MicroRNAs: key regulators of stem cells

Abstract

The hallmark of a stem cell is its ability to self-renew and to produce numerous differentiated cells. This unique property is controlled by dynamic interplays between extrinsic signalling, epigenetic, transcriptional and post-transcriptional regulations. Recent research indicates that microRNAs (miRNAs) have an important role in regulating stem cell self-renewal and differentiation by repressing the translation of selected mRNAs in stem cells and differentiating daughter cells. Such a role has been shown in embryonic stem cells, germline stem cells and various somatic tissue stem cells. These findings reveal a new dimension of gene regulation in controlling stem cell fate and behaviour.

Figure 1. RNA regulation of embryonic stem cells

Embryonic stem (ES) cells have the ability to self-renew or differentiate into progenitor cells, which finally give rise to all of the adult tissue stem cells in the body. MicroRNAs (miRNAs) regulate both self-renewal and differentiation pathways of ES cells by regulating various factors that mediate these processes. miRNAs form an integral network with transcription factors in regulating stem cell processes. For example, RE1-silencing transcription factor (REST), a transcriptional repressor, downregulates miR-21, which targets Nanog, SOX2 and OCT4 (also known as OCT3 and POU5F1). These are essential for stem cell self-renewal. Therefore, REST promotes self-renewal. Self-renewal is also promoted by the miR-290–295 cluster, which targets retinoblastoma like 2 (RBL2) — a repressor of DNA methyl transferases (DNMTs) — which methylate CpG islands and epigenetically silence OCT4 (REFS 29,30). Another mechanism of promoting self-renewal is by the regulation of let-7 miRNA processing by LIN28, which directly binds to a consensus sequence in the pre-let-7 miRNA loop region and inhibits processing by Drosha and Dicer^,. miR-296 promotes ES cell differentiation and miR-22 inhibits ES cell differentiation. However, their mRNA targets have not been identified. Positive and negative regulations are shown by an arrow and a T line respectively; a dotted T line suggests a possible pathway that needs to be confirmed.

Figure 2. RNA regulation of haematopoietic stem cells

Haematopoiesis involves a cascade of cell proliferation and differentiation in which the long-term reconstituting haematopoietic stem cells (LT-HSCs) first give rise to short-term reconstituting HSCs (ST-HSCs), followed by multipotent progenitors (MPs). MPs differentiate into either common lymphoid progenitors (CLPs) or common myeloid progenitors (CMPs). CLPs and CMPs further differentiate to produce various cells of the bloodstream. A number of microRNAs (miRNAs) have been identified that fine-tune each step of the haematopoietic differentiation. miRNAs that function in specific steps are marked, and positive and negative regulations are illustrated by an arrow and a T line, respectively. ErP, erythroid progenitor; GMP, granulocyte–macrophage progenitor; MEP, megakaryocytic–erythroid progenitor; MkP, megakaryocyte progenitor; NK, natural killer.