Abstract
BackgroundIt is well understood that hypoxic-ischemic (HI) brain injury during the highly vulnerable perinatal period can lead to cerebral palsy, the most prevalent cause of chronic disability in children. Recently, human clinical trials have reported safety and some efficacy following treatment of cerebral palsy using umbilical cord blood (UCB) cells. UCB is made up of many different cell types, including endothelial progenitor cells (EPCs), T regulatory cells (Tregs), and monocyte-derived suppressor cells (MDSCs). How each cell type contributes individually towards reducing neuroinflammation and/or repairing brain injury is not known. In this study, we examined whether human (h) UCB, or specific UCB cell types, could reduce peripheral and cerebral inflammation, and promote brain repair, when given early after perinatal HI brain injury.MethodsHI brain injury was induced in postnatal day (PND) 7 rat pups and cells were administered intraperitoneally on PND 8. Behavioral testing was performed 7 days post injury, and then, brains and spleens were collected for analysis.ResultsWe found in vitro that all UCB cell types, except for EPCs, were immunomodulatory. Perinatal HI brain injury induced significant infiltration of CD4+ T cells into the injured cerebral hemisphere, and this was significantly reduced by all hUCB cell types tested. Compared to HI, UCB, Tregs, and EPCs were able to reduce motor deficits, reduce CD4+ T cell infiltration into the brain, and reduce microglial activation. In addition to the beneficial effects of UCB, EPCs also significantly reduced cortical cell death, returned CD4+ T cell infiltration to sham levels, and reduced the peripheral Th1-mediated pro-inflammatory shift.ConclusionThis study highlights that cells found in UCB is able to mediate neuroinflammation and is an effective neuroprotective therapy. Our study also shows that particular cells found in UCB, namely EPCs, may have an added advantage over using UCB alone. This work has the potential to progress towards tailored UCB therapies for the treatment of perinatal brain injury.
Highlights
It is well understood that hypoxic-ischemic (HI) brain injury during the highly vulnerable perinatal period can lead to cerebral palsy, the most prevalent cause of chronic disability in children
In vitro immunomodulatory potential of different human UCB (hUCB) cell types To assess the immunosuppressive ability of hUCB, we used a co-culture assay that incorporated human peripheral blood mononuclear cells (PBMCs) with hUCB mononuclear cells at varying concentrations (Fig. 1a)
With the addition of high concentrations of hUCB mononuclear cells, 1:1–1:5 (P < 0.001) and 1:10 (P < 0.05), human PBMC proliferation was significantly suppressed compared to PBMC stimulation alone
Summary
It is well understood that hypoxic-ischemic (HI) brain injury during the highly vulnerable perinatal period can lead to cerebral palsy, the most prevalent cause of chronic disability in children. A number of studies, using both small and large animal models, have investigated the neuroprotective/neuroreparative potential of umbilical cord blood (UCB) cells for treating adult stroke [1] and perinatal HI brain injury [2,3,4,5,6]. These studies report that UCB cell administration has excellent neuroprotective benefits, as evidenced by improvements in motor control and coordination such as reducing spastic paresis and improving walking patterns, posture, and tone in rodents and lambs [3, 5, 6]. Our knowledge of the mechanisms of action of UCB as a neuroprotective therapy remains poorly understood
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