Publications
90 results found
Tissot FS, Gonzalez-Anton S, Lo Celso C, 2024, Intravital Microscopy to Study the Effect of Matrix Metalloproteinase Inhibition on Acute Myeloid Leukemia Cell Migration in the Bone Marrow., Methods Mol Biol, Vol: 2747, Pages: 211-227
Hematopoiesis is the process through which all mature blood cells are formed and takes place in the bone marrow (BM). Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. AML progression causes drastic remodeling of the BM microenvironment, making it no longer supportive of healthy hematopoiesis and leading to clinical cytopenia in patients. Understanding the mechanisms by which AML cells shape the BM to their benefit would lead to the development of new therapeutic strategies. While the role of extracellular matrix (ECM) in solid cancer has been extensively studied during decades, its role in the BM and in leukemia progression has only begun to be acknowledged. In this context, intravital microscopy (IVM) gives the unique insight of direct in vivo observation of AML cell behavior in their environment during disease progression and/or upon drug treatments. Here we describe our protocol for visualizing and analyzing MLL-AF9 AML cell dynamics upon systemic inhibition of matrix metalloproteinases (MMP), combining confocal and two-photon microscopy and focusing on cell migration.
Grockowiak E, Korn C, Rak J, et al., 2023, Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms, NATURE CANCER
Partridge B, Gonzalez Anton S, Khorshed R, et al., 2022, Heterogeneous run-and-tumble motion accounts for transient non-Gaussian super-diffusion in haematopoietic multi-potent progenitor cells, PLoS One, Vol: 17, Pages: 1-26, ISSN: 1932-6203
Multi-potent progenitor (MPP) cells act as a key intermediary step between haematopoietic stem cells and the entirety of the mature blood cell system. Their eventual fate determination is thought to be achieved through migration in and out of spatially distinct niches. Here we first analyze statistically MPP cell trajectory data obtained from a series of long time-course 3D in vivo imaging experiments on irradiated mouse calvaria, and report that MPPs display transient super-diffusion with apparent non-Gaussian displacement distributions. Second, we explain these experimental findings using a run-and-tumble model of cell motion which incorporates the observed dynamical heterogeneity of the MPPs. Third, we use our model to extrapolate the dynamics to time-periods currently inaccessible experimentally, which enables us to quantitatively estimate the time and length scales at which super-diffusion transitions to Fickian diffusion. Our work sheds light on the potential importance of motility in early haematopoietic progenitor function.
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
Jaffredo T, Balduini A, Bigas A, et al., 2021, The EHA Research Roadmap: Normal Hematopoiesis, HEMASPHERE, Vol: 5
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- Citations: 1
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: 8
Ombrato L, Nolan E, Passaro D, et al., 2021, Generation of neighbor-labeling cells to study intercellular interactions in vivo, NATURE PROTOCOLS, Vol: 16, ISSN: 1754-2189
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- Citations: 9
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: 3
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.
Pospori C, Grey W, Gibson S, et al., 2020, DYNAMIC REGULATION OF HIERARCHICAL HETEROGENEITY IN ACUTE MYELOID LEUKAEMIA, SERVES AS A TUMOUR IMMUNOEVASION MECHANISM., EXPERIMENTAL HEMATOLOGY, Vol: 88, Pages: S75-S75, ISSN: 0301-472X
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: 6
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: 75
Pirillo C, Haltalli M, Gonzalez-Anton S, et al., 2019, Inhibiting Matrix Metalloproteinases Hinders Acute Myeloid Leukaemia and Prevents Healthy Stem Cell Loss, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Burt R, Dey A, Aref S, et al., 2019, Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress, BLOOD, Vol: 134, Pages: 1415-1429, ISSN: 0006-4971
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- Citations: 119
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: 15
Korn C, Rak J, Garcia-Garcia A, et al., 2018, Niche Heterogeneity Impacts Evolution of Myeloproliferative Neoplasms Driven By the Same Oncogenic Pathway, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
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- Citations: 3
Kumar R, Marten M, Minciacchi V, et al., 2018, Specific and Targetable Interactions with the Bone Marrow Microenvironment Govern Outcome in Imatinib-Resistant Chronic Myeloid Leukemia, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
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- Citations: 1
Haltalli M, Glatzel K, Watcham S, et al., 2018, THE ROLE OF BONE MARROW STROMA IN THE RESPONSE OF HAEMATOPOIETIC STEM CELLS TO PLASMODIUM INFECTION, Publisher: ELSEVIER SCIENCE INC, Pages: S70-S70, ISSN: 0301-472X
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 TNFα 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: 12
Haltalli M, Glatzel K, Ruivo N, et al., 2017, INVESTIGATING THE ROLE OF BONE MARROW STROMA IN THE RESPONSE OF HAEMATOPOIETIC STEM CELLS TO PLASMODIUM BERGHEI INFECTION, Publisher: ELSEVIER SCIENCE INC, Pages: S101-S101, ISSN: 0301-472X
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