AUG 30, 2016 08:00 AM PDT

Derivation of a Spectrum of Regional Motor Neuron Phenotypes for Hindbrain and Spinal Cord Regenerative Medicine

  • Assistant Professor, Department of Biomedical Engineering and Wisconsin Institute for Discovery- BIONATES, University of Wisconsin-Madison
      Randolph S. Ashton received his B.S. from Hampton University in 2002 and Ph.D. from Rensselaer Polytechnic Institute in 2007 in Chemical Engineering. During graduate studies under Prof. Ravi Kane, he researched how engineering biomaterials at the nanoscale could regulate the fate of adult neural stem cells. He continued to pursue his interest in stem cells and tissue engineering at the California Institute for Regenerative Medicine and a NIH postdoctoral fellow at the University of California, Berkeley's Stem Cell Center in the lab of Prof. David Schaffer. In 2011, he was appointed to a faculty position in the Wisconsin Institute for Discovery at the University of Wisconsin-Madison as an Assistant Professor of Biomedical Engineering. The goal of Dr. Ashton's research is to provide novel regenerative therapies to treat CNS diseases and injury. His lab is currently developing scalable protocols to generate region-specific central nervous system tissues from human pluripotent stem cells (hPSCs). They also meld state-of-the-art biomaterial approaches with hPSC-derived neural stem cells to engineer brain and spinal cord tissue models in vitro. Among his awards and honors, Dr. Ashton was named the 2016 Young Faculty Investigator Awardee by the Regenerative Medicine Workshop at Hilton Head, a 2015 Emerging Investigator by Chemical Communications, and a 2013 Rising Star by the Biomedical Engineering Society's Cellular and Molecular Bioengineering Special Interest Group. Also, he has been awarded a Burroughs Wellcome Fund Innovation in Regulatory Science Award, a Draper Technology Innovation Award from the Wisconsin Alumni Research Foundation, and a Basic Research Award from the UW Institute for Clinical & Translational Research. His research is also supported by grants from the NIH and EPA.

    The central nervous system (CNS) is a conglomerate of diverse, interconnected tissues that each contain cell phenotypes specific to their distinct anatomical region. Recent studies have demonstrated that CNS cells derived from human pluripotent stem cells (hPSCs) must be of the appropriate regional phenotype to model tissue-specific disease pathologies in vitro as well as produce a regenerative effect upon transplantation. Yet, only a limited number of regional CNS phenotypes can be derived from hPSCs due to the complex regimen of developmental cues necessary to effectively instruct region-specific neural differentiation.
    Here, we present a chemically defined protocol for deriving forebrain neural stem cells (NSCs) from hPSCs with greater than 90% efficiency in under 6 days (Lippmann et al. Stem Cells 2014). Also, we have successfully deciphered the regimen of developmental cues that govern differentiation of hPSCs into NSC phenotypes specific to any diverse hindbrain or spinal cord region (Lippmann et al. Stem Cell Reports 2015). These NSC cultures can be differentiated into a spectrum of respective regional hindbrain and spinal cord motor neuron phenotypes, which can be matured to fire action potentials and innervate skeletal muscle fibers in vitro.
    Hence, our chemically defined protocols vastly expand the diversity of regional CNS phenotypes that can be derived from hPSCs. They enable access to the hundreds of different regional motor neuron phenotypes present in the human hindbrain and spinal cord, which are the sole means of transmitting efferent signals from the CNS to peripheral tissues including skeletal muscles that provide motor function. Our findings have significant implications for modeling degenerative disorders that target hindbrain and spinal cord motor neurons (e.g. Amyotrophic Lateral Sclerosis) and developing regenerative cell therapies for paralysis.    

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