Abstract
The aim of this study is to understand if human mesenchymal stem cells (hMSCs) and neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) have synergistic protective effect that promotes functional recovery in rats with severe spinal cord injury (SCI). To evaluate the effect of delayed combinatorial therapy of PACAP and hMSCs on spinal cord tissue repair, we used the immortalized hMSCs that retain their potential of neuronal differentiation under the stimulation of neurogenic factors and possess the properties for the production of several growth factors beneficial for neural cell survival. The results indicated that delayed treatment with PACAP and hMSCs at day 7 post SCI increased the remaining neuronal fibers in the injured spinal cord, leading to better locomotor functional recovery in SCI rats when compared to treatment only with PACAP or hMSCs. Western blotting also showed that the levels of antioxidant enzymes, Mn-superoxide dismutase (MnSOD) and peroxiredoxin-1/6 (Prx-1 and Prx-6), were increased at the lesion center 1 week after the delayed treatment with the combinatorial therapy when compared to that observed in the vehicle-treated control. Furthermore, in vitro studies showed that co-culture with hMSCs in the presence of PACAP not only increased a subpopulation of microglia expressing galectin-3, but also enhanced the ability of astrocytes to uptake extracellular glutamate. In summary, our in vivo and in vitro studies reveal that delayed transplantation of hMSCs combined with PACAP provides trophic molecules to promote neuronal cell survival, which also foster beneficial microenvironment for endogenous glia to increase their neuroprotective effect on the repair of injured spinal cord tissue.
Highlights
A traumatic primary injury to the spinal cord (SCI) induces axonal degeneration, neural cell death, and microvasculature destruction
HMSCs/ hBMSCs are beneficial for the purpose of autologous transplantation, raising the promising possibility that the cells can be used for stem cell-based approach to treat several neurodegenerative diseases, such as stroke, Parkinson disease, amyotrophic lateral Sclerosis, Alzheimer disease, and spinal cord injury (SCI) [7]
Through in vitro co-culture system using the human mesenchymal stem cells (hMSCs) cell line and primary rat astrocytes, we provided evidence that the hMSC-derived factors increased the production of membrane glutamate transporter-1 (GLT-1) in astrocytes under the influence of pituitary adenylate cyclase-activating polypeptide (PACAP) and promoted astrocytic glutamate uptake activity
Summary
A traumatic primary injury to the spinal cord (SCI) induces axonal degeneration, neural cell death, and microvasculature destruction. These events subsequently trigger a cascade of pathological actions (so called secondary damage) including vascular and biochemical changes, hemorrhagic necrosis, inflammatory process and demyelination [1,2], leading to a second wave of cell death and lesion area extension which impair the affected body functions. It has been indicated that delivery of BMSCs 1 week after injury significantly cell survival and improves the hindlimb locomotor function in animals with moderate SCI [12]. These findings point to the promise of bone marrow derived cell-based strategy for potential SCI repair
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