Cell Cycle Regulation of Stem Cells by MicroRNAs

Abstract

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules involved in the regulation of gene expression. They are involved in the fine-tuning of fundamental biological processes such as proliferation, differentiation, survival and apoptosis in many cell types. Emerging evidence suggests that miRNAs regulate critical pathways involved in stem cell function. Several miRNAs have been suggested to target transcripts that directly or indirectly coordinate the cell cycle progression of stem cells. Moreover, previous studies have shown that altered expression levels of miRNAs can contribute to pathological conditions, such as cancer, due to the loss of cell cycle regulation. However, the precise mechanism underlying miRNA-mediated regulation of cell cycle in stem cells is still incompletely understood. In this review, we discuss current knowledge of miRNAs regulatory role in cell cycle progression of stem cells. We describe how specific miRNAs may control cell cycle associated molecules and checkpoints in embryonic, somatic and cancer stem cells. We further outline how these miRNAs could be regulated to influence cell cycle progression in stem cells as a potential clinical application.

Keywords: Cancer stem cell; Cell cycle; ESC; MicroRNA; Somatic stem cell; Stem cells.

Fig. 1

An overview of cell cycle regulation in ESCs by miRNAs. The figure illustrates the cell cycle progression in embryonic stem cells (ESCs). As shown, multiple key regulatory elements including cyclins, CDKs and CDK inhibitors are forming a network that progress cells through the four different phases of cell cycle. Several miRNA clusters and single miRNAs are involved in the regulation of cell cycle in ESCs by directly or indirectly targeting the cell cycle-associated components (e.g. RB, p53, p21, LATS2, PTEN, cyclin D, cyclin E). Among them, miR-17-92, miR-290-295, miR-302, miR-106b-25 and miR-106a-363 are abundantly expressed in ESCs. Inhibition of E2F by miR-92 and miR-195 decreases transcription of multiple transcription factors and proteins (e.g. E2F-1, E2F-2, E2F-3, CDK2, CDC25A), resulting in a reduction of G1 phase duration. Furthermore, the expression of main G1/S and G2/M checkpoint regulator p53 is decreased via indirect targeting by miR-290-295 and miR-302 in ESCs. This facilitates the G1/S transition. Moreover, p21 expression is reduced via miR-290-295, miR-372a, miR-302 and miR-106b-25 in a direct manner. This inhibits cyclin E-CDK2 activity, and therefore facilitates the G1/S transition. Additionally, miR-106b-25 and miR-17-92 can target pro-apoptotic gene BIM, resulting in a reduction of cells entering apoptosis [51]

Fig. 2

miRNA-mediated regulation of cell cycle in HSCs. (a) The schematic describes miRNAs (e.g. miR-125, miR-126, miR-33, miR-146 and let-7) with critical roles in the cell cycle regulation in adult HSCs by directly targeting cell cycle components. Furthermore, miR-29 and miR-124, which target components involved in DNA methylation, indirectly influence the expression of cell cycle-associated genes. (b) The LIN28-HMGA2 feed-forward loop is among the most important mechanisms that drive fetal HSC self-renewal. LIN28 is highly expressed in fetal HSCs compared to adult HSCs. As LIN28 directly inhibits let-7 expression, this indicates the important role of miRNA let-7 upon stem cell differentiation. Decreased level of let-7 has resulted in higher expression of HMGA2, which induces self-renewal. Additionally, LIN28 can acts independently of the let-7 family and contributes to self-renewal [95, 96]. (c) Adult HSCs are a heterogeneous population that differ in self-renewal and differentiation capacity based on their surface markers. Long-term HSCs (LT-HSCs) are predominantly quiescent (c-kit⁺ Sca-1⁺ Lin⁻ Flk-2⁻ CD34⁻) [103]. However, a large fraction of short term-HSCs (c-kit⁺ Sca-1⁺ Lin⁻ Flk-2⁻ CD34⁺) gives rise to the differentiated progeny, and also shows greater cell proliferation capacity than LT-HSCs [102, 103]. Progenitor cells are associated with proliferation and differentiation into hematopoietic lineages. KSL (c-kit⁺ Sca-1⁺ Lin⁻) with high CD150⁺ expression may give predominant rise to myeloid linages, whereas KSL-CD150⁻ are more likely to a lymphoid outcome [104]. Several studies also demonstrate that specific miRNAs are differentially expressed among HSCs and progenitor cells