Our recently work show that glial restricted precursor cells (GRPs), grafted into a demyelinating or contusive spinal cord injury (SCI), partially restore electrophysiological conduction and hindlimb locomotor recovery. We will build on those data and determine the potential of human embryonic stem cells (hESC) to restore function after engraftment into the damaged spinal cord.
Aim 1. Using the focal VLF+DLF demyelinating lesion and grafting D15A-GRPs (A2B5+/NG2+/O4-), we will determine whether inhibition of BMP and Notch signaling pathways, demonstrated in vitro to inhibit oligodendrocyte differentiation, can enhance the remyelination capacity of the engrafted cells. We will examine a number of genetic and molecular biological approaches to inhibiting BMP and Notch signaling.
Aim 2. Determine whether delivery of CNTF or NRG1 types I or III, neurotrophic factors known to potentiate oligodendrocyte proliferation and maturation in vitro and in vivo, will enhance remyelination by engrafted GRPs.
Aim 3. Using optimal parameters established in Aims 1 and 2 and the more clinically relevant contusion SCI, we will ask whether remyelination can result in enhanced recovery of function. We hypothesize that both remyelination and enhanced white matter sparing are needed for optimal recovery and will distinguish between those effects in these animals.
|Kuypers, Nicholas J; Bankston, Andrew N; Howard, Russell M et al. (2016) Remyelinating Oligodendrocyte Precursor Cell miRNAs from the Sfmbt2 Cluster Promote Cell Cycle Arrest and Differentiation. J Neurosci 36:1698-710|
|Myers, Scott A; Bankston, Andrew N; Burke, Darlene A et al. (2016) Does the preclinical evidence for functional remyelination following myelinating cell engraftment into the injured spinal cord support progression to clinical trials? Exp Neurol 283:560-72|
|Ohri, Sujata Saraswat; Mullins, Ashley; Hetman, Michal et al. (2014) Inhibition of GADD34, the stress-inducible regulatory subunit of the endoplasmic reticulum stress response, does not enhance functional recovery after spinal cord injury. PLoS One 9:e109703|
|Kuypers, Nicholas J; James, Kurtis T; Enzmann, Gaby U et al. (2013) Functional consequences of ethidium bromide demyelination of the mouse ventral spinal cord. Exp Neurol 247:615-22|
|Ohri, Sujata Saraswat; Hetman, Michal; Whittemore, Scott R (2013) Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury. Neurobiol Dis 58:29-37|
|Dincman, Toros A; Beare, Jason E; Ohri, Sujata Saraswat et al. (2012) Isolation of cortical mouse oligodendrocyte precursor cells. J Neurosci Methods 209:219-26|
|Ohri, Sujata Saraswat; Maddie, Melissa A; Zhang, Yiping et al. (2012) Deletion of the pro-apoptotic endoplasmic reticulum stress response effector CHOP does not result in improved locomotor function after severe contusive spinal cord injury. J Neurotrauma 29:579-88|
|Wang, Yaping; Cheng, Xiaoxin; He, Qian et al. (2011) Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins. J Neurosci 31:6053-8|
|Ohri, Sujata Saraswat; Maddie, Melissa A; Zhao, Yongmei et al. (2011) Attenuating the endoplasmic reticulum stress response improves functional recovery after spinal cord injury. Glia 59:1489-502|
|Cao, Qilin; He, Qian; Wang, Yaping et al. (2010) Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury. J Neurosci 30:2989-3001|
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