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
View: Text | PDF
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

×

Figure 3

LFB-PAS staining analysis of effect of DUOC-01 treatment on remyelination following cessation of cuprizone (CPZ) treatment.

Options: View larger image (or click on image) Download as PowerPoint
LFB-PAS staining analysis of effect of DUOC-01 treatment on remyelinatio...
(A) LFB-PAS staining 1 week after intracranial injection of CD14+ monocytes (lower panels), DUOC-1 cells (middle panels), or Ringer’s solution (upper panels) in CPZ-fed NSG mice. Midline corpus callosum (CC) area is shown by dotted green line. Scale bars: 2,000 μm (×20 magnification) and 100 μm (×400 magnification). (B) Myelination score based on LFB-PAS staining of mice fed normal chow (control) or CPZ for 5 weeks 1 week after treatment of CPZ-treated mice with CD14+ monocytes, DUOC-01 cells, or Ringer’s. DUOC-01 treatment for 1 week significantly increased the myelination in the CC area compared to Ringer’s-injected controls. **P < 5.962 × 10–5 for this study. The CD14+ cell–treated sample showed an increased amount of remyelination compared to the Ringer’s-treated group, but it was significantly less than the DUOC-01–treated group. *P < 0.003875. Data are presented as the mean ± SEM. Statistical comparisons were performed using the Wilcoxon rank-sum test for clustered data using the clusrank package in R.