A novel role of BMP4 in adult hematopoietic stem and progenitor cell homing via Smad independent regulation of integrin-α4 expression
A novel role of BMP4 in adult hematopoietic stem and progenitor cell homing via Smad independent regulation of integrin-α4 expression
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DOI：
10.1182/blood-2012-07-446443
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发表时间：
2013-01-31
期刊：
影响因子：
20.3
通讯作者：
Verfaillie, Catherine M.
中科院分区：
文献类型：
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作者：
Khurana, Satish;Buckley, Shannon;Verfaillie, Catherine M.
虽然BMP4在造血系统的发育中起着重要的作用，但对BMP4是否影响成人造血以及如何影响成人造血的研究还不是很清楚。在这里，我们描述了一种新的机制，通过它BMP4调节小鼠和人类造血干细胞/祖细胞(HSPC)的归巢。BMP4处理小鼠骨髓来源的c-kit(+)Lin(-)SCA-1(+)(KLS)和CD150(+)CD48(-)KLS细胞长达5天，可阻止培养诱导的整合素α4(ITGA4)表达的丧失和归巢。BMP4对ITGA4表达的影响是通过非SMAD依赖的p38MAPK的磷酸化来实现的，p38MAPK激活小眼球相关转录因子(MITF)，从而诱导ITGA4的表达。与未经BMP4培养的细胞相比，经BMP4处理的细胞的ITGA4表达显著增强HSPC与骨髓基质细胞的黏附、归巢和长期植入。BMP4还诱导培养的人BM来源的LIN(-)CD34(+)细胞表达ITGA4，这与改善归巢潜能有关。因此，BMP4以一种不依赖于SMAD的方式阻止培养诱导的HSPC上ITGA4表达的丢失，从而改善培养的HSPC的归巢和随后的造血重建。(血。2013；121(5)：781-790)
Although it is well established that BMP4 plays an important role in the development of hematopoietic system, it is less well understood whether BMP4 affects adult hematopoiesis and how. Here, we describe a novel mechanism by which BMP4 regulates homing of murine as well as human hematopoietic stem/progenitor cells (HSPCs). BMP4 treatment of murine BM derived c-kit(+)Lin(-)Sca-1(+) (KLS) and CD150(+)CD48(-)KLS cells for up to 5 days in vitro prevented the culture-induced loss of Integrin-alpha 4 (ITGA4) expression as well as homing. The effect on ITGA4 expression in response to BMP4 is mediated via SMAD-independent phosphorylation of p38 MAPK, which activates microphthalmia-associated transcription factor (MITF), known to induce ITGA4 expression. Elevated ITGA4 expression significantly enhanced HSPC attachment to bone marrow stromal cells, homing and long-term engraftment of the BMP4 treated cells compared with the cells cultured without BMP4. BMP4 also induced expression of ITGA4 on human BM derived Lin(-)CD34(+) cells in culture, which was associated with improved homingpotential. Thus, BMP4 prevents culture-induced loss of ITGA4 expression on HSPCs in a SMAD-independent manner, resulting in improved homing of cultured HSPCs and subsequent hematopoietic reconstitution. (Blood. 2013;121(5):781-790)