title: Human Mesenchymal Stem Cell Treatment Normalizes Cortical Gene Expression after Traumatic Brain Injury.
abstract: Traumatic brain injury (TBI) results in a progressive disease state with many adverse and long-term neurological consequences. Mesenchymal stem cells (MSCs) have emerged as a promising cytotherapy and have been previously shown to reduce secondary apoptosis and cognitive deficits associated with TBI. Consistent with the established literature, we observed that systemically administered human MSCs (hMSCs) accumulate with high specificity at the TBI lesion boundary zone known as the penumbra. Substantial work has been done to illuminate the mechanisms by which MSCs, and the bioactive molecules they secrete, exert their therapeutic effect. However, no such work has been published to examine the effect of MSC treatment on gene expression in the brain post-TBI. In the present study, we use high-throughput RNA sequencing (RNAseq) of cortical tissue from the TBI penumbra to assess the molecular effects of both TBI and subsequent treatment with intravenously delivered hMSCs. RNAseq revealed that expression of almost 7000 cortical genes in the penumbra were differentially regulated by TBI. Pathway analysis using the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database revealed that TBI regulated a large number of genes belonging to pathways involved in metabolism, receptor-mediated cell signaling, neuronal plasticity, immune cell recruitment and infiltration, and neurodegenerative disease. Remarkably, hMSC treatment was found to normalize 49% of all genes disrupted by TBI, with notably robust normalization of specific pathways within the categories mentioned above, including neuroactive receptor-ligand interactions (57%), glycolysis and gluconeogenesis (81%), and Parkinson's disease (100%). These data provide evidence in support of the multi-mechanistic nature of stem cell therapy and suggest that hMSC treatment is capable of simultaneously normalizing a wide variety of important molecular pathways that are disrupted by brain injury.
authors.affiliation: 1 Department of Biomedical Sciences, Florida State University College of Medicine , Tallahassee, Florida.|2 Program in Neuroscience, Florida State University College of Medicine , Tallahassee, Florida.
authors.forename: Ali
authors.initials: A
authors.lastname: Darkazalli
authors.affiliation: 1 Department of Biomedical Sciences, Florida State University College of Medicine , Tallahassee, Florida.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Vied
authors.affiliation: 1 Department of Biomedical Sciences, Florida State University College of Medicine , Tallahassee, Florida.
authors.forename: Crystal-Dawn
authors.initials: CD
authors.lastname: Badger
authors.affiliation: 1 Department of Biomedical Sciences, Florida State University College of Medicine , Tallahassee, Florida.|2 Program in Neuroscience, Florida State University College of Medicine , Tallahassee, Florida.
authors.forename: Cathy W
authors.initials: CW
authors.lastname: Levenson
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D002540:Cerebral Cortex / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D053858:Metabolic Networks and Pathways / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
keywords: controlled cortical impact; genomics; stem cells; traumatic brain injury