Abstract
We have recently described sustained clinical recovery associated with dampened neuroinflammation and remyelination following transplantation of neural precursor cells (NPCs) derived from human embryonic stem cells (hESCs) in a viral model of the human demyelinating disease multiple sclerosis. The hNPCs used in that study were derived by a novel direct differentiation method (direct differentiation, DD-NPCs) that resulted in a unique gene expression pattern when compared to hNPCs derived by conventional methods. Since the therapeutic potential of human NPCs may differ greatly depending on the method of derivation and culture, we wanted to determine whether NPCs differentiated using conventional methods would be similarly effective in improving clinical outcome under neuroinflammatory demyelinating conditions. For the current study, we utilized hNPCs differentiated from a human induced pluripotent cell line via an embryoid body intermediate stage (EB-NPCs). Intraspinal transplantation of EB-NPCs into mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in decreased accumulation of CD4+ T cells in the central nervous system that was concomitant with reduced demyelination at the site of injection. Dampened neuroinflammation and remyelination was correlated with a transient increase in CD4+FOXP3+ regulatory T cells (Tregs) concentrated within the peripheral lymphatics. However, compared to our earlier study, pathological improvements were modest and did not result in significant clinical recovery. We conclude that the genetic signature of NPCs is critical to their effectiveness in this model of viral-induced neurologic disease. These comparisons will be useful for understanding what factors are critical for the sustained clinical improvement.
Highlights
Multiple sclerosis (MS) is considered a chronic autoimmune disorder affecting the central nervous system (CNS) in which infiltration and accumulation of lymphocytes in the brain and spinal cord leads to demyelination followed by axonal degeneration
In order to evaluate graft survival and migration following intraspinal delivery of embryoid body-like structures (EBs)-Neural precursor cells (NPCs), the feeder-free adapted HDF51iPS1 induced pluripotent stem cells (iPSCs) line was transduced with lentivirus expressing the Photinus pyralis firefly luciferase gene
This method results in heterogeneous cultures of neural stem and precursor cells, neural crest cells, and glial cells, and Human pluripotent stem cells (hPSCs) exhibit variability in their potential to differentiate to NPCs [22, 23]
Summary
Multiple sclerosis (MS) is considered a chronic autoimmune disorder affecting the central nervous system (CNS) in which infiltration and accumulation of lymphocytes in the brain and spinal cord leads to demyelination followed by axonal degeneration. Endogenous myelin repair is not sustainable and gives way to a stage of chronic neurodegeneration and progressive accumulation of disability. Current FDA-approved disease-modifying therapies (DMTs) target the immune component of MS and have demonstrated effectiveness in reducing relapse rates, this is often not sustainable [3]. The most commonly prescribed DMTs do not directly address white matter damage in the CNS and are ineffective at treating advanced stages of MS. There remains an unmet need for a treatment strategy that addresses inflammatory cell infiltration while promoting longterm remyelination
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