In 2008, Yu et al. identified a compound that dorsalizes structures in growing zebrafish embryos, which they named dorsomorphin. This compound inhibits the bone morphogenetic protein (BMP) signaling pathway, which plays an important role in development and cell differentiation.
Recently, Valizadeh-Arshad et al. hypothesized that small molecules like dorsomorphin could be used to promote human embryonic stem cells to differentiate into motor neurons. One of the goals of regenerative medicine is to produce tissues such as neurons from stem cells, to heal nerve damage that will not heal on its own. Currently, coaxing embryonic stem cells to differentiate into motor neurons is expensive and inefficient.
The researchers modified an existing motor neuron differentiation protocol to include a cocktail of small molecules that have shown promise in previous studies: all-trans retinoic acid, dorsomorphin, A8301, and XAV939. They cultured the embryonic stem cells on plates, and exposed the cells to the small molecules as well as established differentiation factors.
They then used flow cytometry and immunofluorescence staining on the cells to test for expression of genes associated with neurons, such as NESTIN, PAX6, and MAP2. The cells expressed these marker genes with efficiencies greater than 50%. The cells showed voltage-gated currents in a patch-clamp experiment, suggesting the presence of both K+ and Ca++/Na+ channels. However, the cells were unable to generate more than single action potentials. More research needs to be done before this cell differentiation method can produce mature motor neurons.
Valizadeh-Arshad Z, Shahbazi E, Hashemizadeh S, Moradmand A, Jangkhah M, Kiani S. In Vitro Differentiation of Neural-Like Cells from Human Embryonic Stem Cells by A Combination of Dorsomorphin, XAV939, and A8301. Cell J. 2018 19:4. doi: 10.1038/nbt1201-1129.
Yu PB, Hong CC, Sachidanandan C, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2007;4(1):33–41. doi:10.1038/nchembio.2007.54.