ARAP3 functions in hematopoietic stem cells.
ARAP3 functions in hematopoietic stem cells.
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DOI：
10.1371/journal.pone.0116107
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Tong W
中科院分区：
文献类型：
--
作者：
Song Y;Jiang J;Vermeren S;Tong W
ARAP3是一种GTP酶激活蛋白(GAP)，可灭活Arf6和RhoA小GTP酶。小鼠的ARAP3缺乏导致萌发的血管生成缺陷，从而导致E11胚胎死亡。携带ARAP3 R302,303A突变(ARap3KI/Ki)阻止磷脂酰肌醇-3-激酶(PI3K)激活的小鼠具有类似的血管生成表型，尽管一些动物存活到成年。在这里，我们报告了来自罕见的成人ARap3KI/KI骨髓的造血干细胞(HSCs)在重建受体小鼠和自我更新方面的能力受到损害。为了阐明ARAP3在造血中潜在的细胞自主和非细胞自主作用，我们有条件地在造血细胞和HSC生态位内的几种细胞类型中删除了ARap3。用Vav1-Cre切除造血细胞中的ARap3不会改变ARAP3缺陷的祖细胞在体外的增殖和分化能力，也不会改变ARAP3缺陷的HSC在体内提供多谱系重建和自我更新的能力。因此，我们的数据表明ARAP3在HSPC中不起细胞自主作用。使用PRX1-CRE缺失成骨细胞和间充质基质细胞中的ARap3导致成年小鼠的造血发育或HSC动态平衡中没有可辨别的表型。相反，使用血管内皮钙粘素(VEC或CDH5)驱动的CRE缺失ARap3会导致胚胎死亡，但存活的成年小鼠的HSC基本上是正常的。反向移植到血管内皮细胞驱动的ARap3条件基因敲除小鼠中，与对照小鼠相比，在HSC频率或功能上没有明显的差异。综上所述，我们的研究表明，尽管ARAP3在胚胎血管发育中起着关键作用，但它在内皮细胞中的丢失对成人骨髓中的HSCs的影响最小。
ARAP3 is a GTPase-activating protein (GAP) that inactivates Arf6 and RhoA small GTPases. ARAP3 deficiency in mice causes a sprouting angiogenic defect resulting in embryonic lethality by E11. Mice with an ARAP3 R302,303A mutation (Arap3KI/KI) that prevents activation by phosphoinositide-3-kinase (PI3K) have a similar angiogenic phenotype, although some animals survive to adulthood. Here, we report that hematopoietic stem cells (HSCs) from rare adult Arap3KI/KI bone marrow are compromised in their ability to reconstitute recipient mice and to self-renew. To elucidate the potential cell-autonomous and non-cell-autonomous roles of ARAP3 in hematopoiesis, we conditionally deleted Arap3 in hematopoietic cells and in several cell types within the HSC niche. Excision of Arap3 in hematopoietic cells using Vav1-Cre does not alter the ability of ARAP3-deficient progenitor cells to proliferate and differentiate in vitro or ARAP3-deficient HSCs to provide multi-lineage reconstitution and to undergo self-renewal in vivo. Thus, our data suggest that ARAP3 does not play a cell-autonomous role in HSPCs. Deletion of Arap3 in osteoblasts and mesenchymal stromal cells using Prx1-Cre resulted in no discernable phenotypes in hematopoietic development or HSC homeostasis in adult mice. In contrast, deletion of Arap3 using vascular endothelial cadherin (VEC or Cdh5)-driven Cre resulted in embryonic lethality, however HSCs from surviving adult mice were largely normal. Reverse transplantations into VEC-driven Arap3 conditional knockout mice revealed no discernable difference in HSC frequencies or function in comparison to control mice. Taken together, our investigation suggests that despite a critical role for ARAP3 in embryonic vascular development, its loss in endothelial cells minimally impacts HSCs in adult bone marrow.
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影响因子：
64.8
作者：
Chen, Michael J.;Yokomizo, Tomomasa;Zeigler, Brandon M.;Dzierzak, Elaine;Speck, Nancy A.
通讯作者：
Speck, Nancy A.
DOI：
10.4049/jimmunol.1201330
发表时间：
2013-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gambardella L;Anderson KE;Jakus Z;Kovács M;Voigt S;Hawkins PT;Stephens L;Mócsai A;Vermeren S
通讯作者：
Vermeren S
影响因子：
20.3
作者：
Ghiaur, Gabriel;Lee, Andrew;Williams, David A.
通讯作者：
Williams, David A.
影响因子：
56.9
作者：
Gu, Y;Filippi, MD;Williams, DA
通讯作者：
Williams, DA
影响因子：
23.9
作者：
Florian, Maria Carolina;Doerr, Karin;Niebel, Anja;Daria, Deidre;Schrezenmeier, Hubert;Rojewski, Markus;Filippi, Marie-Dominique;Hasenberg, Anja;Gunzer, Matthias;Scharffetter-Kochanek, Karin;Zheng, Yi;Geiger, Hartmut
通讯作者：
Geiger, Hartmut