Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells.
Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells.
复制标题
骨形态发生蛋白调节人造血干细胞的发育程序。
DOI：
10.1084/jem.189.7.1139
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发表时间：
1999-04-05
期刊：
影响因子：
--
通讯作者：
Dick JE
中科院分区：
文献类型：
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作者：
Bhatia M;Bonnet D;Wu D;Murdoch B;Wrana J;Gallacher L;Dick JE
对调节人类造血干细胞的分子的鉴定主要集中在细胞因子上，其中很少有人知道直接作用于干细胞。最近对低等生物和小鼠的研究表明，骨形态发生蛋白（BMPs）可能在中胚层形成造血组织的过程中发挥关键作用。在这里，我们报道bmp调节来自成人和新生儿来源的高度纯化的原始人类造血细胞的增殖和分化。从人造血组织中分离出罕见的CD34+CD38−Lin−干细胞群体，发现它们表达BMP I型受体激活素样激酶(ALK)-3和ALK-6，以及它们的下游传导因子SMAD-1、-4和-5。在非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠移植后，用可溶性BMP-2、-4和-7处理分离干细胞群可诱导增殖、克隆原性、细胞表面表型和多系再生能力的剂量依赖性变化。与转化生长因子β类似，纯化后的细胞用高浓度BMP-2或-7处理可抑制增殖，但保持原始的CD34+CD38 -表型和再生能力。相比之下，低浓度的BMP-4诱导CD34+ CD38 - Lin -细胞的增殖和分化，而高浓度的BMP-4延长了体外培养中维持再生能力的时间，表明对干细胞存活有直接影响。BMP能够调控细胞再生的发现，为控制人类干细胞发育提供了新的途径，也为利用人原代细胞研究BMP作用的生物学机制提供了强有力的模型系统。
The identification of molecules that regulate human hematopoietic stem cells has focused mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34+CD38−Lin− stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor β, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34+CD38− phenotype and repopulation capacity. In contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34+ CD38−Lin− cells, whereas at higher concentrations BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP action using primary human cells.