Date(s) - 02/26/2016
Engineering Region-specific Cells and Tissue Models for Hindbrain and Spinal Cord Regenerative Medicine
The central nervous system (CNS) consists of diverse tissues containing region-specific cell phenotypes. Recent CNS disease studies have demonstrated that cell therapies and tissue models derived from human pluripotent stem cells (hPSCs) must be patterned with the respective regional phenotypes to exert a regenerative effect or display tissue-specific disease pathologies. However, derivation of cell phenotypes from diverse hindbrain and spinal cord regions has been limited by an inability to deterministically control neural stem cell (NSC) patterning along the posterior CNS’s rostrocaudal axis, which is specified by combinatorial HOX gene expression. Using our chemically defined protocol for deriving homogenous NSC cultures1, we have discovered a biphasic morphogen regimen able to differentiate hPSCs into NSCs from any hindbrain or spinal cord region with discrete, corresponding HOX profiles2. Furthermore, we have discovered that Wnt/b-catenin signaling plays a critical role in ventralizing posterior CNS tissues, and can be harnessed to derive a spectrum of regional Olig2+ progenitors and motor neurons from hPSCs in 2-D culture at high efficiency (>70%). Finally, in synergistic efforts, we are working to combined clickable culture substrates3 with microfluidics to enable spatiotemporal control of NSC tissue morphogenesis in vitro. We aim to merge this technology with our novel hPSC differentiation protocols to engineering regional, organotypic spinal cord slice cultures de novo. Such clinically translatable protocols and engineered culture platforms will significantly expanded scientists’ capabilities to derive promising regenerative cell therapies and model diseases throughout the hindbrain and spinal cord.
Randolph S. Ashton received his B.S. from Hampton University (Hampton, Virginia, 2002) and Ph.D. from Rensselaer Polytechnic Institute (Troy, NY, 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 stems cells and tissue engineering as a 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 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, a Basic Research Award from the UW Institute for Clinical & Translational Research, and research grants from the NIH and EPA.