Identification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential

Adolfsson, Jörgen; Månsson, Robert; Buza‐Vidas, Natalija; Hultquist, Anne; Liuba, Karina; Jensen, Christina T.; Bryder, David; Yang, Liping; Borge, Ole-Johan; Thorén, Lina; Anderson, Kristina; Sitnicka, Ewa; Sasaki, Yutaka; Sigvardsson, Mikael; Jacobsen, Sten Eirik W.

doi:10.1016/j.cell.2005.02.013

Cited by 1,057 publications

(1,096 citation statements)

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“…15 Whereas we had shown that most investigated genes affiliated with the Mk and E lineages are no longer expressed in LSKFlt3 hi cells, we did find that Mpl was still expressed in a fraction of LSKFlt3 hi cells, although at reduced levels and frequencies when compared with LSKCD34 Ϫ Flt3 Ϫ and LSKCD34 ϩ Flt3 Ϫ cells. 10,15 Of further note, the fraction of BM LSKFlt3 hi cells expressing Mpl coexpressed genes of the GM lineage but predominantly not of the lymphoid lineage, in contrast to LSKFlt3 hi cells negative for Mpl, which frequently coexpressed lymphoid and GM genes. 15 Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…The strategy developed was based on 2 key findings common to our study and the Forsberg study. 10,11,18 First, that a small fraction (0.4%-1.2%) of LSKFlt3 hi cells are able to generate large MkE-enriched colonies in the spleen (spleen colony-forming unit [CFU-S] 10,11 and used as positive controls for in vitro assays and CFU-S assay, respectively. For detailed information, see Document S1 (available on the Blood website; see the Supplemental Materials link at the top of the online article).…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Luc

Anderson

Kharazi

et al. 2008

Blood

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IntroductionWhereas considerable knowledge has been gained with regard to the identity and roles of extrinsic and intrinsic regulators of blood lineage development, much less is known about the molecular mechanisms regulating lineage commitment of hematopoietic stem cells (HSCs). 1,2 Unraveling the involved molecular determinants and mechanisms of lineage restriction will be facilitated by, and most likely depend on, a more complete understanding of the cellular pathways of the lineage restriction process from pluripotent HSCs to lineage-restricted progenitor cells.It remains unclear and debated 2-4 exactly how the lineage commitment process from pluripotent HSCs to lineage-restricted progenitors occurs in adult bone marrow (BM), and even unequivocal evidence for one such pathway would not exclude the existence of alternative routes for HSC lineage commitment. In the prevailing model of HSC lineage commitment, 1-3 HSCs (long-term and short-term) and multipotent progenitors (MPPs) distinguish themselves from each other, only through gradual loss of self-renewal potential while sustaining the same degree of pluripotentiality, with the first lineage commitment event resulting in a strict separation of myelopoiesis and lymphopoiesis. This model for HSC lineage commitment was supported by the identification of common myeloid and common lymphoid progenitors (CMPs and CLPs, respectively). 5,6 However, the degree to which the identified CMPs and CLPs represent obligatory or even main intermediates for myeloid and lymphoid development in adult hematopoiesis remains to be established.Although conclusively established for long-term HSCs (LTHSCs), 7,8 the existence of short-term HSCs (ST-HSCs) and MPPs in the BM Lin Ϫ Sca-1 ϩ Kit ϩ (LSK) stem and primitive progenitor cell compartment, with sustained pluripotentiality has yet to be demonstrated at the single cell level. 3 Rather, more recent studies have uncovered considerable heterogeneity in the LSK MPP compartment. Through the use of different but overlapping markers such as FMS-like tyrosine kinase 3 (Flt3), 9-11 vascular cell adhesion molecule-1 (Vcam-1), 12,13 and an Ikaros-reporter, 14 the existence of lymphoid-primed MPPs (LMPPs) with combined granulocyte/monocyte (GM) and lymphoid potentials, but little or no megakaryocyte (Mk)/erythroid (E) potentials has been proposed. 3,10,12,14,15 Further, molecular analysis of putative LMPPs show down-regulated transcriptional priming of genes specific for the MkE lineage, and up-regulation of lymphoid-specific genes, not yet expressed in HSCs. 15,16 The identification of a putative LMPP, representing the earliest lineage-restricted lympho-myeloid progenitor identified in adult hematopoiesis, has provided a potential avenue toward uncovering alternative HSC lineage commitment pathways. 2,3,17 However, the existence of the LMPP remains contentious, 2,3,[18][19][20] largely reflecting functional heterogeneity of phenotypically defined candidate LMPPs. 9,10,[12][13][14] While the evidence for a large fraction of LSKFlt3 hi BM cell...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Luc

Anderson

Kharazi

et al. 2008

Blood

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“…G-CSF acts at the level of myeloid progenitors to induce their proliferation and differentiation. Its receptor, G-CSFR, is expressed throughout the myeloid lineage from early stem and progenitor cells to fully differentiated neutrophils 18,19 , and G-CSFR-STAT3 (signal transducer and activator of transcription 3) signaling governs neutrophil formation 20 . The transcription factor RAR-related orphan receptor γ1 (RORC1) is a recently identified regulator of myelopoiesis in tumor-bearing mice and its expression may be induced by G-CSF 21 .…”

Section: Granulopoiesismentioning

confidence: 99%

“…It is currently unclear at which differentiation step these molecules instruct phenotypic changes in neutrophils. For G-CSF, there is evidence that this cytokine can affect gene expression in stem or progenitor cells and fully differentiated cells as G-CSFR is expressed throughout neutrophil development 18,19 . These data suggest that neutrophil polarization is programmed early in the developmental process in the bone marrow, but when and where individual molecules shape neutrophil polarization needs further attention.…”

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confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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“…The role of FLT3 differs between the mouse and the human system. In the mouse system, FLT3 expression is correlated with short-term reconstituting HSC (Lin-Sca-1+c-kit+FLT3+), whereas there is no evidence so far that it is also expressed in long-term repopulating (HSC) [8,9]. In human adult bone marrow (BM), FLT3 expression is restricted to CD34 + cells and a subset of dendritic precursors [10].…”

Section: Introductionmentioning

confidence: 99%