TY - JOUR
T1 - A cord blood monocyte–derived cell therapy product accelerates brain remyelination
AU - Saha, Arjun
AU - Buntz, Susan
AU - Scotland, Paula
AU - Xu, Li
AU - Noeldner, Pamela
AU - Patel, Sachit
AU - Wollish, Amy
AU - Gunaratne, Aruni
AU - Gentry, Tracy
AU - Troy, Jesse
AU - Matsushima, Glenn K.
AU - Kurtzberg, Joanne
AU - Balber, Andrew E.
N1 - Funding Information:
The authors are grateful to the staff at the Carolinas Cord Blood Bank for providing cord blood units for the experiments described, Lynn Cheatham for help with graphics, Marcia Bentz and Roderick Franczak for helping in tissue preparation and staining, Neil Medvitz of Duke Pathology for performing electron microscopy, April Ozamiz, Benjamin Rusche, Norin Meadows, and Frankie Shaw of the GMP lab for helping with DUOC-01 cells preparation, David Snyder of Department of Surgery for IC injections, Michael Cook at the Duke Cancer Institute Core Flow Cytometry Facility for assistance with cell sorting, Zhengzheng Wei at the Duke Institute for Genomic Sciences Microarray Core Facility for performing and helping analyze microar-ray data, and to Benjamin Carlson at the Light Microscopy Core Facility at Duke University for assistance with image analysis. Amy Wollish was supported by a National Cancer Institute of the National Institutes of Health Award (grant 5T32CA074736, Research Training in Neuro-Oncology). This work was supported by the Julian Robertson Foundation and by the Marcus Foundation.
Funding Information:
The authors are grateful to the staff at the Carolinas Cord Blood Bank for providing cord blood units for the experiments described, Lynn Cheatham for help with graphics, Marcia Bentz and Roderick Franczak for helping in tissue preparation and staining, Neil Medvitz of Duke Pathology for performing electron microscopy, April Ozamiz, Benjamin Rusche, Norin Meadows, and Frankie Shaw of the GMP lab for helping with DUOC-01 cells preparation, David Snyder of Department of Surgery for IC injections, Michael Cook at the Duke Cancer Institute Core Flow Cytometry Facility for assistance with cell sorting, Zhengzheng Wei at the Duke Institute for Genomic Sciences Microarray Core Facility for performing and helping analyze microarray data, and to Benjamin Carlson at the Light Microscopy Core Facility at Duke University for assistance with image analysis. Amy Wollish was supported by a National Cancer Institute of the National Institutes of Health Award (grant 5T32CA074736, Research Training in Neuro-Oncology). This work was supported by the Julian Robertson Foundation and by the Marcus Foundation.
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/8/18
Y1 - 2016/8/18
N2 - Microglia and monocytes play important roles in regulating brain remyelination. We developed DUOC-01, a cell therapy product intended for treatment of demyelinating diseases, from banked human umbilical cord blood (CB) mononuclear cells. Immunodepletion and selection studies demonstrated that DUOC-01 cells are derived from CB CD14+ monocytes. We compared the ability of freshly isolated CB CD14+ monocytes and DUOC-01 cells to accelerate remyelination of the brains of NOD/SCID/IL2Rγnull mice following cuprizone feeding–mediated demyelination. The corpus callosum of mice intracranially injected with DUOC-01 showed enhanced myelination, a higher proportion of fully myelinated axons, decreased gliosis and cellular infiltration, and more proliferating oligodendrocyte lineage cells than those of mice receiving excipient. Uncultured CB CD14+ monocytes also accelerated remyelination, but to a significantly lesser extent than DUOC-01 cells. Microarray analysis, quantitative PCR studies, Western blotting, and flow cytometry demonstrated that expression of factors that promote remyelination including PDGF-AA, stem cell factor, IGF1, MMP9, MMP12, and triggering receptor expressed on myeloid cells 2 were upregulated in DUOC-01 compared to CB CD14+ monocytes. Collectively, our results show that DUOC-01 accelerates brain remyelination by multiple mechanisms and could be beneficial in treating demyelinating conditions.
AB - Microglia and monocytes play important roles in regulating brain remyelination. We developed DUOC-01, a cell therapy product intended for treatment of demyelinating diseases, from banked human umbilical cord blood (CB) mononuclear cells. Immunodepletion and selection studies demonstrated that DUOC-01 cells are derived from CB CD14+ monocytes. We compared the ability of freshly isolated CB CD14+ monocytes and DUOC-01 cells to accelerate remyelination of the brains of NOD/SCID/IL2Rγnull mice following cuprizone feeding–mediated demyelination. The corpus callosum of mice intracranially injected with DUOC-01 showed enhanced myelination, a higher proportion of fully myelinated axons, decreased gliosis and cellular infiltration, and more proliferating oligodendrocyte lineage cells than those of mice receiving excipient. Uncultured CB CD14+ monocytes also accelerated remyelination, but to a significantly lesser extent than DUOC-01 cells. Microarray analysis, quantitative PCR studies, Western blotting, and flow cytometry demonstrated that expression of factors that promote remyelination including PDGF-AA, stem cell factor, IGF1, MMP9, MMP12, and triggering receptor expressed on myeloid cells 2 were upregulated in DUOC-01 compared to CB CD14+ monocytes. Collectively, our results show that DUOC-01 accelerates brain remyelination by multiple mechanisms and could be beneficial in treating demyelinating conditions.
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U2 - 10.1172/jci.insight.86667
DO - 10.1172/jci.insight.86667
M3 - Article
C2 - 27699230
AN - SCOPUS:85055608128
SN - 2379-3708
VL - 1
JO - JCI insight
JF - JCI insight
IS - 13
M1 - e86667
ER -