Cell signalling pathways that mediate haematopoietic stem cell specification

Marks-Bluth, Jonathon; Pimanda, John E.

doi:10.1016/j.biocel.2012.09.007

Cited by 13 publications

(10 citation statements)

References 115 publications

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“…The first human definitive haematopoietic stem cells (HSCs) are spatially restricted to the ventral floor of the dorsal aorta6. In the AGM, paracrine signals from tissues ventral to the dorsal aorta (such as the mesenchyme, primitive gut and sympathetic nervous system) promote haematopoiesis, while tissues dorsal to the dorsal aorta (such as the neural tube and notochord) suppress blood formation78910. These observations support our hypothesis that exerting spatial control over the local microenvironment of hPSC-derived HE will modulate blood cell yields and provide a platform to reveal organizing principles for this difficult-to-access developmental event.…”

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confidence: 99%

Engineering the haemogenic niche mitigates endogenous inhibitory signals and controls pluripotent stem cell-derived blood emergence

Rahman

Brauer

et al. 2017

Nat Commun

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Efforts to recapitulate haematopoiesis, a process guided by spatial and temporal inductive signals, to generate haematopoietic progenitors from human pluripotent stem cells (hPSCs) have focused primarily on exogenous signalling pathway activation or inhibition. Here we show haemogenic niches can be engineered using microfabrication strategies by micropatterning hPSC-derived haemogenic endothelial (HE) cells into spatially-organized, size-controlled colonies. CD34+VECAD+ HE cells were generated with multi-lineage potential in serum-free conditions and cultured as size-specific haemogenic niches that displayed enhanced blood cell induction over non-micropatterned cultures. Intra-colony analysis revealed radial organization of CD34 and VECAD expression levels, with CD45+ blood cells emerging primarily from the colony centroid area. We identify the induced interferon gamma protein (IP-10)/p-38 MAPK signalling pathway as the mechanism for haematopoietic inhibition in our culture system. Our results highlight the role of spatial organization in hPSC-derived blood generation, and provide a quantitative platform for interrogating molecular pathways that regulate human haematopoiesis.

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confidence: 99%

Engineering the haemogenic niche mitigates endogenous inhibitory signals and controls pluripotent stem cell-derived blood emergence

Rahman

Brauer

et al. 2017

Nat Commun

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“…Furthermore, NOTCH1 has been shown to be dispensable for primitive hematopoiesis and yolk sac embryonic hematopoiesis. Additionally, deletions of other Notch signaling components such as JAG1 , RBPJ, and Mind bomb‐1 also result in defective hematopoiesis in knockout mice . Taken together, these findings underscore the complexity of Notch signaling during early development and suggest that specific transitions of Notch signaling will be essential to appropriately control step‐wise hematopoietic specification of hESCs/hiPSCs in vitro toward generation of putative HSCs.…”

Section: Notch Signaling In Hematopoietic Differentiation Of Hpscsmentioning

confidence: 77%

Pleiotropic roles of Notch signaling in normal, malignant, and developmental hematopoiesis in the human

et al. 2014

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The Notch signaling pathway is evolutionarily conserved across species and plays an important role in regulating cell differentiation, proliferation, and survival. It has been implicated in several different hematopoietic processes including early hematopoietic development as well as adult hematological malignancies in humans. This review focuses on recent developments in understanding the role of Notch signaling in the human hematopoietic system with an emphasis on hematopoietic initiation from human pluripotent stem cells and regulation within the bone marrow. Based on recent insights, we summarize potential strategies for treatment of human hematological malignancies toward the concept of targeting Notch signaling for fate regulation.

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“…Separate pathways were constructed with upregulated and downregulated genes (Additional file 10: Table S7). Among the five most affected signaling pathways, we identified three hematopoiesis pathways that were upregulated, including glucocorticoid receptor signaling [38,39], IGF-1 signaling [40-42], and IL-17A signaling in fibroblasts [43], and two hematopoiesis-related pathways that were downregulated, including Wnt/β-catenin signaling [44-48] and Aryl hydrocarbon receptor signaling [49] (Table 2). Among these pathways, Wnt/β-catenin signaling has been characterized as essential for formation, self-renewal, and development of hematopoietic stem cells (HSCs) [48], which are closely associated with hematopoiesis.…”

Section: Resultsmentioning

confidence: 99%

Assessment of hematopoietic failure due to Rpl11 deficiency in a zebrafish model of Diamond-Blackfan anemia by deep sequencing

et al. 2013

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BackgroundDiamond–Blackfan anemia is a rare congenital red blood cell dysplasia that develops soon after birth. RPL11 mutations account for approximately 4.8% of human DBA cases with defective hematopoietic phenotypes. However, the mechanisms by which RPL11 regulates hematopoiesis in DBA remain elusive. In this study, we analyzed the transcriptome using deep sequencing data from an Rpl11-deficient zebrafish model to identify Rpl11-mediated hematopoietic failure and investigate the underlying mechanisms.ResultsWe characterized hematological defects in Rpl11-deficient zebrafish embryos by identifying affected hematological genes, hematopoiesis-associated pathways, and regulatory networks. We found that hemoglobin biosynthetic and hematological defects in Rpl11-deficient zebrafish were related to dysregulation of iron metabolism-related genes, including tfa, tfr1b, alas2 and slc25a37, which are involved in heme and hemoglobin biosynthesis. In addition, we found reduced expression of the hematopoietic stem cells (HSC) marker cmyb and HSC transcription factors tal1 and hoxb4a in Rpl11-deficient zebrafish embryos, indicating that the hematopoietic defects may be related to impaired HSC formation, differentiation, and proliferation. However, Rpl11 deficiency did not affect the development of other blood cell lineages such as granulocytes and myelocytes.ConclusionWe identified hematopoietic failure of Rpl11-deficient zebrafish embryos using transcriptome deep sequencing and elucidated potential underlying mechanisms. The present analyses demonstrate that Rpl11-deficient zebrafish may serve as a model of DBA and may provide insights into the pathogenesis of mutant RPL11-mediated human DBA disease.

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Cell signalling pathways that mediate haematopoietic stem cell specification

Cited by 13 publications

References 115 publications

Engineering the haemogenic niche mitigates endogenous inhibitory signals and controls pluripotent stem cell-derived blood emergence

Engineering the haemogenic niche mitigates endogenous inhibitory signals and controls pluripotent stem cell-derived blood emergence

Pleiotropic roles of Notch signaling in normal, malignant, and developmental hematopoiesis in the human

Assessment of hematopoietic failure due to Rpl11 deficiency in a zebrafish model of Diamond-Blackfan anemia by deep sequencing

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