Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis.
Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis.
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DOI：
10.1182/blood-2010-09-307942
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发表时间：
2011-07
期刊：
影响因子：
20.3
通讯作者：
Stephanie N Zimmer;Qing Zhou;Ting Zhou;Ziming Cheng;S. Abboud‐Werner;D. Horn;M. Lecocke;Ruth White;A. Krivtsov;S. Armstrong;A. Kung;D. Livingston;V. I. Rebel
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文献类型：
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作者：
Stephanie N Zimmer;Qing Zhou;Ting Zhou;Ziming Cheng;S. Abboud‐Werner;D. Horn;M. Lecocke;Ruth White;A. Krivtsov;S. Armstrong;A. Kung;D. Livingston;V. I. Rebel
CREB结合蛋白(CREBBP)对包括干细胞室在内的造血系统的细胞自主调控非常重要。在目前的研究中，我们表明CREBBP在微环境介导的造血调控中起着同样关键的作用。我们发现CREBBP(+/-)小鼠的骨髓微环境不能很好地维持未成熟干细胞库和祖细胞库。相反，它刺激髓系分化，进而发展为骨髓增殖表型。CREBBP单倍性不足引起的骨髓微环境改变包括骨小梁明显减少，这主要是由于破骨细胞生成增加引起的。虽然CFU-F和成骨细胞总数减少，但骨形成率与野生型小鼠相似。在分子水平上，我们发现已知的造血调节因子基质金属肽酶-9(MMP9)和KIT配体(KITL)随着CREBBP杂合水平的降低而减少。最后，CREBBP(+/-)内皮细胞上潜在的重要调节蛋白--内皮细胞黏附分子1(ESAM1)和钙粘附素5(CDH5)增加。我们的研究结果表明，在骨髓微环境中，全剂量的CREBBP对于维持正常的造血和防止过度的骨髓增殖是必不可少的。
CREB-binding protein (CREBBP) is important for the cell-autonomous regulation of hematopoiesis, including the stem cell compartment. In the present study, we show that CREBBP plays an equally pivotal role in microenvironment-mediated regulation of hematopoiesis. We found that the BM microenvironment of Crebbp(+/-) mice was unable to properly maintain the immature stem cell and progenitor cell pools. Instead, it stimulates myeloid differentiation, which progresses into a myeloproliferation phenotype. Alterations in the BM microenvironment resulting from haploinsufficiency of Crebbp included a marked decrease in trabecular bone that was predominantly caused by increased osteoclastogenesis. Although CFU-fibroblast (CFU-F) and total osteoblast numbers were decreased, the bone formation rate was similar to that found in wild-type mice. At the molecular level, we found that the known hematopoietic modulators matrix metallopeptidase-9 (MMP9) and kit ligand (KITL) were decreased with heterozygous levels of Crebbp. Lastly, potentially important regulatory proteins, endothelial cell adhesion molecule 1 (ESAM1) and cadherin 5 (CDH5), were increased on Crebbp(+/-) endothelial cells. Our findings reveal that a full dose of Crebbp is essential in the BM microenvironment to maintain proper hematopoiesis and to prevent excessive myeloproliferation.