miRNA-based mechanism for the commitment of multipotent progenitors to a single cellular fate

Abstract

When stem cells and multipotent progenitors differentiate, they undergo fate restriction, enabling a single fate and blocking differentiation along alternative routes. We herein present a mechanism whereby such unequivocal commitment is achieved, based on micro-RNA (miRNA)-dependent repression of an alternative cell fate. We show that the commitment of monocyte RAW264.7 progenitors to active macrophage differentiation involves rapid up-regulation of miR-155 expression, which leads to the suppression of the alternative pathway, namely RANK ligand-induced osteoclastogenesis, by repressing the expression of MITF, a transcription factor essential for osteoclast differentiation. A temporal asymmetry, whereby miR-155 expression precedes and overrides the activation of the osteoclast transcriptional program, provides the means for coherent macrophage differentiation, even in the presence of osteoclastogenic signals. Based on these findings, we propose that miRNA may provide a general mechanism for the unequivocal commitment underlying stem cell differentiation.

MicroRNAs and post-transcriptional regulation of skeletal development

“…In addition, Mann et al performed a differential miRNA screening using the RAW 264.7 cell line under RANKL and M-CSF treatment to induce osteoclastic differentiation. miR-155 was described in this study as an early inhibitor of MITF, a nuclear effector that integrates M-CSF/RANKL signals to initiate the expression of osteoclast-specific genes (Mann et al 2010). The RAW 264.7 cell line can differentiate into either macrophages or osteoclasts, and the results of this study suggest that the upregulation of miR-155 expression facilitates macrophage commitment, therefore inhibiting osteoclast differentiation (by targeting MITF).…”

“…The RAW 264.7 cell line can differentiate into either macrophages or osteoclasts, and the results of this study suggest that the upregulation of miR-155 expression facilitates macrophage commitment, therefore inhibiting osteoclast differentiation (by targeting MITF). These data indicate that miR-155 is involved in the commitment switch of hematopoietic precursors (Mann et al 2010). Zhang et al (2012b) revealed that miR-155 is inhibited by IFNb during osteoclast differentiation, and they identified the effect of miR-155 on the 3 0 -UTR of MITF and suppressor of cytokine signaling 1 (SOCS1).…”

MicroRNAs as regulators of bone homeostasis and bone metastasis

“…9 Conversely, RANK targeting by miR-503 inhibited osteoclastogenesis, whereas silencing miR-503 enhanced in vivo bone resorption. 26 MiR-125a was also shown to inhibit osteoclast differentiation by suppressing TRAF6 expression, 27 whereas miR-155 was shown to regulate cell-fate commitment 28,29 It is important to recognize that the regulation of bone homeostasis depends on carefully orchestrated cross-talk between bone marrow cells. MiR-34c is an essential regulator of Notch signaling in osteoblasts, directly targeting Notch1, Notch2 and Jagged1, as well as Satb2 and Runx2.…”

Chemical modification and design of anti-miRNA oligonucleotides

“…These small, noncoding RNAs modulate gene expression at the post-transcriptional level and are responsible for regulating many biological processes including differentiation, 1 apoptosis, proliferation and cell-fate determination. 2 Considering the role miRNAs have in regulating these cellular processes, it is not surprising that dysregulation of miRNAs has been implicated in a variety of pathologies, such as inflammatory and autoimmune diseases, neurological disorders, 3 myocardial disease, 4 as well as several types of cancer.…”