Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China.
PLoS One. 2013 Jul 25;8(7):e70232. doi: 10.1371/journal.pone.0070232. Print 2013.
Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment, of which osteogenic cells play a crucial role. While evidence is accumulating for an important role of intrinsic miR-17 in regulating HSCs and HPCs, whether miR-17 signaling pathways are also necessary in the cell-extrinsic control of hematopoiesis hereto remains poorly understood.
METHODOLOGY/PRINCIPAL FINDINGS: Using the immortalized clone with the characteristics of osteoblasts, FBMOB-hTERT, in vitro expansion, long-term culture initiating cell (LTC-IC) and non-obese diabetic/severe combined immunodeficient disease (NOD/SCID) mice repopulating cell (SRC) assay revealed that the ectopic expression of miR-17 partly promoted the ability of FBMOB-hTERT to support human cord blood (CB) CD34(+) cell expansion and maintain their multipotency. It also seemed that osteoblastic miR-17 was prone to cause a specific expansion of the erythroid lineage. Conversely, deficient expression of miR-17 partly inhibited the hematopoietic supporting ability of FBMOB-hTERT. We further identified that HIF-1α is responsible for, at least in part, the promoted hematopoietic supporting ability of FBMOB-hTERT caused by miR-17. HIF-1α expression is markedly enhanced in miR-17 overexpressed FBMOB-hTERT upon interaction with CB CD34(+) cells compared to other niche associated factors. More interestingly, the specific erythroid lineage expansion of CB CD34(+) cells caused by osteoblastic miR-17 was abrogated by HIF-1α knock down.
CONCLUSION/SIGNIFICANCE: Our data demonstrated that CB CD34(+) cell expansion can be partly promoted by osteoblastic miR-17, and in particular, ectopic miR-17 can cause a specific expansion of the erythroid lineage through augmenting HIF-1α in osteoblasts.
造血干细胞（HSC）的调节高度依赖于与骨髓微环境的相互作用，其中成骨细胞起着至关重要的作用。虽然有证据表明内在的 miR-17 在调节 HSCs 和 HPCs 方面起着重要作用，但 miR-17 信号通路是否也需要在细胞外造血的控制中仍然知之甚少。
方法/主要发现：使用具有成骨细胞特征的永生化克隆 FBMOB-hTERT，体外扩增、长期培养起始细胞（LTC-IC）和非肥胖糖尿病/严重联合免疫缺陷病（NOD/SCID）小鼠重编程细胞（SRC）测定显示，miR-17 的异位表达部分促进了 FBMOB-hTERT 支持人脐血（CB）CD34(+)细胞扩增和维持其多能性的能力。似乎成骨细胞 miR-17 容易导致红系谱系的特异性扩增。相反，miR-17 表达不足部分抑制了 FBMOB-hTERT 的造血支持能力。我们进一步确定 HIF-1α至少部分负责 miR-17 引起的 FBMOB-hTERT 促进造血支持能力。与其他龛相关因子相比，与 CB CD34(+)细胞相互作用时，miR-17 过表达的 FBMOB-hTERT 中 HIF-1α 的表达明显增强。更有趣的是，成骨细胞 miR-17 引起的 CB CD34(+)细胞的特定红系谱系扩增被 HIF-1α 敲低所阻断。
结论/意义：我们的数据表明，CB CD34(+)细胞的扩增可以部分由成骨细胞 miR-17 促进，特别是异位 miR-17 可以通过增强成骨细胞中的 HIF-1α 引起特定的红系谱系扩增。
