Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress

Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Blood (Impact Factor: 10.45). 10/2012; 120(25). DOI: 10.1182/blood-2012-06-435800
Source: PubMed


The transcription factor Meis1 is preferentially expressed in hematopoietic stem cells (HSCs) and over-expressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. Using inducible knock-out mice, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over long term while steady-state hematopoiesis was sustained in the absence of Meis1. Bone marrow cells of Meis1 deficient mice showed reduced colony formation, contained significantly fewer numbers of long- term HSCs and these Meis1-deficient HSCs exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species (ROS) in HSCs and decreased expression of genes implicated in hypoxia response. Finally, ROS scavenging by N-acetyl cysteine or stabilization of hypoxia-signaling by knockdown of the VHL protein led to reversal of the effects of Meis1-deletion. Taken together, these results demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism.

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Available from: Zeenath Unnisa, Sep 16, 2015
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    • "This resulted in increases in HSC ROS production, cell cycle entry and proliferation , and apoptosis and decreases in the ability of HSCs to reconstitute the hematopoietic system during serial BM transplantation and to tolerate stress such as 5-fluorouracil administration. These HSC defects could be attenuated by treatment of the knockout mice with NAC, knockdown of VHL, or conditional monoallelic knockout of VHL (Kocabas et al., 2012; Simsek et al., 2010; Takubo et al., 2010; Unnisa et al., 2012). However, overactivation of HIF-1 in HSCs induced by conditional biallelic knockout of VHL or inhibition of PHD is detrimental to HSCs and can lead to HSC premature exhaustion (Eliasson et al., 2010; Takubo et al., 2010). "
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    ABSTRACT: Reactive oxygen species (ROS) play an important role in determining the fate of normal stem cells. Low levels of ROS are required for stem cells to maintain quiescence and self-renewal. Increases in ROS production cause stem cell proliferation/differentiation, senescence, and apoptosis in a dose-dependent manner, leading to their exhaustion. Therefore, the production of ROS in stem cells is tightly regulated to ensure that they have the ability to maintain tissue homeostasis and repair damaged tissues for the life span of an organism. In this chapter, we discuss how the production of ROS in normal stem cells is regulated by various intrinsic and extrinsic factors and how the fate of these cells is altered by the dysregulation of ROS production under various pathological conditions. In addition, the implications of the aberrant production of ROS by tumor stem cells for tumor progression and treatment are also discussed.
    Advances in Cancer Research 06/2014; 122C:1-67. DOI:10.1016/B978-0-12-420117-0.00001-3 · 5.32 Impact Factor
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    • "N., unpublished data), although another study did not show such a binding peak within the Hif1a locus [37]. During submission of the present paper, two other groups described the HSC phenotype of Meis1-deficient mice [40], [41]. Although the HSC phenotypes they reported are almost identical with those described in the current study, the role of Meis1 in Hif1a expression was somewhat different among these three reports. "
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    ABSTRACT: Hematopoietic stem cells in the bone marrow have the capacity to both self-renew and to generate all cells of the hematopoietic system. The balance of these two activities is controlled by hematopoietic stem cell-intrinsic regulatory mechanisms as well as extrinsic signals from the microenvironment. Here we demonstrate that Meis1, a TALE family homeodomain transcription factor involved in numerous embryonic developmental processes, is selectively expressed in hematopoietic stem/progenitor cells. Conditional Meis1 knockout in adult hematopoietic cells resulted in a significant reduction in the hematopoietic stem/progenitor cells. Suppression of hematopoiesis by Meis1 deletion appears to be caused by impaired self-renewal activity and reduced cellular quiescence of hematopoietic stem/progenitor cells in a cell autonomous manner, resulting in stem cell exhaustion and defective long-term hematopoiesis. Meis1 deficiency down-regulated a subset of Pbx1-dependent hematopoietic stem cell signature genes, suggesting a functional link between them in the maintenance of hematopoietic stem/progenitor cells. These results show the importance of Meis1 in adult hematopoiesis.
    PLoS ONE 02/2014; 9(2):e87646. DOI:10.1371/journal.pone.0087646 · 3.23 Impact Factor
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    • "Proper Meis1 expression is essential for body and limb bud axis patterning, brain segmentation, angiogenic patterning, and the proliferation of stem cells in developing organ systems such as retina, heart, and hematopoietic centers. However, Meis1 expression also has inhibitory effects that induce cell-cycle arrest and stem cell quiescence in ways that enable non-proliferative cellular differentiation during and after organogenesis while simultaneously preserving pools of multipotent stem cells for lineage renewal [61-64,66,68-74]. Experimental alterations of Meis1 expression are associated with severe, often fatal, prenatal developmental defects in neurologic patterning, the differentiation of hematopoietic stem cells and establishment of definitive hematopoiesis, peripheral angiogenesis, cardiomyocyte cell-cycle regulation, and hematopoietic cancers; but in no case has Meis1 expression been associated with fetal or postnatal growth rates or nutrient acquisition per se. "
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    ABSTRACT: Imprinted genes have been extensively documented in eutherian mammals and found to exhibit significant interspecific variation in the suites of genes that are imprinted and in their regulation between tissues and developmental stages. Much less is known about imprinted loci in metatherian (marsupial) mammals, wherein studies have been limited to a small number of genes previously known to be imprinted in eutherians. We describe the first ab initio search for imprinted marsupial genes, in fibroblasts from the opossum, Monodelphis domestica, based on a genome-wide ChIP-seq strategy to identify promoters that are simultaneously marked by mutually exclusive, transcriptionally opposing histone modifications. We identified a novel imprinted gene (Meis1) and two additional monoallelically expressed genes, one of which (Cstb) showed allele-specific, but non-imprinted expression. Imprinted vs. allele-specific expression could not be resolved for the third monoallelically expressed gene (Rpl17). Transcriptionally opposing histone modifications H3K4me3, H3K9Ac, and H3K9me3 were found at the promoters of all three genes, but differential DNA methylation was not detected at CpG islands at any of these promoters. In generating the first genome-wide histone modification profiles for a marsupial, we identified the first gene that is imprinted in a marsupial but not in eutherian mammals. This outcome demonstrates the practicality of an ab initio discovery strategy and implicates histone modification, but not differential DNA methylation, as a conserved mechanism for marking imprinted genes in all therian mammals. Our findings suggest that marsupials use multiple epigenetic mechanisms for imprinting and support the concept that lineage-specific selective forces can produce sets of imprinted genes that differ between metatherian and eutherian lines.
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