Improved Healing after the Co-Transplantation of HO-1 and BDNF Overexpressed Mesenchymal Stem Cells in the Subacute Spinal Cord Injury of Dogs

Abstract

Abundant expression of proinflammatory cytokines after a spinal cord injury (SCI) creates an inhibitory microenvironment for neuroregeneration. The mesenchymal stem cells help to mitigate the inflammation and improve neural growth and survival. For this purpose, we potentiated the function of adipose-derived mesenchymal stem cells (Ad-MSCs) by transfecting them with brain-derived neurotrophic factor (BDNF) and heme oxygenase-1 (HO-1), through a lentivirus, to produce BDNF overexpressed Ad-MSCs (BDNF-MSCs), and HO-1 overexpressed Ad-MSCs (HO-1-MSCs). Sixteen SCI beagle dogs were randomly assigned into four treatment groups. We injected both HO-1 and BDNF-overexpressed MSCs as a combination group, to selectively control inflammation and induce neuroregeneration in SCI dogs, and compared this with BDNF-MSCs, HO-1-MSCs, and GFP-MSCs injected dogs. The groups were compared in terms of improvement in canine Basso, Beattie, and Bresnahan (cBBB) score during 8 weeks of experimentation. After 8 weeks, spinal cords were harvested and subjected to western blot analysis, immunofluorescent staining, and hematoxylin and eosin (H&E) staining. The combination group showed a significant improvement in hindlimb functions, with a higher BBB score, and a robust increase in neuroregeneration, depicted by a higher expression of Tuj-1, NF-M, and GAP-43 due to a decreased expression of the inflammatory markers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and an increased expression of interleukin-10 (IL-10) (P ≤ 0.05). H&E staining showed more reduced intraparenchymal fibrosis in the combination group than in other groups (P ≤ 0.05). It was thus suggested that the cotransplantation of HO-1 and BDNF-MSCs is more effective in promoting the healing of SCI. HO-1-MSCs reduce inflammation, which favors BDNF-induced neuroregeneration in SCI of dogs.

Transplantation of Neuregulin1-Overexpressing Bone Marrow Mesenchymal Cells Accelerates Motor Functional Recovery by Facilitating Neurite Outgrowth and Reducing Cell Apoptosis in Rat after Spinal Cord Injury

“…In this study, we found that transplantation of NRG1-BMSCs notably reduced neuronal chromatolysis after SCI. Concomitantly, our data also showed that an overt reduction or absence of GAP43 protein expression in SCI rats, which was in agreement with the observations in a previous study [46]. Interestingly, the sharp reduction of GAP43 caused by SCI was distinctly eliminated with NRG1-BMSCs administration.…”

HiPSC-Derived NSCs Effectively Promote The Functional Recovery of Acute Spinal Cord Injury in Mice

“…The huMSCs have been con rmed to differentiate into CNS cell lineages in a rat SCI model [28,30,31] . Some authors investigated BM-MSC transplantation in dogs [32,33] . Among them, Ryu et al [32] recorded improved neurological outcomes in MSC groups after acute transplantation (one week after trauma), since all dogs exhibited purposeful hind limb motion.…”

Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy

“…These cells are found within the adult bone marrow, where they contribute to hematopoiesis and bone regeneration. BM-MSCs can not only be obtained from humans, rodents, or primates, but also from several animal species such as sheep, dogs, cats, and bovines (Figure 3) [88,92,93,94,95,96,97,98].…”