A cord blood monocyte–derived cell therapy product accelerates brain remyelination
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
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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Research Article Neuroscience Therapeutics

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

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 6

Morphometric analysis of electron micrographs of corpus callosum regions of DUOC-01– and Ringer’s-treated mice.

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Morphometric analysis of electron micrographs of corpus callosum regions...
(A) Number of myelinated axons present per ×8,800 electron microscopy field. Data are presented as the mean ± SEM showing all the data points. *P ≤ 4.29 × 10–9. (B) Average number of turns of myelin sheath around axons, with right panels showing a representative electron micrograph of the myelin turns in an axon. *P ≤ 3.4 × 10–6. Scale bars: 100 nm. (C) Scatter plot of g-ratios, showing axonal measurements from 3 different animals in each group. Horizontal lines indicate mean g-ratios. P ≤ 0.014. (D) Average size of mitochondria (area in nm2). Mean difference is significant between DUOC-01 and Ringer’s groups. *P ≤ 9.3 × 10–5. (E) Average number of mitochondria per ×8,800 field. The mean difference is significant between DUOC-01 and Ringer’s groups. *P ≤ 0.02. Each column represents the value of measurements from 3 different animals. Error bars indicate the SEM. Statistical comparisons were performed using an unpaired 2-tailed Student’s t test.