MiR-17 Partly Promotes Hematopoietic Cell Expansion through Augmenting HIF-1α in Osteoblasts

Abstract

BackgroundHematopoietic 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 FindingsUsing 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/SignificanceOur 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.

A serum microRNA signature associated with complete remission and progression after autologous stem-cell transplantation in patients with multiple myeloma

“…For example, miR-16 has previously been found elevated during osteoclast/osteoblast differentiation [30] and its ectopic expression in serum correlated with bone metastasis burden in breast cancer [31]. In addition, the miR-17-92 cluster and paralogs, which includes miR-25, have been related to the regulation of osteoblast proliferation and differentiation [32] and to the promotion of hematopoietic cell expansion by augmenting HIF-1a in osteoblasts [33]. Interestingly, a mouse model with deletion of miR-17-92 cluster showed reduced skeletal growth with delayed ossification likely due to impaired osteoblast proliferation and differentiation [34].…”

Using microarray analysis to identify genes and pathways that regulate fetal hemoglobin levels

“…The microarray expression profile GSE93973 is available from the GEO database (Lai et al., ). Moreover, has‐miR‐17 can promote hematopoietic cell expansion via HIF‐1α (Yang et al., ). Thus, we speculate that miR‐17‐3p cooperates with the TFRC gene in the hematopoietic cell lineage pathway, thereby affecting HBG1/2 expression.…”

CD29 of human umbilical cord mesenchymal stem cells is required for expansion of CD34+ cells

“…LTC‐IC assay was performed as described previously . Briefly, 1.0 × 10 4 CB CD34 + cells were pipetted into six‐well plates containing nearly confluent, irradiated CD29‐deficient hUCMSC or control hUCMSC monolayers in LTC medium (Myelo‐Cult, StemCell Inc., Vancouver, BC, Canada), along with 10 −6 m hydrocortisone sodium hemisuccinate (Sigma, St. Louis, MO, USA).…”