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Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.

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.

SUBMITTER: Plaisted WC

PROVIDER: S-EPMC4911106 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.

Plaisted Warren C WC Zavala Angel A Hingco Edna E Tran Ha H Coleman Ronald R Lane Thomas E TE Loring Jeanne F JF Walsh Craig M CM

PloS one 20160616 6

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 conv ...[more]

PMID: 27310015

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Project description: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. In order to test the general applicability of NPC transplantation, we developed a new method for the differentiation and purification of NPCs from pluripotent stem cells (PSCs). Herein, we investigated the therapeutic potential of NPCs generated from human induced pluripotent stem cells (iPSCs) in mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) that induces an immune-mediated demyelinating disease sharing clinical and histologic similarities to the human demyelinating disease multiple sclerosis (MS). JHMV-infected mice intraspinally transplanted with EB (embryoid body)-derived NPCs (EB-NPCs) exhibited 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. Importantly, pathological improvements were limited in comparison to our previous report on hESC-derived NPCs and did not result in significant clinical recovery. Further examination of EB-NPCs by whole genome expression analysis showed them to be significantly different than our previously published cells. These findings highlight an intrinsic disparity in the therapeutic potential of NPCs generated from pluripotent stem cells. Pluripotent stem cells were differentiated to neural precursor cells (NPCs) by two separate methods to study the differences in final cell type. The first method was a 4 factor 9 day directed differentiation. This was applied to WA09 embryonic stem cells (ESCs) as well as two lines of induced pluripotent stem cells (iPSCs) that were developed in our lab HDF51iPSC and HDF69iPSC. The other method was a multistep process that included transition through an embryoid body (EB) stage. This was done with the used on the HDF51iPCS line. For controls we used the original pluripotent stem cell lines (WA09, HDF51iPSC and HDF69iPSC) as well as HDF417 which is a human dermal fibroblast line collected by our lab.

Dataset Information

Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.

Publications

Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.

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