Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.
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.
Department of Molecular Biology & Biochemistry, Sue and Bill Gross Stem Cell Center, Multiple Sclerosis Research Center, Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
Warren C
WC
Plaisted
Department of Molecular Biology & Biochemistry, Sue and Bill Gross Stem Cell Center, Multiple Sclerosis Research Center, Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
Angel
A
Zavala
Department of Molecular Biology & Biochemistry, Sue and Bill Gross Stem Cell Center, Multiple Sclerosis Research Center, Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
Edna
E
Hingco
Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, United States of America.
Ha
H
Tran
Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, United States of America.
Ronald
R
Coleman
Department of Pathology, University of Utah, School of Medicine, Salt Lake City, Utah, United States of America.
Thomas E
TE
Lane
Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, United States of America.
Jeanne F
JF
Loring
Department of Molecular Biology & Biochemistry, Sue and Bill Gross Stem Cell Center, Multiple Sclerosis Research Center, Institute for Immunology, University of California Irvine, Irvine, California, United States of America.
Craig M
CM
Walsh
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D018352:Coronavirus Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D004195:Disease Models, Animal; D058732:Embryoid Bodies / Q000166:cytology / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D006517:Murine hepatitis virus / Q000254:growth & development / Q000472:pathogenicity; D009186:Myelin Sheath / Q000276:immunology; D058953:Neural Stem Cells / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D009928:Organ Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
D015415:Biomarkers; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse