BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors

Gambaro, Karen; Aberdam, Édith; Virolle, Thierry; Aberdam, Daniel; Rouleau, Matthieu

doi:10.1038/sj.cdd.4401799

Cited by 84 publications

(79 citation statements)

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“…The latter instead function by counteracting the apoptosis induced by BMP4. Indeed, it was previously demonstrated that low doses of BMP4 are able to induce the apoptosis of ESCs, 29 and we demonstrated that suppression of the miRs of the 23a and 23b clusters leads to massive apoptosis of differentiating cells. Therefore, the results support the possibility that the accumulation of these miRs is intended to protect ESCs from an inappropriate apoptosis induced by BMP4.…”

Section: Discussionsupporting

confidence: 53%

“…2 In contrast, it was also observed that low doses of BMP4 induce apoptosis during epidermal differentiation of ESCs. 29 We reasoned that suppression of miR-clusters can result in an enhancement of the endogenous signaling that mimics the exposure of the cells to low doses of BMP4. Thus, we treated ESCs with different doses of BMP4 and the onset of apoptotic phenotype was analyzed by measuring the level of cleaved caspase-3.…”

mentioning

confidence: 99%

“…Moreover, Rogler et al 30 have demonstrated that the miRNAs of 23b cluster target Smad3, 4 and 5 in liver stem cells. 29 We first analyzed the expression profiles of these Smads in ESCs and during differentiation. We found that Smad3 is almost undetectable in ESCs and in the first days of differentiation.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 53%

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confidence: 99%

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

et al. 2014

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“…Similarly, no change in expression of ectodermal markers, including inhibin ␤ B, Fgf5, and neurofilament-200 (N-200;Roche et al, 2005; Fig. 6A,B), or in the expression of the neuronal precursor cell marker, Sox1 (Gambaro et al, 2006) was observed in Gcn5 Ϫ/Ϫ EBs. However, the timing of expression of some mesodermal marker genes was altered in the mutant EBs.…”

Section: Gcn5 Null Es Cells Differentiate Into Ectoderm Mesoderm Anmentioning

confidence: 92%

Developmental potential of Gcn5^−/− embryonic stem cells in vivo and in vitro

Lin

Srajer

Evrard

et al. 2007

Developmental Dynamics

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Gcn5 is a prototypical histone acetyltransferase (HAT) that serves as a coactivator for multiple DNA-bound transcription factors. We previously determined that deletion of Gcn512 (hereafter referred to as Gcn5) causes embryonic lethality in mice. Gcn5 null embryos undergo gastrulation but exhibit high levels of apoptosis, leading to loss of mesodermal lineages. To further define the functions of Gcn5 during development, we created Gcn5 ؊/؊ mouse embryonic stem (ES) cells. These cells survived in vitro and formed embryoid bodies (EBs) that expressed markers for ectodermal, mesodermal, and endodermal lineages.

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“…38,39 Thus the free virus group may perform similar to the lyophilization group in a limited medium environment. Because reducing the infection volume is impractical for in vivo delivery, we localized adenovirus on the material surface by lyophilizing with appropriate excipients that enhanced virus adhesion.…”

Section: Discussionmentioning

confidence: 99%

Localized viral vector delivery to enhance in situ regenerative gene therapy

Wang

Hollister

et al. 2007

Gene Ther

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A lyophilization method was developed to locally release adenoviral vectors directly from biomaterials for in situ regenerative gene therapy. Adenovirus expressing a b-galactosidase reporter gene (AdLacZ) was mixed with different excipient formulations and lyophilized on hydroxyapatite (HA) disks followed by fibroblasts culturing and 5-bromo-4-chloro-3-indolyl-b-D-galactopyranoside (X-gal) staining, suggesting 1 M sucrose in phosphate-buffered saline had best viability. Adenovirus release studies showed that greater than 30% virus remained on the material surface up to 16 h. Lyophilized adenovirus could be precisely localized in defined patterns and the transduction efficiency was also improved. To determine if the lyophilization formulations could preserve viral bioactivity, the lyophilized AdLacZ was tested after being stored at varying temperatures. Bioactivity of adenovirus lyophilized on HA was maintained for greater than 6 months when stored at À801C. In vivo studies were performed using an adenovirus encoding BMP-2 (AdBMP-2). AdBMP-2 was lyophilized in gelatin sponges and placed into rat critical-size calvarial defects for 5 weeks. Micro-computed tomography (m-CT) analysis demonstrated that free-form delivery of AdBMP-2 had only modest effects on bone formation. In contrast, AdBMP-2 lyophilized in gelatin sponges led to more than 80% regeneration of critical-size calvarial defects. Gene Therapy (2007) 14, 891-901.

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BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors

Cited by 84 publications

References 41 publications

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

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

Developmental potential of Gcn5^−/− embryonic stem cells in vivo and in vitro

Localized viral vector delivery to enhance in situ regenerative gene therapy

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BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors

Cited by 84 publications

References 41 publications

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

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

Developmental potential of Gcn5−/− embryonic stem cells in vivo and in vitro

Localized viral vector delivery to enhance in situ regenerative gene therapy

Contact Info

Product

Resources

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Developmental potential of Gcn5^−/− embryonic stem cells in vivo and in vitro