Abstract
In this study, GFP-MSCs were topically applied to the surface of cerebral cortex within 1 hour of experimental TBI. No treatment was given to the control group. Three days after topical application, the MSCs homed to the injured parenchyma and improved the neurological function. Topical MSCs triggered earlier astrocytosis and reactive microglia. TBI penumbra and hippocampus had higher cellular proliferation. Apoptosis was suppressed at hippocampus at 1 week and reduced neuronal damaged was found in the penumbral at day 14 apoptosis. Proteolytic neuronal injury biomarkers (alphaII-spectrin breakdown products, SBDPs) and glial cell injury biomarker, glial fibrillary acidic protein (GFAP)-breakdown product (GBDPs) in injured cortex were also attenuated by MSCs. In the penumbra, six genes related to axongenesis (Erbb2); growth factors (Artn, Ptn); cytokine (IL3); cell cycle (Hdac4); and notch signaling (Hes1) were up-regulated three days after MSC transplant. Transcriptome analysis demonstrated that 7,943 genes were differentially expressed and 94 signaling pathways were activated in the topical MSCs transplanted onto the cortex of brain injured rats with TBI. In conclusion, topical application offers a direct and efficient delivery of MSCs to the brain.
Highlights
Traumatic Brain injury (TBI) is a leading cause of death and disability[1]
By borrowing concept from our tissue engineering technology previously developed for transplantation of cultured epidermal skin graft to burn wound/chronic wounds[9], we have developed a novel technique to deliver a large amount of Mesenchymal stem cells (MSCs) directly to the target organs[10, 11]
TheMSCs isolated from adipose tissue of transgenic Green Fluorescent Protein (GFP)-SD rats were adherent to the plastic culture flasks and exhibited spindle-shape morphology (Fig. 1A)
Summary
Traumatic Brain injury (TBI) is a leading cause of death and disability[1]. The outcomes depend on the extent of the primary injury and the sequel of the secondary injury which involve cerebral edema, hematomas, hydrocephalus, impaired systemic and cellular metabolism, excitotoxicity and intracranial hypertension[2, 3]. Many preclinical studies have shown that differentiation of MSCs into neuronal cells is not considered as the major recovery mechanism in the context brain injury because of low engraftment of MSCs into brain parenchyma[6]. Therapeutic potentials of MSCs are commonly investigated by administrating MSCs through systemic infusion or direct injection into the brain in animal experiment or human studies. It is our hypothesis that when MSCs are topically applied to the surface of recipient organs, the MSCs can home to the injured parenchyma. Our previous experiment showed that topically applied MSCs could migrate from the surface of cerebral cortex in the contralateral side to the penumbra of TBI in the ipsilateral cerebral hemisphere, apparently following pre-existing axons along the corpus callosum[11]. To maximize the therapeutic potential of MSCs in this study, we topically applied MSCs to cerebral cortex of the TBI site. The interactome and reciprocal activation of pathways in the topical MSCs and recipient cortex were studied
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