MiR-17 partly promotes hematopoietic cell expansion through augmenting HIF-1α in osteoblasts.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China.
Yuxia
Y
Yang
Wei
W
Ma
Dan
D
Wu
Yu
Y
Huang
Hongge
H
Li
Junhua
J
Zou
Yanju
Y
Zhang
Meifu
M
Feng
Jianyuan
J
Luo
D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D018952:Antigens, CD34; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering