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Try out PMC Labs and tell us what you think. Learn More. Somatic cells can be reprogrammed to reach an embryonic stem cell-like state by overexpression of defined factors. Recent studies have greatly improved the efficiency of the reprogramming process but the underlying mechanisms regulating the transition from a somatic to a pluripotent state are still relatively unknown. Here we present a systematic and comprehensive study of microRNAs in mouse embryonic fibroblasts MEFs during the early stage of cell fate decisions and reprogramming to a pluripotent state, in which ificant transcriptional and epigenetic changes occur.

One microRNA found to be highly induced during this stage of reprogramming, miRb, targeted the expression of extracellular matrix ECM genes including Wisp1 and Igfbp5. Wisp1 was shown to be a key regulator of additional ECM genes that serve as barriers to reprogramming.

Regulation of Wisp 1 is likely mediated through biglycan, a glycoprotein highly expressed in Amarie lee nude that is silenced in reprogrammed cells. Collectively, this report reveals a novel link between microRNA-mediated regulation of ECM formation and somatic cell reprogramming, and demonstrates that microRNAs are powerful tools to dissect the intracellular and extracellular molecular mechanisms of reprogramming.

Since the first report that mouse fibroblasts can be reprogrammed into a pluripotent state reminiscent of embryonic stem cells termed induced pluripotent stem cells, iPSC Takahashi and Yamanakathis phenomenon has been confirmed using many different mouse and human cell types Takahashi et al. One of the challenges for the development of successful application of iPSCs for medical purposes is their low reprogramming efficiency. Several approaches have been applied to enhance induced reprogramming efficiency, including strategies focusing on the use of mRNA Warren et al.

Intriguingly, a recent study reported in which somatic cells were completely reprogrammed to a pluripotent state only using a combination of seven small molecules Hou et al.

However, the molecular mechanisms by which the four factors are able to reprogram somatic cells remain largely unknown. A of studies suggest that somatic cell reprogramming is a complex and dynamic process involving many different transcriptional and epigenetic changes. Systematic analysis of the promoters targeted by overexpression of the four reprogramming factors has demonstrated that expression of the factor target genes is similar in iPSCs and mouse embryonic stem mES cells, and is altered in some partially reprogrammed cells Sridharan et al.

Microrna-mediated regulation of extracellular matrix formation modulates somatic cell reprogramming

The p53 pathway has been identified as one primary barrier to reprogramming Banito et al. In addition, it was suggested that a mesenchymal-to-epithelial transition MET is a key step that takes place at an early stage of reprogramming Li et al. During reprogramming, expression of markers on the initial somatic cell, such as mouse embryonic fibroblasts MEFsare down-regulated and characteristic mES markers, such as alkaline phosphatase, SSEA1, Nanog, and endogenous Oct4 become expressed Brambrink et al.

In addition, recent reports suggest that a privileged somatic state exists in which cells with accelerated cell cycles overcome the stochastic nature of reprogramming and efficiently generate iPSC Guo et al. However, iPSCs do not seem to have a generic epigenetic state that could clearly define the fully reprogrammed state Carey et al.

Despite this progress, there remains only limited information on the mechanisms by which the four transgenes and other cellular factors reprogram MEFs to an undifferentiated or ES-like state. Recent functional genomics studies have provided insight into essential and barrier pathways involved in iPSC generation during various steps of reprogramming Qin et al.

While ificant progress is being made in understanding the intracellular aling pathways governing somatic cell reprogramming, little is known about the extracellular events also associated with the reprogramming process. The extracellular matrix ECM is a multifunctional system that is involved in many stages of mammalian development Sanes ; Adams and Watt ; Rozario and DeSimone and human disease progressions, including tumor formation Kessenbrock et al.

ECM is made of secreted Amarie lee nude and proteins that are organized into a well-defined complex structure surrounding the surface of cells that produce them.

A variety of proteins and polysaccharides are involved in ECM, which could be divided into at least two groups: proteins with structural role, such as fibrous proteins and glycosaminoglycans; and proteins with regulatory role, including different growth factors e. ECM plays a crucial role in regulating various cellular behaviors and maintaining the identity and normal function of those cells Kessenbrock et al.

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For embryonic stem cells, ECM components are essential for establishing the proper niche for long-term ES cell survival and self-renewal Bendall et al. Moreover, recent studies have shown that culture media supplemented with FGF2 can enhance iPSC induction through the regulation of collagen gene expression, thus bringing attention to the role of the microenvironment in reprogramming Jiao et al.

In fact, given the dramatic changes of both cellular morphology and functional characteristics during the course of reprogramming, potential iPSCs would need to establish their own niche for supporting their growth and colony formation. At the same time, successful iPSCs also need to exclude the effects brought by secreted ECM proteins from surrounding cells that are not reprogrammed. Understanding the molecular mechanisms that govern ECM remodeling during reprogramming would provide fundamental knowledge essential in efficiently creating and controlling various states of pluripotent stem cells.

Small RNAs are usually generated from noncoding regions of gene transcripts and function to suppress gene expression by translational repression and mRNA degradation Ambros ; Chu and Rana; Rana ; Djuranovic et al. In addition, our recent findings suggest that the microRNA biogenesis machinery may be required for efficient reprogramming Li et al.

Moreover, during somatic reprogramming, many microRNAs undergo small changes in expression in the early stages while only a select few microRNAs undergo large changes in expression in the later stages of reprogramming Polo et al. These data indicate Amarie lee nude transition from a deterministic to stochastic process and suggest that microRNAs are regulated in a highly stage-dependent manner during reprogramming.

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These findings clearly suggest that microRNAs play crucial roles during the reprogramming process by targeting key barrier aling networks. However, most studies to date have focused on intracellular aling networks regulated by microRNAs, and the ability of microRNAs to influence critical cellular interactions with the microenvironmental niche during reprogramming has not yet been investigated. Here, we performed a systematic analysis of expression of microRNAs and their potential target genes at an early stage of reprogramming, and identified a novel link between microRNAs, ECM formation, and reprogramming of MEFs.

In particular, we found that microRNAb is highly induced and modulating its expression ificantly affected the reprogramming process. Interestingly, the effects of Wisp 1 are mediated through biglycan, a glycoprotein that is highly expressed in MEFs and is incompletely silenced in reprogramming cells.

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Notably, knockdown or overexpression of biglycan enhanced or suppressed MEF reprogramming, respectively. Collectively, our have identified a novel role for microRNA-mediated regulation of ECM formation in iPSC generation, and further, demonstrate that microRNAs can be powerful tools to dissect and understand the intracellular and extracellular molecular mechanisms of somatic cell reprogramming. findings indicate that reprogramming of MEFs is accompanied by sequential modulation of somatic cell and stem cell markers at different reprogramming stages Brambrink et al.

Thy1 is highly expressed in MEFs but its expression is repressed at the initiation of reprogramming. To identify key microRNAs in reprogramming, we focused on the early reprogramming stage in the first 5 d after transduction of MEFs with the four factors 4F; OSKM in what is reported to be the first stage of major transcriptional changes in the biphasic reprogramming process Polo et al.

Among them, miRb was the most highly induced and showed a statistically ificant change in expression Supplemental Table 2 and Fig. Our analysis also revealed a set of microRNAs that were ificantly repressed Fig. Of these, we chose to evaluate the potential barrier function of miR and miR, because they are highly expressed Amarie lee nude MEFs. Identification of highly regulated microRNAs during the early reprogramming stage.

A Scheme of experimental de. MEFs were infected with 4F virus for 5 d, and sorted based on expression of the Thy1 surface antigen.

Cells were harvested for AP staining at Day 14 post-infection. Hits are labeled as red dots. G Set of ificantly induced microRNAs. MicroRNAs induced by at least twofold are shown. H Set of ificantly repressed microRNAs.

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MicroRNAs repressed by at least twofold are shown. In similar experiments, cells were transfected with miR or miR mimics, which had minor inhibitory effects on reprogramming Fig. This observation is potentially due to the saturation effect of endogenous miRs as these miRs already have high expression in MEFs. To confirm our findings, we used microRNA inhibitors. Following transfection with miRb mimics or inhibitors, miRb expression levels were quantified by RT-qPCR to confirm overexpression or down-regulation, respectively Supplemental Fig.

Overall, these data demonstrate that miRb enhances reprogramming, consistent with its high induction by the 4F factors, while miR, which our analysis showed to be the most highly repressed microRNA, serves as a barrier. Data represent two independent experiments with triplicate wells. Let-7a was used as a control. C Blocking of miRb compromises reprogramming. D miRb iPSCs reach a fully reprogrammed Amarie lee nude. Endogenous Oct4 expression was monitored by GFP expression. The three tested miRb iPSC clones clones 1, 3, and N1 showed similar expression patterns to mES cells, which were quite different from the expression profile of the original starting MEFs.

Because GFP expression by putative iPSC could result from inappropriate reactivation of the Oct4 locus, we asked whether miRb-transfected iPSCs reached a fully reprogrammed state, both phenotypically and functionally.

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Moreover, these cells had the full capacity to differentiate into three germ layers as indicated by marker analysis Supplemental Fig. These data demonstrated that miRb transfection in iPSCs did not adversely affect their pluripotency. We next sought to identify genes that are directly regulated by miRb. Thus, we performed a genome-wide mRNA expression analysis to detect potential miRb targets. This was not observed in genes that were induced by miRb transfection group 1of which approximately half are normally suppressed during reprogramming uncorrelatedand the other half are increased correlated.

These data suggest that miRb targets a subset of genes that are normally repressed during reprogramming. Genome-wide identification of potential miRb target genes. C List of correlated miRb-repressed genes. D Representative miRb-regulated genes from microarray. Error bar represents two independent experiments with duplicate samples. Total Amarie lee nude were harvested for Western blotting analysis at Day 2 post-transfection with miR mimic. A miRtransfected sample was included as a negative control. Potential target sites were identified based on seed region matches and overall predicted binding energy.

Of 27 genes repressed by miRb by at least twofold, 14 contained at least one predicted miRb target site Supplemental Fig. Among them, Wisp1Tgfbr2and Igfbp5 showed high expression intensity detected by microarray and appeared to have direct miRb target sites. Therefore, they were chosen for further validation. We also noticed that the combination of miR and b showed additive effects on Tgfbr2 repression Supplemental Fig.