Toma JS, Shettar BC, Chipman PH, Pinto DM, Borowska JP, Ichida JK, Fawcett JP, Zhang Y, Eggan K, Rafuse VF. 2015. Motoneurons derived from induced pluripotent stem cells develop mature phenotypes typical of endogenous spinal motoneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(3):1291-306. Pubmed: 25609642 DOI:10.1523/JNEUROSCI.2126-14.2015


Induced pluripotent cell-derived motoneurons (iPSCMNs) are sought for use in cell replacement therapies and treatment strategies for motoneuron diseases such as amyotrophic lateral sclerosis (ALS). However, much remains unknown about the physiological properties of iPSCMNs and how they compare with endogenous spinal motoneurons or embryonic stem cell-derived motoneurons (ESCMNs). In the present study, we first used a proteomic approach and compared protein expression profiles between iPSCMNs and ESCMNs to show that <4% of the proteins identified were differentially regulated. Like ESCs, we found that mouse iPSCs treated with retinoic acid and a smoothened agonist differentiated into motoneurons expressing the LIM homeodomain protein Lhx3. When transplanted into the neural tube of developing chick embryos, iPSCMNs selectively targeted muscles normally innervated by Lhx3 motoneurons. In vitro studies showed that iPSCMNs form anatomically mature and functional neuromuscular junctions (NMJs) when cocultured with chick myofibers for several weeks. Electrophysiologically, iPSCMNs developed passive membrane and firing characteristic typical of postnatal motoneurons after several weeks in culture. Finally, iPSCMNs grafted into transected mouse tibial nerve projected axons to denervated gastrocnemius muscle fibers, where they formed functional NMJs, restored contractile force. and attenuated denervation atrophy. Together, iPSCMNs possess many of the same cellular and physiological characteristics as ESCMNs and endogenous spinal motoneurons. These results further justify using iPSCMNs as a source of motoneurons for cell replacement therapies and to study motoneuron diseases such as ALS.
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Kevin Eggan investigates the mechanisms that cause motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS), and seeks to translate new discoveries into new therapeutic options for patients.

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