Publications
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Pirillo C, Birch F, Tissot FS, et al., 2022, Metalloproteinase inhibition reduces AML growth, prevents stem cell loss, and improves chemotherapy effectiveness, BLOOD ADVANCES, Vol: 6, Pages: 3126-3141, ISSN: 2473-9529
Zhou L, Kong G, Palmisano I, et al., 2022, Reversible CD8 T cell-neuron cross-talk causes aging-dependent neuronal regenerative decline., Science, Vol: 376, Pages: 1-15, ISSN: 0036-8075
INTRODUCTIONAxonal regeneration and neurological functional recovery are extremely limited in the elderly. Consequently, injuries to the nervous system are typically followed by severe and long-term disability. Our understanding of the molecular mechanisms underlying aging-dependent regenerative failure is poor, hindering progress in the development of effective therapies for neurological repair. To facilitate the design of repair strategies, there is a pressing need to identify critical molecular and cellular mechanisms that cause regenerative failure in aging.RATIONALEAging causes a broad spectrum of modifications in cell signaling, including changes in metabolism, immunity, and overall tissue homeostasis, which play key roles in nervous system physiology and response to insults. Thus, we hypothesized that injuries to the aged nervous system would be followed by unique molecular and cellular modifications that would contribute to aging-dependent regenerative decline. To this end, molecular and cellular signatures associated with aging and injury to the nervous system were systematically investigated by performing RNA sequencing from dorsal root ganglia (DRG) in a well-established model of sciatic nerve injury in young versus aged mice. Insight into these mechanisms could allow the discovery of previously unrecognized molecular targets to counteract aging-dependent regenerative decline.RESULTSInitial analysis of RNA sequencing data identified that aging was mainly associated with a marked increase in T cell activation and signaling in DRG after sciatic nerve injury in mice. Subsequent experiments demonstrated that aging was associated with increased inflammatory cytokines including lymphotoxins in DRG both preceding and following sciatic nerve injury. Specifically, we found that lymphotoxin β was required for the phosphorylation of NF-κB that drives the expression of the chemokine CXCL13 in DRG sensory neurons. CXCL13 attracted CD8+ T cells that expresse
Soto CA, Lo Celso C, Purton LE, et al., 2021, From the niche to malignant hematopoiesis and back: reciprocal interactions between leukemia and the bone marrow microenvironment, Publisher: WILEY
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- Citations: 5
Haltalli MLR, Lo Celso C, 2021, Intravital Imaging of Bone Marrow Niches, BONE MARROW ENVIRONMENT, Vol: 2308, Pages: 203-222, ISSN: 1064-3745
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- Citations: 2
Haltalli MLR, Watcham S, Wilson NK, et al., 2020, Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection, Nature Cell Biology, Vol: 22, Pages: 1399-1410, ISSN: 1465-7392
Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and—coupled with reactive oxygen species quenching—enables partial rescuing of HSC function.
Haltalli MLR, Lo Celso C, 2020, Targeting adhesion to the vascular niche to improve therapy for acute myeloid leukemia, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
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- Citations: 5
Batsivari A, Haltalli MLR, Passaro D, et al., 2020, Dynamic responses of the haematopoietic stem cell niche to diverse stresses (vol 57, pg 1052, 2019), NATURE CELL BIOLOGY, Vol: 22, Pages: 257-257, ISSN: 1465-7392
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- Citations: 1
Batsivari A, Haltalli MLR, Passaro D, et al., 2020, Dynamic responses of the haematopoietic stem cell niche to diverse stresses, NATURE CELL BIOLOGY, Vol: 22, Pages: 7-17, ISSN: 1465-7392
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- Citations: 65
Duarte D, Amarteifio S, Ang H, et al., 2019, Defining the in vivo characteristics of acute myeloid leukemia cells behavior by intravital imaging, Immunology and Cell Biology, Vol: 97, Pages: 229-235, ISSN: 0818-9641
The majority of acute myeloid leukemia (AML) patients have a poor response to conventional chemotherapy. The survival of chemoresistant cells is thought to depend on leukemia-bone marrow (BM) microenvironment interactions, which are not well understood. The CXCL12/CXCR4 axis has been proposed to support AML growth but was not studied at the single AML cell level. We recently showed that T-cell acute lymphoblastic leukemia (T-ALL) cells are highly motile in the BM; however, the characteristics of AML cell migration within the BM remain undefined. Here, we characterize the in vivo migratory behavior of AML cells and their response to chemotherapy and CXCR4 antagonism, using high-resolution 2-photon and confocal intravital microscopy of mouse calvarium BM and the well-established MLL-AF9-driven AML mouse model. We used the Notch1-driven T-ALL model as a benchmark comparison and AMD3100 for CXCR4 antagonism experiments. We show that AML cells are migratory, and in contrast with T-ALL, chemoresistant AML cells become less motile. Moreover, and in contrast with T-ALL, the in vivo exploratory behavior of expanding and chemoresistant AML cells is unaffected by AMD3100. These results expand our understanding of AML cells-BM microenvironment interactions, highlighting unique traits of leukemia of different lineages.
Tjin G, Flores-Figueroa E, Duarte D, et al., 2019, Imaging methods used to study mouse and human HSC niches: Current and emerging technologies, BONE, Vol: 119, Pages: 19-35, ISSN: 8756-3282
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- Citations: 13
Willis A, Lo Celso C, Filloux A, et al., 2018, Shigella-induced emergency granulopoiesis protects zebrafish larvae from secondary infection, mBio, Vol: 9, ISSN: 2150-7511
Emergency granulopoiesis is a hematopoietic program of stem cell-driven neutrophil production used to counteract immune cell exhaustion following infection. Shigella flexneri is a Gram-negative enteroinvasive pathogen controlled by neutrophils. In this study, we use a Shigella-zebrafish (Danio rerio) infection model to investigate emergency granulopoiesis in vivo. We show that stem cell-driven neutrophil production occurs in response to Shigella infection and requires macrophage-independent signaling by granulocyte colony-stimulating factor (Gcsf). To test whether emergency granulopoiesis can function beyond homoeostasis to enhance innate immunity, we developed a reinfection assay using zebrafish larvae that have not yet developed an adaptive immune system. Strikingly, larvae primed with a sublethal dose of Shigella are protected against a secondary lethal dose of Shigella in a type III secretion system (T3SS)-dependent manner. Collectively, these results highlight a new role for emergency granulopoiesis in boosting host defense and demonstrate that zebrafish larvae can be a valuable in vivo model to investigate innate immune memory.IMPORTANCE Shigella is an important human pathogen of the gut. Emergency granulopoiesis is the enhanced production of neutrophils by hematopoietic stem and progenitor cells (HSPCs) upon infection and is widely considered a homoeostatic mechanism for replacing exhausted leukocytes. In this study, we developed a Shigella-zebrafish infection model to investigate stem cell-driven emergency granulopoiesis. We discovered that zebrafish initiate granulopoiesis in response to Shigella infection, via macrophage-independent signaling of granulocyte colony-stimulating factor (Gcsf). Strikingly, larvae primed with a sublethal dose of Shigella are protected against a secondary lethal dose of Shigella in a type III secretion system (T3SS)-dependent manner. Taken together, we show that zebrafish infection can be used to capture Shigella-mediated stem c
Brown E, Carlin LM, Nerlov C, et al., 2018, Multiple membrane extrusion sites drive megakaryocyte migration into bone marrow blood vessels, Life Science Alliance, Vol: 1, ISSN: 2575-1077
Platelets, cells central to hemostasis and thrombosis, are formed from parent cell megakaryocytes. Whilst the process is highly efficient in vivo, our ability to generate them in vitro is still remarkably inefficient. We proposed that greater understanding of the process in vivo is needed and used an imaging approach, intravital correlative light-electron microscopy, to visualize platelet generation in bone marrow in the living mouse. In contrast to current understanding we found that most megakaryocytes enter the sinusoidal space as large protrusions rather than extruding fine proplatelet extensions. The mechanism for large protrusion migration also differed from that of proplatelet extension. In vitro, proplatelets extend by sliding of dense bundles of microtubules, whereas in vivo our data showed an absence of microtubule bundles in the large protrusion, but the presence of multiple fusion points between the internal membrane and the plasma membrane, at the leading edge of the protruding cell. Mass membrane fusion therefore drives megakaryocyte large protrusions into the sinusoid, significantly revising our understanding of the fundamental biology of platelet formation in vivo.
Khan AB, Carpenter B, Santos e Sousa P, et al., 2018, Redirection to the bone marrow improves T cell persistence and antitumor functions, Journal of Clinical Investigation, Vol: 128, Pages: 2010-2024, ISSN: 0021-9738
A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15–dependent homeostatic expansion and promoted the differentiation of memory precursor–like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.
Duarte D, Hawkins ED, Lo Celso C, 2018, The interplay of leukemia cells and the bone marrow microenvironment, Blood, Vol: 131, Pages: 1507-1511, ISSN: 1528-0020
The interplay of cancer cells and surrounding stroma is critical in disease progression. This is particularly evident in hematological malignancies that infiltrate the bone marrow and peripheral lymphoid organs. Despite clear evidence for the existence of these interactions, the precise repercussions on the growth of leukemic cells are poorly understood. Recent development of novel imaging technology and preclinical disease models have advanced our comprehension of leukemia-microenvironment crosstalk and have potential implications for development of novel treatment options.
Lo Celso C, Akinduro O, Weber TS, et al., 2018, Proliferation dynamics of acute myeloid leukaemia and haematopoietic progenitors competing for bone marrow space, Nature Communications, Vol: 9, Pages: 1-12, ISSN: 2041-1723
Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood. Combining cell number measurements with a short-timescale dual pulse labelling method, we simultaneously determine the proliferation dynamics of primitive haematopoietic compartments and acute myeloid leukaemia (AML). We observe an unchanging proportion of AML cells entering S phase per hour throughout disease progression, with substantial BM egress at high levels of infiltration. For healthy haematopoiesis, we find haematopoietic stem cells (HSCs) make a significant contribution to cell production, but we phenotypically identify a quiescent subpopulation with enhanced engraftment ability. During AML progression, we observe that multipotent progenitors maintain a constant proportion entering S phase per hour, despite a dramatic decrease in the overall population size. Primitive populations are lost from BM with kinetics that are consistent with ousting irrespective of cell cycle state, with the exception of the quiescent HSC subpopulation, which is more resistant to elimination.
Lo Celso C, Hawkins ED, Akinduro O, et al., 2017, Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML, Cell Stem Cell, Vol: 22, Pages: 64-77.e6, ISSN: 1875-9777
Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML.
Wang W, Fujii H, Kim HJ, et al., 2017, Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell-mediated TNF alpha signaling, SCIENCE TRANSLATIONAL MEDICINE, Vol: 9, ISSN: 1946-6234
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- Citations: 14
MacLean AL, Smith MA, Liepe J, et al., 2017, Single Cell Phenotyping Reveals Heterogeneity Among Hematopoietic Stem Cells Following Infection, STEM CELLS, Vol: 35, Pages: 2292-2304, ISSN: 1066-5099
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- Citations: 10
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.
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.
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.
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
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