 58th Annual Meeting and Exposition of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Hawkins ED, Duarte D, Akinduro O, et al., 2016, T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments, NATURE, Vol: 538, Pages: 518-522, ISSN: 0028-0836
MacLean AL, Lo Celso C, Stumpf MP, 2016, Stem Cell Population Biology: Insights from Haematopoiesis, Stem Cells, ISSN: 1549-4918
Stem cells are fundamental to human life and offer great therapeutic potential, yet their biology remains incompletely – or in cases even poorly – understood. The field of stem cell biology has grown substantially in recent years due to a combination of experimental and theoretical contributions: the experimental branch of this work provides data in an ever-increasing number of dimensions, while the theoretical branch seeks to determine suitable models of the fundamental stem cell processes that these data describe. The application of population dynamics to biology is amongst the oldest applications of mathematics to biology, and the population dynamics perspective continues to offer much today. Here we describe the impact that such a perspective has made in the field of stem cell biology. Using haematopoietic stem cells as our model system, we discuss the approaches that have been used to study their key properties, such as capacity for self-renewal, differentiation, and cell fate lineage choice. We will also discuss the relevance of population dynamics in models of stem cells and cancer, where competition naturally emerges as an influential factor on the temporal evolution of cell populations.
Khorshed RA, Lo Celso C, 2016, Automated identification and measurement of Hematopoietic Stem Cells in 3D Intravital Microscopy Data, Microscopy and Analysis, Editors: Stanciu, Publisher: InTech, ISBN: 978-953-51-2578-5
Image analysis and quantification of Haematopoietic stem cells (HSCs) position within their surrounding microenvironment in the bone marrow is a fast growing area of research, as it holds the key to understanding the dynamics of HSC-niche interactions and their multiple implications in normal tissue development and in response to various stress events. However, this area of research is very challenging due to the complex cellular structure of such images. Therefore, automated image analysis tools are required to simplify the biological interpretation of 3D HSC microenvironment images. In this chapter, we describe how 3D intravital microscopy data can be visualised and analysed using a computational method that allows the automated quantification of HSC position relative to surrounding niche components.
Silberstein L, Goncalves KA, Kharchenko PV, et al., 2016, Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators., Cell Stem Cell, Vol: 19, Pages: 530-543
Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on the differential single-cell gene expression analysis of mesenchymal osteolineage cells close to, and further removed from, hematopoietic stem/progenitor cells (HSPCs) to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. We functionally examined, among the genes that were preferentially expressed in proximal cells, three secreted or cell-surface molecules not previously connected to HSPC biology-the secreted RNase angiogenin, the cytokine IL18, and the adhesion molecule Embigin-and discovered that all of these factors are HSPC quiescence regulators. Therefore, our proximity-based differential single-cell approach reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance the understanding of microenvironmental regulation of stem cell function.
Hawkins E, Duarte D, Akinduro F, et al., 2016, T cell acute leukaemia development and chemo-resistance are mediated by dynamic interactions with heterogeneous bone marrow microenvironments, International Congress of Immunology (ICI), Publisher: WILEY-BLACKWELL, Pages: 329-329, ISSN: 0014-2980
Vainieri ML, Blagborough AM, MacLean AL, et al., 2016, Systematic tracking of altered haematopoiesis during sporozoite-mediated malaria development reveals multiple response points, Open Biology, Vol: 6, ISSN: 2046-2441
Haematopoiesis is the complex developmental process that maintainsthe turn-over of all blood cell lineages. It critically depends on the correct functioning of rare, quiescent haematopoietic stem cells (HSCs) and more numerous, HSC-derived, highly proliferative and differentiating haematopoietic progenitor cells (HPCs). Infection is known to affect HSCs, with severe and chronic inflammatory stimuli leading to stem cell pool depletion, while acute, non-lethal infections exert transient and even potentiating effects. Both whetherthis paradigm applies to all infections and whether the HSC response is the dominant driver of the changes observed during stressed haematopoiesis remain open questions. We use a mouse model of malaria, based on natural, sporozoite-driven Plasmodium bergheiinfection as an experimental platform to gain a global view of haematopoietic perturbations during infection progression. We observe coordinated responses by the most primitive HSCs and multiple HPCs, some starting before blood parasitaemia is detected. Weshow that, despite highly variable inter-host responses, primitive HSCsbecome highly proliferative, but mathematical modelling suggests that this alone is not sufficient to significantly impact the whole haematopoietic cascade. We observe that the dramatic expansion of Sca-1þ progenitors results from combined proliferation of direct HSC progeny and phenotypic changes in downstream populations. We observe that the simultaneous perturbation of HSC/HPC population dynamics is coupled with early signs of anaemia onset. Our data uncover a complex relationship between Plasmodium and itshost’s haematopoiesis and raise the question whether the variable responses observed may affect the outcome of the infection itself and its long-term consequences on the host.
Khorshed R, Lo Celso C, 2016, Machine learning classification of complex vasculature structures from in vivo bone marrow 3D data, ISBI 2016, Publisher: IEEE, ISSN: 1945-8452
Blood vessels inside the bone marrow (BM) play a vital role in the maintenance of hematopoietic stem cell (HSCs). Investigating the interaction of HSCs relative to vasculature has become the main headline for many recent studies. Advances in microscopy and image analysis using mouse models have allowed detection, identification and automated quantification of HSCs alongside their vascular niche. This resulted in new hypotheses concerning the activation state of HSCs adjacent to different blood vessel types (for example sinusoids vs. arterioles). Identifying the different types of BM vasculature has become critically important, however it still requires the use of complex immunostainings ex vivo or transgenic reporter mouse lines in vivo. To eliminate these requirements and increase the throughput of studies focusing on the HSC niche, we present a machine learning classification approach based on the Decision Tree Classifier to classify different regions of bone marrow vasculature into four distinct classes based on their discriminative features.
Engert A, Balduini C, Brand A, et al., 2016, The European Hematology Association Roadmap for European Hematology Research: a consensus document., Haematologica, Vol: 101, Pages: 115-208, ISSN: 0390-6078
The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap.The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders.The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
Khorshed R, Hawkins ED, Duarte D, et al., 2015, Automated identification and localization of hematopoietic stem cells in 3D intravital microscopy data, Stem Cell Reports, Vol: 5, Pages: 139-153, ISSN: 2213-6711
Measuring three-dimensional (3D) localization of hematopoietic stem cells (HSCs) within the bone marrow microenvironment usingintravital microscopy is a rapidly expanding research theme. This approach holds the key to understanding the detail of HSC-niche interactions,which are critical for appropriate stem cell function. Due to the complex tissue architecture of the bone marrow and to theprogressive introduction of scattering and signal loss at increasing imaging depths, there is no ready-made software to handle efficientsegmentation and unbiased analysis of the data. To address this, we developed an automated image analysis tool that simplifies and standardizesthe biological interpretation of 3D HSC microenvironment images. The algorithm identifies HSCs and measures their localizationrelative to surrounding osteoblast cells and bone collagen. We demonstrate here the effectiveness, consistency, and accuracy of theproposed approach compared to current manual analysis and its wider applicability to analyze other 3D bone marrow components
Meister M, Spencer JA, Wu J, et al., 2014, The Microanatomy of the Leukemic Stem Cell Niche in Murine Chronic Myelogenous Leukemia, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
- Author Web Link
- Cite
- Citations: 2
Batista S, Maniati E, Reynolds LE, et al., 2014, Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723
- Author Web Link
- Cite
- Citations: 13
Scott MK, Akinduro O, Lo Celso C, 2014, In vivo 4-dimensional tracking of hematopoietic stem and progenitor cells in adult mouse calvarial bone marrow, Jove-Journal of Visualized Experiments, ISSN: 1940-087X
Through a delicate balance between quiescence and proliferation, self renewal and production of differentiated progeny, hematopoietic stem cells (HSCs) maintain the turnover of all mature blood cell lineages. The coordination of the complex signals leading to specific HSC fates relies upon the interaction between HSCs and the intricate bone marrow microenvironment, which is still poorly understood[1-2].We describe how by combining a newly developed specimen holder for stable animal positioning with multi-step confocal and two-photon in vivo imaging techniques, it is possible to obtain high-resolution 3D stacks containing HSPCs and their surrounding niches and to monitor them over time through multi-point time-lapse imaging. High definition imaging allows detecting ex vivo labeled hematopoietic stem and progenitor cells (HSPCs) residing within the bone marrow. Moreover, multi-point time-lapse 3D imaging, obtained with faster acquisition settings, provides accurate information about HSPC movement and the reciprocal interactions between HSPCs and stroma cells.Tracking of HSPCs in relation to GFP positive osteoblastic cells is shown as an exemplary application of this method. This technique can be utilized to track any appropriately labeled hematopoietic or stromal cell of interest within the mouse calvarium bone marrow space.
Rashidi NM, Scott MK, Scherf N, et al., 2014, In vivo time-lapse imaging shows diverse niche engagement by quiescent and naturally activated hematopoietic stem cells, BLOOD, Vol: 124, Pages: 79-83, ISSN: 0006-4971
- Author Web Link
- Cite
- Citations: 49
Rashidi NM, Lo Celso C, 2014, Flying back to the nest: Intravital microscopy reveals how the niche can induce stemness., Intravital, Vol: 3, ISSN: 2165-9087
Joseph C, Quach JM, Walkley CR, et al., 2013, Deciphering Hematopoietic Stem Cells in Their Niches: A Critical Appraisal of Genetic Models, Lineage Tracing, and Imaging Strategies, CELL STEM CELL, Vol: 13, Pages: 520-533, ISSN: 1934-5909
- Author Web Link
- Cite
- Citations: 119
Carlson AL, Fujisaki J, Wu J, et al., 2013, Tracking Single Cells in Live Animals Using a Photoconvertible Near-Infrared Cell Membrane Label, PLOS ONE, Vol: 8, ISSN: 1932-6203
- Author Web Link
- Cite
- Citations: 44
Roeder I, Krinner A, Scherf N, et al., 2013, QUANTIFICATION OF STEM CELL/NICHE INTERACTIONS BY COUPLING IN VIVO IMAGING AND IN SILICO SIMULATION, 42nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology-and-Stem-Cells (ISEH), Publisher: ELSEVIER SCIENCE INC, Pages: S31-S31, ISSN: 0301-472X
Lo Celso C, 2013, IN VIVO IMAGING OF QUIESCENT AND PHYSIOLOGICALLY ACTIVATED HAEMATOPOIETIC STEM CELLS, 42nd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology-and-Stem-Cells (ISEH), Publisher: ELSEVIER SCIENCE INC, Pages: S4-S4, ISSN: 0301-472X
Progatzky F, Dallman MJ, Lo Celso C, 2013, From seeing to believing: labelling strategies for <i>in vivo</i> cell-tracking experiments, INTERFACE FOCUS, Vol: 3, ISSN: 2042-8898
- Author Web Link
- Cite
- Citations: 181
MacLean AL, Lo Celso C, Stumpf MPH, 2013, Population dynamics of normal and leukaemia stem cells in the haematopoietic stem cell niche show distinct regimes where leukaemia will be controlled, JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 10, ISSN: 1742-5689
- Author Web Link
- Cite
- Citations: 24
Fink J, Kent D, Li J, et al., 2013, Homozygous JAK2V617F drives rapid hematopoietic stem cell proliferation and differentiation at the expense of self-renewal, Publisher: Elsevier, Pages: S15-S15
Sottocornola R, Lo Celso C, 2012, Dormancy in the stem cell niche, STEM CELL RESEARCH & THERAPY, Vol: 3, ISSN: 1757-6512
- Author Web Link
- Cite
- Citations: 25
Barrett O, Sottocornola R, Lo Celso C, 2012, In vivo imaging of hematopoietic stem cells in the bone marrow niche., Methods Mol Biol, Vol: 916, Pages: 231-242
Even though hematopoietic stem cells (HSC) are amongst the first somatic stem cells exploited for therapeutic purposes, their application is still limited by the inability to expand them ex vivo without impairing their function. Moreover, it has recently emerged that several types of leukemia develop and relapse through complex interactions with bone marrow (BM) components and may directly affect the HSC and their niche. Increasing attention has therefore been dedicated to the BM microenvironment the HSC reside in, with the view that a better understanding of the molecular regulators of HSC-niche interaction in vivo will allow improving HSC mobilization, collection and transplantation and provide clues for the development of innovative leukemia treatments. This chapter focuses on a recently established technique for the visualization of transplanted hematopoietic stem and progenitor cells (HSPC) within the calvarium bone marrow of live mice (Lo Celso et al. Nature 457:92-96, 2007). Intravital microscopy is a rapidly developing field, driven by constant improvement in both detection technologies (i.e., spatial resolution, depth of penetration, spectral definition) and probe availability (i.e., increasingly sophisticated genetic and chemical reporter systems). We therefore discuss the current limitations and challenges related to intravital microscopy of the HSC niche and introduce a number of potential imaging approaches, which could be promising candidates for future development of this technique.
Hawkins ED, Celso CL, 2012, Subdivision of bone marrow microenvironments: purpose built homes for haematopoietic stem cells, The EMBO Journal
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.