Hyaluronan Expressed by the Hematopoietic Microenvironment Is Required for Bone Marrow Hematopoiesis
Hyaluronan Expressed by the Hematopoietic Microenvironment Is Required for Bone Marrow Hematopoiesis
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DOI：
10.1074/jbc.m112.376699
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发表时间：
2012-07-20
影响因子：
4.8
通讯作者：
Khaldoyanidi, Sophia
中科院分区：
文献类型：
--
作者：
Goncharova, Valentina;Serobyan, Naira;Khaldoyanidi, Sophia
透明质酸（HA）的造血微环境的调控网络的贡献进行了研究，使用敲除小鼠的三个透明质酸合酶基因（Has 1，Has 2和Has 3）。与野生型（WT）和Has 1（-/-）; Has 3（-/-）双基因敲除（dKO）小鼠相比，Prx 1-Cre; Has 2（flox/flox）; Has 1（-/-）; Has 3（-/-）三基因敲除（tKO）小鼠骨髓中的造血祖细胞数量减少，髓外部位的造血祖细胞数量增加。与该观察结果一致，在来自tKO小鼠的长期骨髓培养物（LTBMC）中观察到造血活性降低，而在WT和dKO培养物中粘附层的形成和造血细胞的生成没有差异。4-用甲基伞形酮（4 MU）抑制LTBMC中HA的产生。4 MU抑制LTBMC中HA的合成，降低HAS 2和HAS 3的表达，并消除造血，这种作用可通过加入外源性HA而减轻。外源性HA还增强了LTBMC中的细胞运动性，这与HA刺激的趋化因子和生长因子的产生相关。HA诱导的LTBMC的条件培养基增强了造血干/祖细胞（HSPC）对SDF-1的趋化性。内皮细胞暴露于4 MU降低了其支持HSPC滚动和粘附的能力。此外，移植的HSPC向4 MU预处理小鼠骨髓中的迁移低于未处理小鼠。总的来说，结果表明HA耗竭降低了微环境支持HSPC的能力，并证实了HA作为造血微环境结构中必要的调控元件的作用。
The contribution of hyaluronan (HA) to the regulatory network of the hematopoietic microenvironment was studied using knock-out mice of three hyaluronan synthase genes (Has1, Has2, and Has3). The number of hematopoietic progenitors was decreased in bone marrow and increased in extramedullary sites of Prx1-Cre;Has2(flox/flox); Has1(-/-); Has3(-/-) triple knock-out (tKO) mice as compared with wild type (WT) and Has1(-/-); Has3(-/-) double knock-out (dKO) mice. In line with this observation, decreased hematopoietic activity was observed in long term bone marrow cultures (LTBMC) from tKO mice, whereas the formation of the adherent layer and generation of hematopoietic cells in WT and dKO cultures was not different. 4-Methylumbelliferone (4MU) was used to pharmacologically inhibit the production of HA in LTBMC. Treatment with 4MU inhibited HA synthesis, decreased expression of HAS2 and HAS3, and eliminated hematopoiesis in LTBMC, and this effect was alleviated by the addition of exogenous HA. Exogenous HA also augmented the cell motility in LTBMC, which correlated with the HA-stimulated production of chemokines and growth factors. Conditioned media from HA-induced LTBMC enhanced the chemotaxis of hematopoietic stem/progenitor cells (HSPC) in response to SDF-1. Exposure of endothelial cells to 4MU decreased their ability to support HSPC rolling and adhesion. In addition, migration of transplanted HSPC into the marrow of 4MU-pretreated mice was lower than in untreated mice. Collectively, the results suggest that HA depletion reduces the ability of the microenvironment to support HSPC, and confirm a role for HA as a necessary regulatory element in the structure of the hematopoietic microenvironment.