Stem cell proliferation inhibitors

Wright, Esmond; Pragnell, Ian B.

doi:10.1016/s0950-3536(11)80014-4

Cited by 9 publications

(6 citation statements)

References 48 publications

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“…Since proliferating hematopoietic stem cells respond with growth inhibition to physiological (TGF-β, MIP-1α) and pathological (radiation, mutagenic agents, endogenous reactive metabolites) stimuli, we also arrested these cells in the G1 phase (Supplem. Figure 5d ) 39 , 40 . Like THP-1 cells, monocyte precursors treated with mimosine were characterised by decreased PARP1 expression and required the simultaneous administration of iHDAC and iEZH2 to restore PARP1 transcription (Fig.…”

Section: Resultsmentioning

confidence: 99%

Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes

Wiśnik

Płoszaj

Robaszkiewicz

2017

Sci Rep

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Differentiation of certain cell types is followed by a downregulation of PARP1 expression. We show that the reduction in the abundance of PARP1 in hematopoietic progenitor cells and monocytes is tightly controlled by the cell cycle. The differentiation-associated cell cycle exit induces E2F1 replacement with E2F4 at the PARP1 promoter and the assembly of an E2F4-RBL2-HDAC1-BRM(SWI/SNF) repressor complex which deacetylates nucleosomes and compacts chromatin. In G1 arrested cells, PARP1 transcription is reduced by the recruitment of E2F1-RB1-HDAC1-EZH2(PRC2)-BRM/BRG1(SWI/SNF), which additionally trimethylates H3K27 and causes an even higher increase in nucleosome density. The re-establishment of an active chromatin structure by treating post-mitotic monocytes with the HDAC inhibitor and G1 arrested cells with a combination of HDAC and EZH2 inhibitors restores PARP1 expression completely but does not affect the interaction between the components of the repressor complex with chromatin. This suggests that RB1 and RBL2, as well as PRC2, SWI/SNF and HDAC1, do not interfere with the transcription machinery. Interestingly, reinstatement of PARP1 expression by the silencing of RBL2 or by the inhibition of HDACs in monocytes and by transfection with the PARP1 expression vector in differentiated THP-1 cells substantially increased transcription of pluripotency stem cell factors such as POU5F1, SOX2 and NANOG.Although PARP1 is involved in the regulation of numerous intracellular processes such as DNA repair, gene transcription, signalling or metabolism, the differentiation of certain cell types is associated with downregulation of PARP1 transcription 1,2 . Decreased abundance of PARP1 also occurs in human monocytes derived from hematopoietic progenitor and stem cells (HSPCs), which belong to a group of multipotent cells capable of self-renewal and, upon stimulation, of giving rise to a wide range of blood cells. Lineage commitment in HPSC caused by cytokines or cell-cell signalling, involves the inhibition of cell cycle progression, repression of HPSC specific transcription factors and induction of lineage-specific expression of genes involved in cell fate. For example, PU.1 (also known as SPI-1) acts in monocytes/macrophages as a lineage-determining transcription factor 3 . Neither the mechanism nor the physiological significance of PARP1 repression in determining monocyte phenotype, function or differentiation has been documented. The low level of this enzyme has been shown to sensitise human monocytes to oxidative stress, while in myotubes it served as a protective mechanism against oxidative stress, helping with maintaining the cellular functions of skeletal muscles 4,5 . According to recent findings PARP1 repression favours commitment and differentiation of some cell types. In differentiating osteoclasts,

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Section: Resultsmentioning

confidence: 99%

Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes

Wiśnik

Płoszaj

Robaszkiewicz

2017

Sci Rep

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“…Both MIP1-and TGF-inhibit CFU-S in vivo, but whereas MIP1causes an effect within 4 h (by inhibiting DNA synthesis), TGFmay take up to 5 d, suggesting an indirect method (Cooper et al, 1994;Wright & Pragnell, 1992). Both MIP1-and TGF-inhibit CFU-S in vivo, but whereas MIP1causes an effect within 4 h (by inhibiting DNA synthesis), TGFmay take up to 5 d, suggesting an indirect method (Cooper et al, 1994;Wright & Pragnell, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, MIP1acts on a faster time scale than other negative regulators. Both MIP1-and TGF-inhibit CFU-S in vivo, but whereas MIP1causes an effect within 4 h (by inhibiting DNA synthesis), TGFmay take up to 5 d, suggesting an indirect method (Cooper et al, 1994;Wright & Pragnell, 1992). Both factors may prove to be important for humoral inhibition in Diamond Blackfan anaemia, and it is possible that a combination of inhibitors could well be causative in certain cases.…”

Section: Discussionmentioning

confidence: 99%

Diamond Blackfan anaemia: differential pattern of in vitro progenitor response to macrophage inflammatory protein 1‐alpha

McGuckin¹,

Liu²,

Ball³

et al. 1996

Br J Haematol

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The congenital disorder of erythropoiesis Diamond Blackfan anaemia (DBA) exhibits a defect in the stem/progenitor cell compartment, located at the erythroid progenitor level (CFU-GEMM, BFU-E, CFU-E). Treatment of DBA with interleukin-3 (IL-3) has had limited effect, despite in vitro studies suggesting that progenitor cells were capable of responding to IL-3. Whether IL-3 is not reaching the appropriate defective target cell, the cells cannot respond, or the marrow humoral inhibitory system is overriding it, is not clear. To investigate humoral inhibitory activities we examined the response of 15 DBA bone marrows in vitro to the inhibitory chemokine macrophage inflammatory protein 1-alpha (MIP1-alpha) in the presence of the stimulatory cytokines erythropoietin, granulocyte-macrophage colony-stimulating factor, IL-3, and stem cell factor. In vitro data agreed with our previous work showing that our patients formed three statistically different groups in response to stimulatory cytokines (type I DBA erythroid colony numbers approximately normal > type II DBA > type III DBA). Addition of MIP1-alpha to cultures caused average erythroid and myeloid suppression, which sequentially increased with DBA type (type I inhibition < type II < type III). The differential level of inhibition shown by MIP1-alpha in these DBA patients lends further evidence for the presence of distinct subgroups in this disorder.

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“…In addition, a number of laboratories have highlighted the role of negatively acting factors that may contribute to stem cell quiescence, such as TGF-~ (Cardoso et at., 1993;de Vos et Dubois et Elias et Mayani et at., 1995), TNF-a (Maciejewski et at., 1995;Mayani et at., 1995;Oez et at., 1993;Rusten et at., 1994b), MIP-1a (Avalos et at., 1994; Lu et at., 1993b;Mayani et at., 1995;Verfaillie et Wright and Pragnell, 1992), and IFN-y (Selleri et Shah et at., 1983;Shiohara et at., 1993;.…”

Section: Induction Of Cycling In Phscunclassified