Publications
31 results found
Matsuoka S, Facchini R, Luis TC, et al., 2023, Loss of endothelial membrane KIT ligand affects systemic KIT ligand levels but not bone marrow hematopoietic stem cells, Blood, Vol: 142, Pages: 1622-1632, ISSN: 0006-4971
A critical regulatory role of hematopoietic stem cell (HSC) vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT ligand. However, endothelial-derived KIT ligand is expressed in both a soluble and membrane-bound form and not unique to bone marrow niches, and it is also systemically distributed through the circulatory system. Here, we confirm that upon deletion of both the soluble and membrane-bound forms of endothelial-derived KIT ligand, HSCs are reduced in mouse bone marrow. However, the deletion of endothelial-derived KIT ligand was also accompanied by reduced soluble KIT ligand levels in the blood, precluding any conclusion as to whether the reduction in HSC numbers reflects reduced endothelial expression of KIT ligand within HSC niches, elsewhere in the bone marrow, and/or systemic soluble KIT ligand produced by endothelial cells outside of the bone marrow. Notably, endothelial deletion, specifically of the membrane-bound form of KIT ligand, also reduced systemic levels of soluble KIT ligand, although with no effect on stem cell numbers, implicating an HSC regulatory role primarily of soluble rather than membrane KIT ligand expression in endothelial cells. In support of a role of systemic rather than local niche expression of soluble KIT ligand, HSCs were unaffected in KIT ligand deleted bones implanted into mice with normal systemic levels of soluble KIT ligand. Our findings highlight the need for more specific tools to unravel niche-specific roles of regulatory cues expressed in hematopoietic niche cells in the bone marrow.
Cheong S-S, Luis T, Stewart M, et al., 2023, TReATS: a novel method for TAT-Cre recombinase mediated floxed Allele modification in ex vivo tissue slices, Disease Models and Mechanisms, Vol: 16, ISSN: 1754-8403
Precision-Cut Lung Slices (PCLS) are used for a variety of applications. However, methods to manipulate genes in PCLS are currently limited. We developed a novel method, TAT-Cre Recombinase-mediated floxed Allele modification in Tissue Slices (TReATS), to induce highly effective and temporally controlled gene deletion or activation in ex vivo PCLS. Treatment of PCLS from Rosa26-flox-stop-flox-EYFP mice with cell-permeant TAT-Cre recombinase induced ubiquitous EYFP protein expression, indicating successful Cre-mediated excision of the upstream loxP-flanked stop sequence. Quantitative real-time PCR confirmed induction of EYFP. We successfully replicated the TReATS method in PCLS from Vangl2flox/flox mice, leading to the deletion of loxP-flanked exon 4 of the Vangl2 gene. Cre-treated Vangl2flox/flox PCLS exhibited cytoskeletal abnormalities, a known phenotype caused by VANGL2 dysfunction. We report a novel method that by-passes conventional Cre-Lox breeding, allowing rapid and highly effective gene manipulation in ex vivo tissue models.
Luis TC, Barkas N, Carrelha J, et al., 2023, Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner., Nature Communications, Vol: 14, ISSN: 2041-1723
Hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow are responsible for the balanced output of multiple short-lived blood cell lineages in steady-state and in response to different challenges. However, feedback mechanisms by which HSCs, through their niches, sense acute losses of specific blood cell lineages remain to be established. While all HSCs replenish platelets, previous studies have shown that a large fraction of HSCs are molecularly primed for the megakaryocyte-platelet lineage and are rapidly recruited into proliferation upon platelet depletion. Platelets normally turnover in an activation-dependent manner, herein mimicked by antibodies inducing platelet activation and depletion. Antibody-mediated platelet activation upregulates expression of Interleukin-1 (IL-1) in platelets, and in bone marrow extracellular fluid in vivo. Genetic experiments demonstrate that rather than IL-1 directly activating HSCs, activation of bone marrow Lepr+ perivascular niche cells expressing IL-1 receptor is critical for the optimal activation of quiescent HSCs upon platelet activation and depletion. These findings identify a feedback mechanism by which activation-induced depletion of a mature blood cell lineage leads to a niche-dependent activation of HSCs to reinstate its homeostasis.
Jackson WD, Giacomassi C, Ward S, et al., 2023, TLR7 activation at epithelial barriers promotes emergency myelopoiesis and lung antiviral immunity, eLife, Vol: 12, ISSN: 2050-084X
Monocytes are heterogeneous innate effector leukocytes generated in the bone marrow and released into circulation in a CCR2-dependent manner. During infection or inflammation, myelopoiesis is modulated to rapidly meet the demand for more effector cells. Danger signals from peripheral tissues can influence this process. Herein we demonstrate that repetitive TLR7 stimulation via the epithelial barriers drove a potent emergency bone marrow monocyte response in mice. This process was unique to TLR7 activation and occurred independently of the canonical CCR2 and CX3CR1 axes or prototypical cytokines. The monocytes egressing the bone marrow had an immature Ly6C-high profile and differentiated into vascular Ly6C-low monocytes and tissue macrophages in multiple organs. They displayed a blunted cytokine response to further TLR7 stimulation and reduced lung viral load after RSV and influenza virus infection. These data provide insights into the emergency myelopoiesis likely to occur in response to the encounter of single-stranded RNA viruses at barrier sites.
Secchi M, Gonzalez-Anton S, Tromans-Coia C, et al., 2023, INTRAVITAL MICROSCOPY OF HIGHLY PURE HAEMATOPOIETIC STEM CELLS USING A NOVEL TRANSGENIC REPORTER STRATEGY UNCOVERS UNEXPECTED INTERACTION DYNAMICS WITHIN THE STEM CELL NICHE, 52nd Annual Meeting of the International-Society-for-Experimental-Hematology (ISEH), Publisher: ELSEVIER SCIENCE INC, Pages: S136-S136, ISSN: 0301-472X
Luis TC, 2021, Unwinding the role of Chd8 helicase in hematopoiesis, Blood, Vol: 138, Pages: 206-207, ISSN: 0006-4971
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.
Carrelha J, Lin DS, Rodriguez-Fraticelli AE, et al., 2020, Single-cell lineage tracing approaches in hematology research: technical considerations, Experimental Hematology, Vol: 89, Pages: 26-36, ISSN: 0301-472X
Luis TC, Lawson H, Kranc KR, 2020, Divide and rule: mitochondrial fission regulates quiescence in hematopoietic stem cells, Cell Stem Cell, Vol: 26, Pages: 299-301, ISSN: 1934-5909
Luis TC, Wilkinson AC, Beerman I, et al., 2019, Biological implications of clonal hematopoiesis, Experimental Hematology, Vol: 77, Pages: 1-5, ISSN: 0301-472X
Duarte S, Woll PS, Buza-Vidas N, et al., 2018, Canonical Notch signaling is dispensable for adult steady-state and stress myelo-erythropoiesis, Blood, Vol: 131, Pages: 1712-1719, ISSN: 0006-4971
Although an essential role for canonical Notch signaling in generation of hematopoietic stem cells in the embryo and in thymic T-cell development is well established, its role in adult bone marrow (BM) myelopoiesis remains unclear. Some studies, analyzing myeloid progenitors in adult mice with inhibited Notch signaling, implicated distinct roles of canonical Notch signaling in regulation of progenitors for the megakaryocyte, erythroid, and granulocyte-macrophage cell lineages. However, these studies might also have targeted other pathways. Therefore, we specifically deleted, in adult BM, the transcription factor recombination signal-binding protein J κ (Rbpj), through which canonical signaling from all Notch receptors converges. Notably, detailed progenitor staging established that canonical Notch signaling is fully dispensable for all investigated stages of megakaryocyte, erythroid, and myeloid progenitors in steady state unperturbed hematopoiesis, after competitive BM transplantation, and in stress-induced erythropoiesis. Moreover, expression of key regulators of these hematopoietic lineages and Notch target genes were unaffected by Rbpj deficiency in BM progenitor cells.
Carrelha J, Meng Y, Kettyle LM, et al., 2018, Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells, Nature, Vol: 554, Pages: 106-111, ISSN: 0028-0836
Breitbach M, Kimura K, Luis TC, et al., 2018, In vivo labeling by CD73 marks multipotent stromal cells and highlights endothelial heterogeneity in the bone marrow niche, Cell Stem Cell, Vol: 22, Pages: 262-+, ISSN: 1934-5909
Despite much work studying ex vivo multipotent stromal cells (MSCs), the identity and characteristics of MSCs in vivo are not well defined. Here, we generated a CD73-EGFP reporter mouse to address these questions and found EGFP+ MSCs in various organs. In vivo, EGFP+ mesenchymal cells were observed in fetal and adult bones at proliferative ossification sites, while in solid organs EGFP+ cells exhibited a perivascular distribution pattern. EGFP+ cells from the bone compartment could be clonally expanded ex vivo from single cells and displayed trilineage differentiation potential. Moreover, in the central bone marrow CD73-EGFP+ specifically labeled sinusoidal endothelial cells, thought to be a critical component of the hematopoietic stem cell niche. Purification and molecular characterization of this CD73-EGFP+ population revealed an endothelial subtype that also displays a mesenchymal signature, highlighting endothelial cell heterogeneity in the marrow. Thus, the CD73-EGFP mouse is a powerful tool for studying MSCs and sinusoidal endothelium.
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.
Luis TC, Luc S, Mizukami T, et al., 2016, Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors, Nature Immunology, Vol: 17, Pages: 1424-1435, ISSN: 1529-2908
The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell–restricted progenitors. Instead, single-cell molecular and functional analysis demonstrated that most fetal T-IPs expressed genes of and had the potential to develop into lymphoid as well as myeloid components of the immune system. Moreover, studies of embryos deficient in the transcriptional regulator RBPJ demonstrated that canonical Notch signaling was not involved in pre-thymic restriction to the T cell lineage or the migration of T-IPs.
Luis TC, Tremblay CS, Manz MG, et al., 2016, Inflammatory signals in HSPC development and homeostasis: too much of a good thing?, Experimental Hematology, Vol: 44, Pages: 908-912, ISSN: 0301-472X
Grover A, Sanjuan-Pla A, Thongjuea S, et al., 2016, Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells, NATURE COMMUNICATIONS, Vol: 7, ISSN: 2041-1723
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- Citations: 176
Buono M, Facchini R, Matsuoka S, et al., 2016, A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors, NATURE CELL BIOLOGY, Vol: 18, Pages: 157-+, ISSN: 1465-7392
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- Citations: 39
Boiers C, Carrelha J, Lutteropp M, et al., 2013, Lymphomyeloid Contribution of an Immune-Restricted Progenitor Emerging Prior to Definitive Hematopoietic Stem Cells, CELL STEM CELL, Vol: 13, Pages: 535-548, ISSN: 1934-5909
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- Citations: 180
Sanjuan-Pla A, Macaulay IC, Jensen CT, et al., 2013, Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy, NATURE, Vol: 502, Pages: 232-+, ISSN: 0028-0836
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- Citations: 399
Luc S, Luis TC, Boukarabila H, et al., 2012, The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential, NATURE IMMUNOLOGY, Vol: 13, Pages: 412-419, ISSN: 1529-2908
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- Citations: 100
Luis TC, Ichii M, Brugman MH, et al., 2012, Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development, LEUKEMIA, Vol: 26, Pages: 414-421, ISSN: 0887-6924
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- Citations: 157
Luis TC, Killmann NM-B, Staal FJT, 2012, Signal transduction pathways regulating hematopoietic stem cell biology: Introduction to a series of Spotlight Reviews, LEUKEMIA, Vol: 26, Pages: 86-90, ISSN: 0887-6924
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- Citations: 26
Luis TC, Naber BAE, Roozen PPC, et al., 2011, Canonical Wnt Signaling Regulates Hematopoiesis in a Dosage-Dependent Fashion, CELL STEM CELL, Vol: 9, Pages: 345-356, ISSN: 1934-5909
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- Citations: 237
Luis TC, Naber BAE, Fibbe WE, et al., 2010, Wnt3a nonredundantly controls hematopoietic stem cell function and its deficiency results in complete absence of canonical Wnt signaling, BLOOD, Vol: 116, Pages: 496-497, ISSN: 0006-4971
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- Citations: 34
Staal FJT, Luis TC, 2010, Wnt Signaling in Hematopoiesis: Crucial Factors for Self-Renewal, Proliferation, and Cell fate Decisions, JOURNAL OF CELLULAR BIOCHEMISTRY, Vol: 109, Pages: 844-849, ISSN: 0730-2312
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- Citations: 61
Luis TC, Weerkamp F, Naber BAE, et al., 2009, Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation, BLOOD, Vol: 113, Pages: 546-554, ISSN: 0006-4971
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- Citations: 153
Luis TC, Staal FJT, 2009, WNT Proteins: Environmental Factors Regulating HSC Fate in the Niche, HEMATOPOIETIC STEM CELLS VII, Vol: 1176, Pages: 70-76, ISSN: 0077-8923
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- Citations: 12
Staal FJT, Luis TC, Tiemessen MM, 2008, WNT signalling in the immune system: WNT is spreading its wings, NATURE REVIEWS IMMUNOLOGY, Vol: 8, Pages: 581-593, ISSN: 1474-1733
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- Citations: 431
Weerkamp F, Luis TC, Naber BAE, et al., 2006, Identification of Notch target genes in uncommitted T-cell progenitors: no direct induction of a T-cell specific gene program, LEUKEMIA, Vol: 20, Pages: 1967-1977, ISSN: 0887-6924
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- Citations: 45
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