JOURNAL OF CELLULAR PHYSIOLOGY 209:266–269 (2006) MINI REVIEWS MicroRNA: A New Player in Stem Cells BAOHONG ZHANG,* XIAOPING PAN, AND TODD A. ANDERSON The Institute of Environmental and Human Health (TIEHH), and Department of Environmental Toxicology, Texas Tech University, Lubbock, Texas microRNAs (miRNAs) are an abundant class of endogenous non-protein-coding small RNAs, which negatively regulate gene expression at the posttranscriptional level in many developmental and metabolic processes. miRNAs regulate a variety of biological processes, including developmental timing, signal transduction, tissue differentiation and maintenance, disease, and carcinogenesis. Emerging evidence demonstrates that miRNAs also play an essential role in stem cell self-renewal and differentiation. Some miRNAs are specifically expressed in stem cells, control stem cell self-renewal, and differentiation through negatively regulating the expression of certain key genes in stem cells. J. Cell. Physiol. 209: 266 – 269, 2006. ß 2006 Wiley-Liss, Inc. Stem cells are a group of specifically remarkable cells, which have two important fundamental properties: self- renewal and multipotency (Cheng et al., 2005). Self- renewal means that stem cells have unlimited capacity for division without senescence; multipotency means that stem cells can form different cell types under suitable conditions in vivo and in vitro (Friel et al., 2005). These dual properties make stem cells clearly distinct from mature cells, including progenitor or precursor cells, which are directly derived from stem cells (Friel et al., 2005). Stem cells exist and persist in many tissues or organs throughout life, such as embryonic tissues, brain, spine, and bone. Due to their high potential to differentiate new cells and tissues, they have attracted interest among scientists for their potential in clinical and regenerative medicine, includ- ing cancer therapy (Zhao et al., 2005; Cedar, 2006). The mechanism by which stem cells maintain self- renewal and differentiation is complicated. In the past, several genes, including transcription factors were isolated and thought to be essential players in stem cell self-renewal and differentiation. However, the exact molecular mechanism still remains a mystery. Recent studies indicate that the expression profiles of micro- RNAs (miRNAs) in stem cells are different from other tissues, and this phenomena plus other emerging evidence suggests that miRNAs may play an essential role in stem cell self-renewal and differentiation (Yang et al., 2001; Houbaviy et al., 2003; Kuwabara et al., 2004; Suh et al., 2004; Cheng et al., 2005; Forstemann et al., 2005; Hatfield et al., 2005; Kanellopoulou et al., 2005; Lechman et al., 2005; Lee et al., 2005; Murchison et al., 2005; Tang et al., 2006). miRNAs are an abound class of non-protein-coding small RNAs (Lee et al., 1993; Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001). Com- pared with other coding and non-coding RNAs, miRNAs have a specific secondary stem-loop hairpin structure within their primary transcripts (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001) with a higher minimal folding free energy index (MFEI) (Zhang et al., 2006c). miRNAs originated 425 million years ago (Pasquinelli et al., 2000; Floyd and Bowman, 2004; Zhang et al., 2005, 2006a); they play essential and versatile roles in multiple biological processes (Carring- ton and Ambros, 2003; Wienholds and Plasterk, 2005; Zhang et al., 2006b). miRNAs negatively regulate gene expression at the posttranscriptional level (Carrington and Ambros, 2003; Ambros, 2004; Bartel, 2004) through direct mRNA cleavage (Aukerman and Sakai, 2003; Chen, 2004; Yekta et al., 2004; Yu et al., 2005), trans- lational repression (Wightman et al., 1993), or mRNA decay mediated by miRNA deadenylation (Giraldez et al., 2006; Wu et al., 2006). miRNAs were first identi- fied in 1993 serendipitously (Lee et al., 1993). Their versatile functions have attracted interests among scientists, especially since miRNAs were recognized in 2001 (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001). Since then, thousands of miRNAs have been identified in animals, plants, and viruses (Griffiths-Jones et al., 2006). miRNAs have become one of the most important gene regulators in eukaryotic organisms. Recent study suggests that miRNAs reg- ulate gene expression in more than 30% of protein- coding genes in humans and other organisms (Berezikov et al., 2005). microRNA AND STEM CELLS A good approach to study the function of miRNAs in stem cells is to use dicer (dcr) mutants. Dicer-1 (dcr-1), a multidomain ribonuclease with specificity for double- stranded RNAs, is an essential enzyme in miRNA biogenesis (Lee et al., 2004; Jiang et al., 2005; Saito et al., 2005). Loss-of-function of dcr-1 disrupted miRNA processing and blocked the miRNA pathway of gene expression, resulting in animal death and developmen- tal abnormalities (Bernstein et al., 2003; Wienholds et al., 2003; Muljo et al., 2005; Yang et al., 2005; Harris et al., 2006). Genetic studies indicated that Dicer loss compromised miRNA maturation in murine embryonic stem (ES) cells, leading to a defect in miRNA-mediated gene silencing (Murchison et al., 2005). Upon loss of Dicer activity, ES cells have division and proliferation defects (Murchison et al., 2005), causing death in mice at 7.5 days (embryonic) with a complete loss of pluripotent stem cells (Bernstein et al., 2003). In addition to Dicer, stem cell maintenance also requires the double- stranded RNA-binding domain protein Loquacious ß 2006 WILEY-LISS, INC. *Correspondence to: Dr. Baohong Zhang, The Institute of Environmental and Human Health (TIEHH), and Department of Environmental Toxicology, Texas Tech University, Lubbock, TX 79409-1163. E-mail: baohong.zhang@ttu.edu Received 18 May 2006; Accepted 19 May 2006 DOI: 10.1002/jcp.20713