Key result
Small molecule inhibition of TGF-β signalling with A83-01 induced the expansion of neonatal Nkx2.5-eGFP+ cardiomyoblasts, an effect dependent on MEK signalling.
Small molecule inhibition of TGF-β signaling with A83-01 promotes the expansion of postnatal Nkx2.5+ cardiomyoblasts, offering a potential strategy for cardiomyogenesis.
Should not yet change practice; leaves open TGF-β/MEK modulation to expand neonatal cardiomyoblasts.
Abstract •Introduction to postnatal cardiac progenitor cells •Methods to examine postnatal CPCs with small molecules ‐Transgenic mice ‐Cell culture ‐Measurement of cell proliferation ‐Flow cytometry ‐Immunofluorescence ‐Chemical reagents •Results and discussion of small molecule effects on CPCs ‐Modulation of TGF‐β but not activin A or BMP2 signalling affects smooth muscle cell differentiation of neonatal Nkx2.5 + cardiomyoblasts ‐Small molecule inhibition of Alk receptors induces an expansion of neonatal Nkx2.5‐eGFP + cells While recent data have supported the capacity for a neonatal heart to undergo cardiomyogenesis, it is unclear whether these new cardiomyocytes arise from an immature cardiomyoblast population or from the division of mature cardiomyocytes. By following the expression of enhanced Green Fluorescent Protein ( eGFP ) in an Nkx 2.5 enhancer‐ eGFP transgenic mice, we have identified a population of immature cells that can undergo cardiomyogenic as well as smooth muscle cell differentiation in the neonatal heart. Here, we examined growth factors and small molecule regulators that potentially regulate the proliferation and cardiomyogenic versus smooth muscle cell differentiation of neonatal Nkx 2.5‐ GFP + cells in vitro . We found that A 83‐01 ( A 83), an inhibitor of TGF ‐βRI, was able to induce an expansion of neonatal Nkx 2.5‐ eGFP + cells. In addition, the ability of A 83 to expand eGFP + cells in culture was dependent on signalling from the mitogen‐activated protein kinase kinase ( MEK ) as treatment with a MEK inhibitor, PD 0325901, abolished this effect. On the other hand, activation of neonatal Nkx 2.5‐ eGFP + cells with TGF ‐β1, but not activin A nor BMP 2, led to smooth muscle cell differentiation, an effect that can be reversed by treatment with A 83. In summary, small molecule inhibition of TGF ‐β signalling may be a promising strategy to induce the expansion of a rare population of postnatal cardiomyoblasts.
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Chen et al. (2011) studied Postnatal cardiac progenitor cells. A83-01 (TGF-βRI inhibitor) was evaluated on Expansion and differentiation of neonatal Nkx2.5-eGFP+ cells. Small molecule inhibition of TGF-β signalling with A83-01 induced the expansion of neonatal Nkx2.5-eGFP+ cardiomyoblasts, an effect dependent on MEK signalling.
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