Immunomodulation with Human Umbilical Cord Blood Stem Cells Ameliorates Ischemic Brain Injury – A Brain Transcriptome Profiling Analysis

Abstract

Our group previously demonstrated that administration of a CD34-negative fraction of human non- hematopoietic umbilical cord blood stem cells (UCBSC) 48 h after ischemic injury could reduce infarct volume by 50% as well as significantly ameliorate neurological deficits. In the present study, we explored possible mechanisms of action using next generation RNA sequencing to analyze the brain transcriptome profiles in rats with ischemic brain injury following UCBSC therapy. Two days after ischemic injury, rats were treated with UCBSC. Five days after administration, total brain mRNA was then extracted for RNAseq analysis using Illumina Hiseq 2000. We found 275 genes that were significantly differentially expressed after ischemic injury compared with control brains. Following UCBSC treatment, 220 of the 275 differentially expressed genes returned to normal levels. Detailed analysis of these altered transcripts revealed that the vast majority were associated with activation of the immune system following cerebral ischemia which were normalized following UCBSC therapy. Major alterations in gene expression profiles after ischemia include blood-brain-barrier breakdown, cytokine production, and immune cell infiltration. These results suggest that UCBSC protect the brain following ischemic injury by down regulating the aberrant activation of innate and adaptive immune responses.

Optimizing Stem Cell Therapy after Ischemic Brain Injury

“…64 In addition, UC-BSCs can inhibit the immune response and decrease the size of the ischemic brain lesion. 65 These results indicate their potential in ischemic brain injury.…”

“…39 NSCs, BM-MSCs, AD-MSCs, or UC-BSCs IV administration has shown neuroprotection in ischemic stroke. 39,48,60,64,65,69 Despite these results, stem cells delivered by the IV route are subjected to trapping in peripheral tissues (lungs, liver, spleen, and kidneys), particularly the lungs, 70 limiting cell delivery to the brain. Additionally, pulmonary embolism complications were noted in a Korean family following IV AD-MSCs administration.…”

“…UC-BSCs have protective effects against ischemic injury, resulting in brainderived neurotrophic factor expression recovery [ 64 ]. In addition, UC-BSCs can inhibit the immune response and decrease the size of the ischemic brain lesion [ 65 ]. These results indicate their potential in ischemic brain injury.…”

“…Intravenously injected NSCs can traverse the BBB and localize to ischemic injury areas [ 39 ]. NSCs, BM-MSCs, AD-MSCs, or UC-BSCs IV administration has shown neuroprotection in ischemic stroke [ 39 , 48 , 60 , 64 , 65 , 69 ].…”

Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: Mechanistic and therapeutic implications

“…How each of these routes impacts dosing or targeting of cells to the brain is not yet clear, even after intravenous injection, the most common route of administration. Animal studies have shown that some unidentified CB cells are present near brain lesions for short periods of time following intravenous treatment of acute stroke [53, 54] or neonatal HIE with CB-MNC [55] but the function of these cells is unclear. Some evidence suggests that CB-MNC respond to chemokines by migrating to ischemic brain regions [56–58].…”