GENERATION OF BRACHIAL MOTOR NEURONS FROM MOUSE EMBRYONIC STEM CELLS PASSING THROUGH A NEUROMESODERMAL PROGENITOR STATE
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2019-04-01
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en
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The self-renewing population of cells known as the embryonic stem cells (ESCs) provide a universal source of cells for studying the embryogenesis and human development. Moreover, they represent a suitable in vitro model for the studying and treatment of human diseases as well as drug screening and cell replacement therapies. The in vitro generation of spinal cord lower motor neurons (LMNs) from PSCs has so far remained challenging. LMNs include motor neurons of the brachial spinal cord segment, which is responsible for the forelimb muscle innervation and are among the first MNs to degenerate in the neuromuscular disorder named Amyotrophic Lateral Sclerosis (ALS).
In this study brachial motor neurons were generated from the mouse pluripotent stem cells, passing through a neuromesodermal progenitor (NMP) state, providing a different origin of motor neurons than the anterior neural plate-dependent formation model proposed by Nieuwkoop et al (1952). Moreover, spinal cord patterning events were examined by testing the role of posteriorizing retinoic acid (RA) signaling in the induction of brachial identity as well as manipulating the Sonic Hedgehog (Shh) signaling that acts as a ventralizing factor in order to determine what concentration is the most suitable for the motor pool generation. Additionally, organoids with ventral neural progenitor and motor neuron identities were generated in 3D culture and examined by the immunofluorescence stainings. Together the findings revealed that motor neurons of brachial identity can be successfully generated in vitro by combining RA together with lower concentration of Shh.
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Faculteit der Sociale Wetenschappen