Wnt, Activin, and BMP Signaling Regulate Distinct Stages in the Developmental Pathway from Embryonic Stem Cells to Blood

Nostro, M. Cristina; Cheng, Xin; Keller, Gordon; Gadue, Paul

doi:10.1016/j.stem.2007.10.011

Cited by 289 publications

(315 citation statements)

References 49 publications

Supporting

Mentioning

273

Contrasting

Order By: Relevance

“…5F). Our data agree with recent evidence obtained from murine ES cell cultures modeling primitive and definitive hematopoietic programs (7). In these studies, β-catenin, BMP, and Activin signaling synergized to regulate the formation of Flk1 + mesoderm, which has hematopoietic potential, and β-catenin signaling was required for specification of the primitive erythroid lineage (7).…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

Wnt/β-catenin signaling is involved in the induction and maintenance of primitive hematopoiesis in the vertebrate embryo

Tran

Sekkali

Imschoot

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The formation of primitive (embryonic) blood in vertebrates is mediated by spatio-temporally restricted signaling between different tissue layers. In Xenopus , in which primitive blood originates in the ventral blood island, this involves the secretion of bone morphogenetic protein (BMP) ligands by the ectoderm that signal to the underlying mesoderm during gastrulation. Using novel transgenic reporter lines, we report that the canonical Wnt/β-catenin pathway is also activated in the blood islands in Xenopus . Furthermore, Wnt-reporter activity was also detected in the blood islands of the mouse yolk sac. By using morpholino-mediated depletion in Xenopus , we identified Wnt4 as the ligand that is expressed in the mesoderm of the ventral blood island and is essential for the expression of hematopoietic and erythroid marker genes. Injection of an inducible Wnt-interfering construct further showed that, during gastrulation, Wnt/β-catenin signaling is required both in the mesoderm and in the overlying ectoderm for the formation of the ventral blood island. Using recombination assays with embryonic explants, we document that ectodermal BMP4 expression is dependent on Wnt4 signals from the mesoderm. Our results thus reveal a unique role for Wnt4-mediated canonical signaling in the formation and maintenance of the ventral blood island in Xenopus .

show abstract

Section: Discussionsupporting

confidence: 91%

“…Recent studies using in vitro differentiation of ES cells and manipulation of zebrafish embryos point to a role for Wnt signaling in primitive blood development (7,8). However, there is still no direct conclusive evidence for a role for Wnt signaling in the formation of primitive blood in vivo.…”

mentioning

confidence: 99%

Wnt/β-catenin signaling is involved in the induction and maintenance of primitive hematopoiesis in the vertebrate embryo

Tran

Sekkali

Imschoot

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The establishment of a defined and stepwise strategy for generating hematopoietic cells from embryonic stem cells is valuable for the study of early hematopoietic development, and the EB strategy has been reported in the hematopoietic differentiation of mouse embryonic stem cells (mESCs) [8][9][10]. In these systems, hematopoietic differentiation was generally divided into steps containing BRACHYURY + embryonic primitive streak (PS), KDR + /Flk1 + mesoderm and CD41 + hematopoietic progenitor generation.…”

Section: Introductionmentioning

confidence: 99%

TGFβ inhibition enhances the generation of hematopoietic progenitors from human ES cell-derived hemogenic endothelial cells using a stepwise strategy

et al. 2011

View full text Add to dashboard Cite

Embryonic hematopoiesis is a complex process. Elucidating the mechanism regulating hematopoietic differentiation from pluripotent stem cells would allow us to establish a strategy to efficiently generate hematopoietic cells. However, the mechanism governing the generation of hematopoietic progenitors from human embryonic stem cells (hESCs) remains unknown. Here, on the basis of the emergence of CD43 + hematopoietic cells from hemogenic endothelial (HE) cells, we demonstrated that VEGF was essential and sufficient, and that bFGF was synergistic with VEGF to specify the HE cells and the subsequent transition into CD43 + hematopoietic cells. Significantly, we identified TGFβ as a novel signal to regulate hematopoietic development, as the TGFβ inhibitor SB 431542 significantly promoted the transition from HE cells into CD43 + hematopoietic progenitor cells (HPCs) during hESC differentiation. By defining these critical signaling factors during hematopoietic differentiation, we can efficiently generate HPCs from hESCs. Our strategy could offer an in vitro model to study early human hematopoietic development.

show abstract

“…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.…”

mentioning

confidence: 99%

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

et al. 2014

View full text Add to dashboard Cite

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...

show abstract

Wnt, Activin, and BMP Signaling Regulate Distinct Stages in the Developmental Pathway from Embryonic Stem Cells to Blood

Cited by 289 publications

References 49 publications

Wnt/β-catenin signaling is involved in the induction and maintenance of primitive hematopoiesis in the vertebrate embryo

Wnt/β-catenin signaling is involved in the induction and maintenance of primitive hematopoiesis in the vertebrate embryo

TGFβ inhibition enhances the generation of hematopoietic progenitors from human ES cell-derived hemogenic endothelial cells using a stepwise strategy

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

Contact Info

Product

Resources

About