BMP signalling differentially regulates distinct haematopoietic stem cell types

Crisan, Mihaela; Kartalaei, Parham Solaimani; Vink, Chris S.; Yamada-Inagawa, Tomoko; Bollérot, Karine; IJcken, Wilfred F. J. van; Linden, Reinier van der; Lopes, Susana M. Chuva de Sousa; Monteiro, Rui; Mummery, Christine L.; Dzierzak, Elaine

doi:10.1038/ncomms9040

Cited by 76 publications

(71 citation statements)

References 34 publications

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“…Various haematopoietic diseases originate prenatally (Hunger et al, 1998;Greaves, 2005;Hong et al, 2008;Roy et al, 2012;Barrett et al, 2016), and oncogenic mutations in developing haematopoietic progenitors or stem cells can lead to pre-leukaemic changes that may not be manifested if the oncogene is activated in the adult counterparts (Barrett et al, 2016). The molecular mechanisms that regulate development and maintenance of haematopoietic progenitor and stem cells in the embryo differ significantly from those in the adult, and the functional heterogeneity that appears within the emerging HSC population during development further complicates our understanding of HSC regulation (Copley et al, 2012;Crisan et al, 2015;Beaudin et al, 2016). Although the impetus to study human haematopoietic development is clear, poor availability and heterogeneity of human embryonic material makes the analyses challenging.…”

Section: Future Directions and Challengesmentioning

confidence: 99%

Human haematopoietic stem cell development: from the embryo to the dish

et al. 2017

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Haematopoietic stem cells (HSCs) emerge during embryogenesis and give rise to the adult haematopoietic system. Understanding how early haematopoietic development occurs is of fundamental importance for basic biology and medical sciences, but our knowledge is still limited compared with what we know of adult HSCs and their microenvironment. This is particularly true for human haematopoiesis, and is reflected in our current inability to recapitulate the development of HSCs from pluripotent stem cells in vitro. In this Review, we discuss what is known of human haematopoietic development: the anatomical sites at which it occurs, the different temporal waves of haematopoiesis, the emergence of the first HSCs and the signalling landscape of the haematopoietic niche. We also discuss the extent to which in vitro differentiation of human pluripotent stem cells recapitulates bona fide human developmental haematopoiesis, and outline some future directions in the field.

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Section: Future Directions and Challengesmentioning

confidence: 99%

Human haematopoietic stem cell development: from the embryo to the dish

et al. 2017

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“…In mouse and human embryos, BMP4 is expressed in the mesenchyme underlying the aorta and is required for HSC maintenance [30][31][32]. It has been shown using BMP responsive element (BRE) green fluorescent protein (GFP) transgenic mouse embryos that the first HSCs emerging in vivo in the AGM region are HSCs favouring a more myeloid-lymphoid balanced differentiation programme [33]. Explant studies using E11 AGM have revealed that over the 3 day culture period GFP -non-BMP activated HSCs emerge and these cells are controlled by the Hh/Vascular Endothelial Growth Factor (VEGF) pathway.…”

Section: Bmp Pathway and The Initiation And Maintenance Of Embryonic mentioning

confidence: 99%

Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis

Toofan

Wheadon

2016

Biochemical Society Transactions

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Myeloid leukaemia's share the common characteristics of being stem cell-derived clonal diseases, characterised by excessive proliferation of one or more myeloid lineage. Chronic myeloid leukaemia (CML) arises from a genetic alteration in a normal haemopoietic stem cell (HSC) giving rise to a leukaemic stem cell (LSC) within the bone marrow (BM) 'niche'. CML is characterised by the presence of the oncogenic tyrosine kinase fusion protein BCR-ABL, which is responsible for driving the disease through activation of downstream signal transduction pathways. Recent evidence from our group and others indicates that important regulatory networks involved in establishing primitive and definitive haemopoiesis during development are reactivated in myeloid leukaemia, giving rise to an LSC population with altered self-renewal and differentiation properties. In this review we explore the role BMP signalling plays in stem cell pluripotency, developmental haemopoiesis, HSC maintenance and the implication of altered BMP signalling on LSC persistence in the BM niche. Overall we highlight how the BMP and Wnt pathways converge to alter the Cdx-Hox axis and the implications of this in the pathogenesis of myeloid malignancies.

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“…Since the AGM region consists of hematopoietic, endothelial, gonadal, mesonephric and unclassified mesenchymal cells, the region likely comprises a niche regulating IAC activity. IACs reportedly express several receptor genes (IL-3Ra, Mpl, Ptc1, Alk3, Alk6, Bmpr2 and Notch1) and proteins (c-Kit, IL-3Ra and MPL) [29][30][31][32][33][34][35][36]. Relevant to ligands, endothelial cells express ligand gene (Jag1) and protein (SCF) [22,33,34].…”

Section: Discussionmentioning

confidence: 98%

Embryonic Intra-Aortic Clusters Undergo Myeloid Differentiation Mediated by Mesonephros-Derived CSF1 in Mouse

Sasaki

Tanaka

Kulkeaw

et al. 2016

Stem Cell Rev and Rep

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The aorta-gonad-mesonephros (AGM) region contains intra-aortic clusters (IACs) thought to have acquired hematopoietic stem cell (HSC) potential in vertebrate embryos. To assess extrinsic regulation of IACs in the AGM region, we employed mouse embryos harboring a Sall1-GFP reporter gene, which allows identification of mesonephros cells based on GFP expression. Analysis of AGM region tissue sections confirmed mesonephros GFP expression. Mesonephric cells sorted at E10.5 expressed mRNA encoding Csf1, a hematopoietic cytokine, and corresponding protein, based on real-time PCR and immunocytochemistry, respectively. Further analysis indicated that some IACs express the CSF1 receptor, CSF1R. Expression of Cebpa and Irf8 mRNAs was higher in CSF1R-positive IACs, whereas that of Cebpε and Gfi1 mRNAs was lower relative to CSF1R-negative IACs, suggesting that CSF1/CSF1R signaling functions in IAC myeloid differentiation by modulating expression of these transcription factors. Colony formation assays using CSF1R-positive IACs revealed increased numbers of myeloid colonies in the presence of CSF1. Analysis using an intra-cellular signaling array indicated the greatest fold increase of Cleaved Caspase-3 in AGM cells in the presence of CSF1. Immunohistochemistry revealed that Cleaved Caspase-3 is primarily expressed in IACs in the AGM region, and incubation of IACs with CSF1 up-regulated Cleaved Caspase-3. Overall, our findings suggest that CSF1 secreted from mesonephros accelerates IAC myeloid differentiation in the AGM region, possibly via Caspase-3 cleavage.

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BMP signalling differentially regulates distinct haematopoietic stem cell types

Cited by 76 publications

References 34 publications

Human haematopoietic stem cell development: from the embryo to the dish

Human haematopoietic stem cell development: from the embryo to the dish

Role of the bone morphogenic protein pathway in developmental haemopoiesis and leukaemogenesis

Embryonic Intra-Aortic Clusters Undergo Myeloid Differentiation Mediated by Mesonephros-Derived CSF1 in Mouse

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