인간 골수 유래 중간엽 기질 세포의 치료효과를 높이기 위한 실험적 전략

Abstract

The potential of human Bone Marrow–Derived Mesenchymal Stromal Cells (hBM-MSCs) is to differentiate the diverse cell types and secrete a variety of trophic factors. It enables them as a cell therapy tool for intractable diseases. However, their therapeutic efficacy has not yet been satisfied in pre-clinical and/or clinical trials with stem cells therapy. In this study, we evaluated the effects of valproic acid (VPA), an HDAC inhibitor, in human BM-MSCs and assessed the expression of trophic factors (ANG, BDNF, ECFG1, GDNF, HGF, IGF, PIGF, TGF-β1, and β-Pix) in MSCs treated with 200 μg/ml VPA for 12 hours. Under these conditions, the features of MSCs were not changed. The VPA-treated MSCs also showed increased in cell protective effects against oxidative injuries in cell viability and improved migratory ability. This suggests that hBM-MSCs may be improved by treatment with an optimal VPA dose and incubation time that may increase the efficacy of stem cell therapy. We also evaluated hBM-MSCs transduced with the erythropoietin gene (EPO-MSCs) to promote the neural cell survival and found improvement in neurological deficits caused by Amyotrophic Lateral Sclerosis (ALS). EPO reveals diverse cellular functions, including neurotrophic, anti-oxidant, anti-apoptotic, and anti-inflammatory effects in non-hematopoietic tissues. Transplantation of EPO-MSCs in G93A-SOD1 mouse model of ALS significantly improved motor neuron survival, prolonged the life span and reduced inflammatory. Western blot analysis demonstrated that EPO-MSCs significantly increased phosphorylated Akt level and decreased COX-2, HMGB1 and MCP-1 level. This result demonstrate that transduction of the EPO gene into MSCs induced secretion of EPO that may provide neuroprotective effects and reduce inflammation in vivo models of ALS. In conclusion, this study demonstrated that treatment of VPA and transduction of EPO in stem cell culture might be promising methods for the enhancement of hBM-MSC therapeutic efficacy.