PDF(Pubmed)
Abstract：
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable paralytic disorder caused by the progressive death of upper and lower motoneurons. Although numerous strategies have been developed to slow disease progression and improve life quality, to date only a few therapeutic treatments are available with still unsatisfactory therapeutic benefits. The secretome of dental pulp stem cells (DPSCs) contains numerous neurotrophic factors that could promote motoneuron survival. Accordingly, DPSCs confer neuroprotective benefits to the SOD1G93A mouse model of ALS. However, the mode of action of DPSC secretome on motoneurons remains largely unknown. Here, we used conditioned medium of human DPSCs (DPSCs-CM) and assessed its effect on survival, axonal length, and electrical activity of cultured wildtype and SOD1G93A motoneurons. To further understand the role of individual factors secreted by DPSCs and to circumvent the secretome variability bias, we focused on GDF15 and HB-EGF whose neuroprotective properties remain elusive in the ALS pathogenic context. DPSCs-CM rescues motoneurons from trophic factor deprivation-induced death, promotes axon outgrowth of wildtype but not SOD1G93A mutant motoneurons, and has no impact on the spontaneous electrical activity of wildtype or mutant motoneurons. Both GDF15 and HB-EGF protect SOD1G93A motoneurons against nitric oxide-induced death, but not against death induced by trophic factor deprivation. GDF15 and HB-EGF receptors were found to be expressed in the spinal cord, with a two-fold increase in expression for the GDF15 low-affinity receptor in SOD1G93A mice. Therefore, the secretome of DPSCs appears as a new potential therapeutic candidate for ALS.
摘要：
肌萎缩侧索硬化症（ALS）是一种致命且无法治愈的麻痹性疾病，由上下运动神经元的进行性死亡引起。尽管已经开发了许多策略来减缓疾病进展并改善生活质量，迄今为止,只有少数治疗性治疗可用,但仍不能令人满意的治疗益处。牙髓干细胞（DPSC）的分泌组含有许多可以促进运动神经元存活的神经营养因子。因此，DPSC赋予ALS的SOD1G93A小鼠模型神经保护益处。然而,DPSC分泌组对运动神经元的作用方式仍然未知。这里,我们使用人DPSC（DPSC-CM）的条件培养基，并评估其对存活的影响，轴突长度,和培养的野生型和SOD1G93A运动神经元的电活动。为了进一步了解DPSC分泌的个体因子的作用，并规避分泌组变异性偏倚，我们关注的是GDF15和HB-EGF,它们的神经保护特性在ALS发病背景下仍然难以捉摸.DPSC-CM从营养因子剥夺诱导的死亡中拯救运动神经元，促进野生型而不是SOD1G93A突变运动神经元的轴突生长，并且对野生型或突变型运动神经元的自发电活动没有影响。GDF15和HB-EGF均可保护SOD1G93A运动神经元免受一氧化氮诱导的死亡，但不反对营养因子剥夺引起的死亡。发现GDF15和HB-EGF受体在脊髓中表达，SOD1G93A小鼠中GDF15低亲和力受体的表达增加了两倍。因此,DPSC的分泌组似乎是ALS新的潜在治疗候选物。
