Duke University DURHAM, North Carolina, United States
Background/Case Studies: White matter diseases such as multiple sclerosis (MS) and leukodystrophies are characterized by neuroinflammation, demyelination, and neurodegeneration, resulting in cognitive and motor impairments. While existing therapies can manage symptoms and slow disease progression, no current therapeutics promote recovery. Macrophage-like microglia are resident immune cells in the nervous system that engulf myelin debris and regulate myelin dynamics. A novel macrophage-based cell therapy derived from umbilical cord blood has been developed to address white matter diseases. Cord blood-derived macrophages (CB-Macs; referred to as DUOC-01 in a clinical trial for primary progressive MS (NCT04943289)) are protective in mouse models with demyelination and show promise in promoting the maturation of oligodendrocyte progenitor cells (OPCs), primarily through the release of bioactive factors. Despite encouraging preclinical data, the precise mechanism of action remains unclear. This study investigates how CB-Macs promote remyelination.
Study
Design/Methods: The interaction between CB-Macs and oligodendrocytes was assessed in two demyelination models: experimental autoimmune encephalomyelitis (EAE) and acute demyelination induced by direct injections of lysophosphotidyl choline (LPC). To track the biodistribution of CB-Mac-derived peptides, CB-Macs were metabolically labeled with the bioorthogonal threonine analog β-ethynylserine (βES) and administered into the cerebrospinal fluid. βES-labeled cells and proteins were measured using flow cytometry and immunhiostchemistry. Secreted factors were analyzed using mass spectrometry to identify potential bioactive components in the CB-Mac secretome.
Results/Findings: CB-Macs were found to reduce disease severity in the EAE model, and their secretome promoted remyelination in the spinal cord following LPC-induced demyelination. In the spinal cord, mice injected with CB-Macs exhibited increased number of proliferation OPCs and mature myelinating oligodendrocytes. Of the 350,000 CB-Macs infused into the cerebrospinal fluid, a small number were detected in the brain and spinal cord, predominantly near CD31+ endothelial cells. Additionally, CB-Mac-derived proteins were present in the draining lymph nodes. Mass spectrometry identified 229 proteins secreted by five different CB-Mac cultures. Analysis using CellTalkDB identified 112 ligand–receptor pairs, with 53 pairs involving receptors expressed by oligodendrocyte lineage cells.
Conclusions: Overall, factors secreted by CB-Macs promote maturation of OPCs and remyelination. Further work will identify specific bio-active factors released by CB-Macs that offer protection.
