Abstract
BackgroundEmbryonic stem (ES) cells have unlimited proliferation potential, and can differentiate into several cell types, which represent ideal sources for cell-based therapy. This high-level proliferative ability is attributed to an unusual type of cell cycle. The Signaling pathways that regulate the proliferation of ES cells are of great interest.Methodology/Principal FindingsIn this study, we show that murine ES cells specifically express brain natriuretic peptide (BNP), and its signaling is essential for ES cell proliferation. We found that BNP and its receptor (NPR-A, natriuretic peptide receptor-A) were highly expressed in self-renewing murine ES cells, whereas the levels were markedly reduced after ES cell differentiation by the withdrawal of LIF. Targeting of BNP with short interfering RNA (siRNA) resulted in the inhibition of ES cell proliferation, as indicated by a marked reduction in the cell number and colony size, a significant reduction in DNA synthesis, and decreased numbers of cells in S phase. BNP knockdown in ES cells led to the up-regulation of gamma-aminobutyric acid receptor A (GABAAR) genes, and activation of phosphorylated histone (γ-H2AX), which negatively affects ES cell proliferation. In addition, knockdown of BNP increased the rate of apoptosis and reduced the expression of the transcription factor Ets-1.Conclusions/SignificanceAppropriate BNP expression is essential for the maintenance of ES cell propagation. These findings establish BNP as a novel endogenous regulator of ES cell proliferation.
Highlights
Embryonic stem (ES) cells have the remarkable capacity to divide indefinitely while retaining their wide range differentiation potential, and they represent a promising source for cell transplantation therapies [1]
Brain natriuretic peptide (BNP), a member of natriuretic peptide family, is produced predominately in the heart [4,5], and recently, we have shown that BNP is expressed in ES cell-derived cardiomyocytes [6].The physiological effects of natriuretic peptides are initiated by binding to two particulate guanylate cyclase receptors; natriuretic peptide receptor type A (NPR-A), which is sensitive to ANP and BNP [7], natriuretic peptide receptor type B (NPR-B), which is specific for CNP (c-type natriuretic peptide) [8] to produce intracellular cyclic guanosine monophosphate in response to hormone binding [7]
We found that BNP and its receptor NPR-A are expressed in selfrenewing ES cells, and the BNP signaling plays an important role in maintaining the proliferation of ES cells by inhibiting GABAAR and Ets-1 genes
Summary
Embryonic stem (ES) cells have the remarkable capacity to divide indefinitely while retaining their wide range differentiation potential, and they represent a promising source for cell transplantation therapies [1]. They exhibit a very unusual cell cycle structure, characterized by a short G1 phase and a high proportion of cells in the S phase [2,3], which is associated with a unique mechanism of cell cycle regulation. Embryonic stem (ES) cells have unlimited proliferation potential, and can differentiate into several cell types, which represent ideal sources for cell-based therapy This high-level proliferative ability is attributed to an unusual type of cell cycle. The Signaling pathways that regulate the proliferation of ES cells are of great interest
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