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A cord blood monocyte–derived cell therapy product accelerates brain remyelination
Arjun Saha, … , Joanne Kurtzberg, Andrew E. Balber
Arjun Saha, … , Joanne Kurtzberg, Andrew E. Balber
Published August 18, 2016
Citation Information: JCI Insight. 2016;1(13):e86667. https://doi.org/10.1172/jci.insight.86667.
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Research Article Neuroscience Therapeutics

A cord blood monocyte–derived cell therapy product accelerates brain remyelination

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Abstract

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.

Authors

Arjun Saha, Susan Buntz, Paula Scotland, Li Xu, Pamela Noeldner, Sachit Patel, Amy Wollish, Aruni Gunaratne, Tracy Gentry, Jesse Troy, Glenn K. Matsushima, Joanne Kurtzberg, Andrew E. Balber

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Figure 1

Severe demyelination of the midline corpus callosum (CC) area and glial infiltration of NSG mouse brain by cuprizone feeding.

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Severe demyelination of the midline corpus callosum (CC) area and glial ...
(A) LFB-PAS staining of NSG mice brain after 5 weeks of feeding with (right panel) and without (left panel) 0.2% cuprizone (CPZ). The midline CC area is shown by dotted red boxes in the top panels and then shown at higher magnification in the lower panels. Myelinated axons in the CC of mice fed normal laboratory chow are stained blue. Demyelination of the midline CC region of CPZ-treated animals is shown by the absence of the blue-colored fibers. Scale bars: 2,000 μm (×20 magnification) and 100 μm (×400 magnification). (B) Myelin basic protein immunostaining (green) after 5 weeks of feeding without (left panel) and with CPZ (right panel). Two different magnifications (top row is ×100 and bottom row is ×400) of the CC areas are shown. CC areas are shown by white dotted lines. (C) Immunostaining with microglial marker Iba1 (red, upper panels) and astrocyte marker GFAP (pink, lower panels) after 5 weeks of feeding without (left panels) and with CPZ (right panels). CC areas are shown by white dotted lines. Scale bars: 200 μm. (D) Quantitative analysis of area covered by Iba1-positive (upper panel) and GFAP-positive (lower panel) cells, indicative of their numbers, along the CC. Both Iba1-positive and GFAP-positive cell numbers were significantly higher in the CPZ-treated animals. *P < 0.02, **P < 0.004. n = 3 mice per group . C, control. Data are presented as the mean ± SEM.

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