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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    • "N., unpublished data), although another study did not show such a binding peak within the Hif1a locus [37].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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    • "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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