Analysis of the human fetal liver hematopoietic microenvironment
Analysis of the human fetal liver hematopoietic microenvironment
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DOI：
10.1089/scd.2005.14.493
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发表时间：
2005-10-01
影响因子：
4
通讯作者：
Bhatia, M
中科院分区：
文献类型：
--
作者：
Martin, MA;Bhatia, M
在成人中，造血干细胞 (HSC) 驻留在骨髓 (BM) 室中，并与 BM 基质微环境直接相关。然而，人类成人造血干细胞大部分处于静止状态，自我更新能力有限。这与胎儿发育过程中造血短暂定位于胎儿肝脏 (FL) 时循环 HSC 进行自我更新的频率较高形成鲜明对比，表明 FL 提供了更有利的微环境来支持 HSC。在这里，我们提供了能够支持人类再生祖细胞的原代人 FL 基质细胞的表型和分子特征。定性和定量分析显示，与成人骨髓来源的基质相比，FL 基质细胞具有一些独特的特性，其中包括与成人骨髓相比，FL 基质的增殖能力增强 10 倍以上，以及表达 N-钙粘蛋白和骨桥蛋白的细胞数量增加 2 倍。全局基因表达微阵列分析支持可能调节 HSC 扩增的外在影响，表明与成人 BM 基质相比，FL 基质具有更高的 Wnt 信号通路调节因子表达，这表明 Notch 信号通路的表达增加。我们的结果表明，与成人 BM 基质相比，人 FL 基质细胞通过在人类胎儿造血发育过程中控制 HSC 的 Wnt 信号传导，为 HSC 提供了独特的微环境，而 Notch 信号传导在成人中受到 HSC 微环境的严格调节。我们提出，人类 HSC 生态位在人类发育过程中受到个体发育控制，以提供胎儿 HSC 的适当扩增和成人 HSC 的后续维持。
In the adult, hematopoietic stem cells (HSCs) are resident in the bone marrow (BM) compartment and are in direct association with the BM stromal microenvironment. However, human adult HSCs are largely quiescent and undergo limited self-renewal. This is in contrast to the higher frequency of cycling HSCs undergoing self-renewal during fetal development when hematopoiesis is transiently localized to the fetal liver (FL), suggesting that FL provides a more conducive microenvironment to support HSCs. Here, we provide phenotypic and molecular characterization of primary human FL stromal cells capable of supporting human repopulating progenitors. Qualitative and quantitative analysis revealed several properties unique to FL stromal cells compared to adult BM-derived stroma that included a greater than 10-fold enhanced proliferative capacity of FL stromal vs adult BM, and a 2-fold increase in the number of N-cadherin- and osteopontin-expressing cells. Supportive of extrinsic influences likely to modulate HSC expansion, global gene expression microarray analysis revealed that FL stroma has higher expression of regulators of the Wnt signaling pathway compared to adult BM stroma, which demonstrated an increased expression of the Notch signaling pathway. Our results suggest that human FL stromal cells provide a unique microenvironment to HSCs compared to adult BM stroma by controlling Wnt signaling of HSCs during human fetal hematopoietic development, while Notch signaling is tightly regulated by the HSC microenvironment in the adult. We propose that the human HSC niche is ontogenically controlled during human development to provide appropriate expansion of fetal HSCs and subsequent maintenance of adult HSCs.