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BMP4 Signaling Plays a Critical Roles in Self-renewal of R2i Mouse Embryonic Stem Cells

ABSTRACT: Mouse embryonic stem cells (mESCs) can be maintained in a pluripotent state under R2i culture conditions that inhibit the TGF-β and ERK signaling pathways. BMP4 is another member of the TGF-β family that plays a crucial role in maintaining the pluripotency state of mESCs. It has been reported that inhibition of BMP4 caused the death of R2i-grown cells. In this study, we used the loss-of-function approach to investigate the role of BMP4 signaling in mESC self-renewal. Inhibition of this pathway with Noggin and dorsomorphin, two bone morphogenetic protein (BMP) antagonists, elicited a quick death of the R2i-grown cells. We showed that the canonical pathway of BMP4 (BMP/SMAD) was dispensable for self-renewal and maintaining pluripotency of these cells. Transcriptome analysis of the BMPi-treated cells revealed that the p53 signaling and two adhesion (AD) and apoptotic mitochondrial change (MT) pathways could be involved in the cell death of the BMPi-treated cells. According to our results, inhibition of BMP4 signaling caused a decrease in cell adhesion and ECM detachment, which triggered anoikis in the R2i-grown cells. Altogether, these findings demonstrate that endogenous BMP signaling is required for survival of mESCs under the R2i condition.

ORGANISM(S): Mus musculus

PROVIDER: GSE174277 | GEO | 2022/05/01

REPOSITORIES: GEO

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Project description:H1299 cells were stably transfected with the Oct4 promoter/GFP or Nestin promoter/GFP reporter vectors. By FACS, 106 cells expressing high levels of GFP were isolated and placed into cell culture for twenty-four hours. Total RNA was used. Bone morphogenetic proteins (BMP) are aberrantly expressed in most lung carcinomas. BMPs mediate cell fate decisions and self-renewal of stem cells. Inhibition of BMP signaling decreases the growth and induces cell death of lung cancer cells lines. It is not known whether the BMP signaling cascade is growth promoting in lung cancer cells expressing the stem cell markers Oct4 and/or nestin. Lung cancer cells expressing Oct4 or nestin were isolated from lung cancer cell lines by stably transfecting the Oct4 promoter or Nestin promoter expression vectors that activate the green fluorescent protein reporter. Our studies support that lung cancer cells activating the Oct4 or nestin promoter are different cell populations. Microarray and quantitative RT-PCR demonstrated that the expression levels of specific stem cell markers were different between the isolated Oct4 and nestin cells. Both the Oct4 and nestin populations were more tumorigenic that controls but histologically they were quite different. The isolated Oct4 and nestin cells also responded differently to inhibition of BMP signaling. Blockade of BMP signaling with the BMP receptor antagonist DMH2 caused significant growth inhibition in both the Oct4 and nestin cell populations but only increased cell death in the nestin population. DMH2 also induced the expression of nestin in the Oct4 population but not in the nestin cells. We also show that BMP signaling is an important regulator of the inhibitor differentiation proteins Id1 and Id3 in Oct4 and nestin cell populations Lung cancer cells expressing Oct4 or nestin were isolated and transfected with Oct4 or Nestin promoter expression vectors that activate the green fluorescent protein reporter. Microarray and quantitative RT-PCR were performed to study the differentially expressed genes. BMPs mediate cell fate decisions and self-renewal of stem cells were investigated.

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BMP4 Signaling Plays a Critical Roles in Self-renewal of R2i Mouse Embryonic Stem Cells

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