miR-145 and miR-143 regulate smooth muscle cell fate and plasticity

Abstract

SUMMARY microRNAs are regulators of myriad cellular events, but evidence for a single microRNA that can efficiently differentiate multipotent cells into a specific lineage or regulate direct reprogramming of cells into an alternate cell fate has been elusive. Here, we show that miR-145 and miR-143 are co-transcribed in multipotent cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem cell–derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2.5, and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4, myocardin, and Elk-1 to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.

miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors

“…Furthermore, studies have shown that miR-145 reduces cell viability in colon and cervical cancer cell lines after prolonged exposure (Shi et al, 2007;Schepeler et al, 2008;Wang et al, 2008). Finally, the expression of miR-145 has been shown to be induced by p53 (Sachdeva et al, 2009) and regulated by an enhancer element activated by SRF and Nkx-2 transcription factors (Cordes et al, 2009).…”

“…Approximately 50% of the known miRNAs are located within regions of genomic instability that are amplified or deleted in cancer (Calin et al, 2004), which may in part explain the aberrant expression observed. MIR145 is located at chromosome 5q32 in a putative bicistronic cluster with MIR143 (Cordes et al, 2009), a region commonly lost in myelodysplastic syndromes (Horrigan et al, 1996). miRNAs are predominantly transcribed by polymerase II and processed by Drosha into B70-100 nt precursor molecules (Lee et al, 2003).…”

“…The downregulation is evident already in precancerous stages of breast and colon cancer (Michael et al, 2003;Sempere et al, 2007), suggesting loss of miR-145 as a common early neoplastic event. In situ hybridization (ISH) analysis has identified miR-145 expression in myoepithelial cells of the mammary lobules and ducts as well as in smooth muscle cells (Sempere et al, 2007;Cordes et al, 2009). Furthermore, studies have shown that miR-145 reduces cell viability in colon and cervical cancer cell lines after prolonged exposure (Shi et al, 2007;Schepeler et al, 2008;Wang et al, 2008).…”

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

“…miR‐143‐3p (miR‐143) has an established role in the function of smooth muscle myoblasts and adipogenesis (Esau et al ., 2004; Cordes et al ., 2009; Elia et al ., 2009; Xin et al ., 2009). miR‐143‐5p is highly expressed in skeletal muscle tissue, and its expression is downregulated during aging (Kim et al ., 2014).…”

MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis

“…Thus, EC dysfunction and ageing‐related degenerative problems lie, at least in part, within the tissue‐specific released miRNAs 6, 15, 29, 50, 51, 80.…”