Abstract
Adult human cardiomyocytes have an extremely limited proliferative capacity, which poses a great barrier to regenerative medicine and research. Human embryonic stem cells (hESCs) have been proposed as an alternative source to generate large numbers of clinical grade cardiomyocytes (CMs) that can have potential therapeutic applications to treat cardiac diseases. Previous studies have shown that bioactive lipids are involved in diverse cellular responses including cardiogenesis. In this study, we explored the novel function of the chemically synthesized bioactive lipid O-cyclic phytosphingosine-1-phosphate (cP1P) as an inducer of cardiac differentiation. Here, we identified cP1P as a novel factor that significantly enhances the differentiation potential of hESCs into cardiomyocytes. Treatment with cP1P augments the beating colony number and contracting area of CMs. Furthermore, we elucidated the molecular mechanism of cP1P regulating SMAD1/5/8 signaling via the ALK3/BMP receptor cascade during cardiac differentiation. Our result provides a new insight for cP1P usage to improve the quality of CM differentiation for regenerative therapies.
Highlights
Cardiovascular diseases are recognized as a global health crisis and a leading cause of deaths worldwide annually
Our results suggest that cyclic phytosphingosine-1-phosphate (cP1P) provides partial stimulation of S1P receptor (S1PR)-mediated SMAD signaling during cardiac differentiation
Our results showed an upregulation in the expression of the S1PR downstream targets RhoA and Rock1 upon cP1P treatment, which decreased upon the inhibition of S1P receptor 1/3 (S1PR1/3) using VPC (Figure 3C)
Summary
Cardiovascular diseases are recognized as a global health crisis and a leading cause of deaths worldwide annually. Cardiomyocyte (CM) damage due to cardiac injury or heart failure cannot be reversed due to the limited regenerative capacity possessed by the adult mammalian heart [1] This limitation has driven several scientists to establish novel methods for generating large numbers of high-purity CMs for therapeutic purposes. The importance of the activin/nodal/transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) pathways during cardiogenesis has been reported [9,10,11] Bioactive lipids such as sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are critical signaling molecules regulating the cell cycle and pluripotency of ESCs [12,13,14] and are necessary for stem cell differentiation and cardiovascular development [15]. Our findings are the first to demonstrate the function of the novel biomolecule cP1P in regulating CM differentiation via the BMPR- and S1PR-mediated signaling pathways
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