Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells

Abstract

BackgroundPluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types.Methodology/ Principal FindingsWe describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells.Conclusions/ SignificanceAdministration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine.

IdGene Regulation and Function in the Prosensory Domains of the Chicken Inner Ear: A Link between Bmp Signaling andAtoh1

“…This is consistent with the fast turnover of the Id mRNA and protein which have reported half-lives of 20 -60 min, depending on the cell type (Deed et al, 1996;Bounpheng et al, 1999;Norton, 2000). Dorsomorphin specifically blocks the phosphorylation of R-Smad mediated by type I Bmp-receptors without affecting other signaling pathways that can be activated by Bmps (Anderson and Darshan, 2008;Cuny et al, 2008;Hao et al, 2008;Yu et al, 2008). This suggests that Id expression in the prosensory domains of the early otocyst depends strictly on the steady activation of the Bmpinduced Smad signaling pathway.…”

Nodal Signaling Regulates the Bone Morphogenic Protein Pluripotency Pathway in Mouse Embryonic Stem Cells

“…Dorsomorphin, a selective small-molecule inhibitor to the type I BMP-responsive receptors (ALK2/3/6), has recently been identified to block BMP-mediated Smad1/5 phosphorylation (40,41). To determine if the Id induction elicited by SB431542 treatment is indirectly mediated through BMP signaling, an analysis of cells treated with SB431542 and dorsomorphin was performed.…”

Link Protein N-terminal Peptide Binds to Bone Morphogenetic Protein (BMP) Type II Receptor and Drives Matrix Protein Expression in Rabbit Intervertebral Disc Cells

“…To prove a specific role for BMP signaling pathways in LPPmediated cell responses, we employed a specific BMP type I receptor (BMP-RI) antagonist, dorsomorphin, which specifically inhibits BMP-RI-mediated signal transduction and thus blocks BMP-induced Smad1/5/8 phosphorylation (37,38). As a control we utilized SB-431542, a specific inhibitor that blocks TGF␤-mediated Smad2/3 phosphorylation.…”