Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications.
Abstract
Cord blood (CB) mononuclear cells (MNC) are being tested in clinical trials to treat
hypoxic-ischemic (HI) brain injuries. Although early results are encouraging, mechanisms
underlying potential clinical benefits are not well understood. To explore these mechanisms
further, we exposed mouse brain organotypic slice cultures to oxygen and glucose deprivation
(OGD) and then treated the brain slices with cells from CB or adult peripheral blood
(PB). We found that CB-MNCs protect neurons from OGD-induced death and reduced both
microglial and astrocyte activation. PB-MNC failed to affect either outcome. The protective
activities were largely mediated by factors secreted by CB-MNC, as direct cell-to-cell
contact between the injured brain slices and CB cells was not essential. To determine
if a specific subpopulation of CB-MNC are responsible for these protective activities,
we depleted CB-MNC of various cell types and found that only removal of CB CD14+ monocytes
abolished neuroprotection. We also used positively selected subpopulations of CB-MNC
and PB-MNC in this assay and demonstrated that purified CB-CD14+ cells, but not CB-PB
CD14+ cells, efficiently protected neuronal cells from death and reduced glial activation
following OGD. Gene expression microarray analysis demonstrated that compared to PB-CD14+
monocytes, CB-CD14+ monocytes over-expressed several secreted proteins with potential
to protect neurons. Differential expression of five candidate effector molecules,
chitinase 3-like protein-1, inhibin-A, interleukin-10, matrix metalloproteinase-9
and thrombospondin-1, were confirmed by western blotting, and immunofluorescence.
These findings suggest that CD14+ monocytes are a critical cell-type when treating
HI with CB-MNC.
Type
Journal articleSubject
MicrogliaNeurons
Leukocytes, Mononuclear
Monocytes
Cells, Cultured
Fetal Blood
Animals
Mice
Hypoxia-Ischemia, Brain
Oxygen
Glucose
Cytokines
Immunophenotyping
Cell Communication
Cell Survival
Biomarkers
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https://hdl.handle.net/10161/24568Published Version (Please cite this version)
10.1371/journal.pone.0218906Publication Info
Saha, Arjun; Patel, Sachit; Xu, Li; Scotland, Paula; Schwartzman, Jonathan; Filiano,
Anthony J; ... Balber, Andrew E (2019). Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain
cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications. PloS one, 14(9). pp. e0218906. 10.1371/journal.pone.0218906. Retrieved from https://hdl.handle.net/10161/24568.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Anthony J Filiano
Assistant Professor in Neurosurgery
Immune dysfunction has been described in most neurological disorders. Preclinical
strategies targeting these disorders have primarily concentrated on directly targeting
synaptic function; however, most of these approaches have failed. Our lab is interested
in understanding the complex interactions between the immune system and nervous system
with the intent to uncover novel therapeutic targets to combat diseases such as autism
spectrum disorder.
Projects in the Lab:
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Joanne Kurtzberg
Jerome S. Harris Distinguished Professor of Pediatrics
Dr. Kurtzberg is an internationally renowned expert in pediatric hematology/oncology,
pediatric blood and marrow transplantation, umbilical cord blood banking and transplantation,
and novel applications of cord blood and birthing tissues in the emerging fields of
cellular therapies and regenerative medicine. Dr. Kurtzberg serves as the Director
of the Marcus Center for Cellular Cures (MC3), Director of the Pediatric Transplant
and Cellular Therapy Program, Director of the Carolina
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