miRNA 34a, 100, and 137 modulate differentiation of mouse embryonic stem cells

Tarantino, Carolina; Paolella, Gaetana; Cozzuto, Luca; Minopoli, Giuseppina; Pastore, Lucio; Parisi, Silvia; Russo, Tommaso

doi:10.1096/fj.09-152207

Cited by 131 publications

(123 citation statements)

References 44 publications

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“…MicroRNAs-200 are in fact known to suppress the expression of BMI1, SOX2, KLF4 9 and SIRT1, 10 whereas miR-34a to target SIRT1. 11 Moreover, our bioinformatics research by TargetScan (http:// www.targetscan.org/) indicated the other stem cell markers we analyzed SCA1, FOXA1 and SIRT1 as putative targets of miR-200 family, and KLF4 as a target of miR-34a.…”

Section: Resultsmentioning

confidence: 99%

“…9,20,21 MiR-34a, first identified as direct transcriptional target of p53, 22 has been found to regulate apoptosis, 23,24 expression of metabolic enzymes in the liver 16 and embryonic stem cells differentiation. 11 We gathered a number of evidences regarding Snail: (1) hepatic stem cells constitutively express Snail; (2) their spontaneous differentiation into hepatocytes is underlined by negative regulation of Snail expression; (3) Snail silencing causes downregulation of stemness markers; (4) its ectopic expression in hepatocytes is sufficient both to restore expression of several stemness markers and (5) to repress miR-200c and -34a. This latter activity is probably due to a direct mechanism as suggested by the binding of endogenous Snail to miR-200c and -34a promoters in RLSC and in RLSCdH induced to EMT by TGF-b.…”

Section: Discussionmentioning

confidence: 99%

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An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

et al. 2011

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Preservation of the epithelial state involves the stable repression of epithelial-to-mesenchymal transition program, whereas maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular minicircuitry between master elements of these biological processes might provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4a, directly represses the expression of the epithelial microRNAs (miRs)-200c and -34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4a, previously identified as a transcriptional repressor of Cellular differentiation implies an orchestrated sequence of events guiding stem cells/precursors toward specialized cell types based on the contemporary and strictly correlated phenomena of loss of stemness and acquisition of histotypic markers and functions. The homeostasis of the stem cell compartment requires mechanisms actively counteracting differentiation; 1 similarly, the maintenance of the differentiated state involves a stable repression of elements capable to induce morphological transition and dedifferentiation. 2 The observation that a number of stem cells are restricted to a specific differentiation fate suggests that elements pivotal for the coordinated execution of the opposite processes could be tissue-specific. Considering that stem cell compartments are rare and give rise to a heterogeneous cellular population capable to reversibly shift among different states, 3 the availability of a stable stem cell line executing specific differentiation programs discloses an unique possibility to investigate mechanisms regulating alternative cellular choices. A simple and direct molecular mini-circuitry of master elements of mutually exclusive biological processes, also able to reciprocally influence their own expression, may provide the theoretically best device to trigger such complex phenomena.We previously characterized a number of stable liver stem cell lines named RLSCs (from resident liver stem cells) that spontaneously acquire an epithelial morphology and differentiate into hepatocytes (named RLSCdH from RLSC-derived hepatocytes). Notably, RLSCs were also proved to recapitulate the hepatocyte post-differentiation patterning defined as 'zonation': their spontaneous differentiation, in fact, generates periportal hepatocytes that may be induced to switch into perivenular hepatocytes by means of the convergence of Wnt signaling on the HNF4a-driven transcription. 4 Furthermore, we identified a simple cross-regulatory circuitry between HNF4a (master regulator of hepatocyte differentiation) and Snail (master regulator of the epithelial-to-mesenchymal transition, EMT), whose expression is mutually exclusive because of their direct reciprocal transcriptional repression. 2,5 These findings, relevant for the comprehension of the EMT and of the reverse process mesenchymal-...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

et al. 2011

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“…As miR-34a, which is a direct target of p53, has been well-characterized as an apoptosis executor through direct targeting of apoptosis-related genes including bcl-2, it is very likely that the distinctive regulation of miR-34a accounts for the differential apoptosis mechanism observed between MSCs and De-MSCs on oxidative stress. Conversely, a role for miR-34a in cell differentiation has been recently reported [63][64][65]. Intriguingly, Aranha et al has demonstrated that overexpression of miR-34a increases the proportion of postmitotic neurons in distinct models of neural differentiation including mouse embryonic stem cells and neural stem cells.…”

Section: Discussionmentioning

confidence: 99%

Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved Therapeutic Potential

et al. 2011

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Stem cell transplantation has been shown to improve functional outcome in degenerative and ischemic disorders. However, low in vivo survival and differentiation potential of the transplanted cells limits their overall effectiveness and thus clinical usage. Here we show that, after in vitro induction of neuronal differentiation and dedifferentiation, on withdrawal of extrinsic factors, mesenchymal stem cells (MSCs) derived from bone marrow, which have already committed to neuronal lineage, revert to a primitive cell population (dedifferentiated MSCs) retaining stem cell characteristics but exhibiting a reprogrammed phenotype distinct from their original counterparts. Of therapeutic interest, the dedifferentiated MSCs exhibited enhanced cell survival and higher efficacy in neuronal differentiation compared to unmanipulated MSCs both in vitro and in vivo, with significantly improved cognition function in a neonatal hypoxic-ischemic brain damage rat model. Increased expression of bcl-2 family proteins and micro-RNA-34a appears to be the important mechanism giving rise to this previously undefined stem cell population that may provide a novel treatment strategy with improved therapeutic efficacy.

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“…17 We have studied the expression profiles of miRNAs during mouse ESC differentiation. 18 Among these miRs, we found that miR-125a regulates the fine balance between BMP4 and Nodal/Activin pathways in the initial phases of ESC differentiation. 19 This regulation occurs through an efficient auto-regulatory loop in which BMP4 controls the transcription of miR-125a that targets the BMP4 co-receptor, Dies1.…”

mentioning

confidence: 86%

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

et al. 2014

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Numerous studies have indicated that BMP4 signaling is involved in the regulation of the early steps of development. In mouse embryonic stem cells (ESCs), BMP4 is crucial to sustain pluripotency and blocks differentiation towards neural fate. Here, through a systematic analysis of miRNAs in ESCs, we establish that BMP4 signaling regulates miR-23a, 27a and 24-2, through the recruitment of phospho-Smads at the promoter of the gene encoding this miRNA cluster. Suppression of miR-23a/b, 27a/b and 24 does not affect self-renewal or pluripotency, but induces an evident change of ESC differentiation, with a significant increase of the cells undergoing apoptosis after the transition from ESCs to epiblast stem cells (EpiSCs). BMP4 has been previously reported to cause apoptosis during ESC differentiation. By blocking BMP4 signaling, we completely prevent the apoptosis induced by suppression of the miRs. This suggests that the effects of miR suppression are the result of enhanced BMP4 signaling. This hypothesis is further supported by the observation that Smad5, the transcription factor downstream of the BMP4 receptor, is targeted by the miRNAs of the 23a and 23b clusters. Altogether, our results highlight the existence of a regulatory loop, involving Smad5 and the miR-23a clusters, that modulates the apoptotic response of ESCs to BMP4. Cell Death and Differentiation (2015) 22, 1047-1057 doi:10.1038/cdd.2014; published online 5 December 2014ESCs represent a precious experimental model of the early stages of embryo development. They can be grown indefinitely in vitro and induced to differentiate, thus mimicking two events taking place in the blastocyst: (i) the differentiation of the cells of the inner cell mass into epiblast cells and (ii) the commitment of epiblast cells to neuroectodermal or mesendodermal precursors. 1,2 These differentiation events are regulated by extrinsic signals. BMP4, a member of the TGF-β superfamily of cytokines, has a crucial role in ESCs. Many results indicate that it is able, together with LIF, to maintain mouse ESCs in the pluripotent state. 3 This effect is mediated by the regulation of many direct targets of Smad1, 5 and 8, the transcription factors downstream of the BMP4 receptor. 4 BMP4 also contributes to govern early steps of differentiation. First, BMP4 acts by regulating ESC-epiblast transition and then by suppressing neural differentiation and promoting non-neural lineage formation. 2 Moreover, BMP4 promotes the differentiation towards mesendodermal lineages and also regulates, either positively or negatively, the further commitment of mesendodermal precursors into their different fates. [5][6][7][8] Gene expression in ESCs is regulated by a complex network of transcription factors. 9,10 In addition, numerous results indicate that miRNAs are crucial regulators of the gene expression programs that drive ESC differentiation. Suppression of miRNA biogenesis, obtained by knocking out Dicer or DCGR8 genes, leads to an early arrest of mouse embryonic development and of in vitro differenti...

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miRNA 34a, 100, and 137 modulate differentiation of mouse embryonic stem cells

Cited by 131 publications

References 44 publications

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved Therapeutic Potential

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

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