Kim Kwang S, Lee Hong J, An Jin, Kim Yun B, Ra Jung Chan, Lim Inja, Kim Seung U
Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea.
Cell Transplant. 2014;23(12):1585-97. doi: 10.3727/096368913X673450. Epub 2013 Sep 18.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons in the cortex, brain stem, and spinal cord. The precise pathogenic mechanism remains unknown, and there is currently no effective therapy. We evaluated the therapeutic effects of human adipose tissue-derived stem cells (ASCs) in an animal model of ALS. Human abdominal subcutaneous fat tissues were obtained by simple liposuction from donors, and ASCs were isolated from the fat stromal vascular fraction. ASCs were found to differentiate into adipocytes, chondrocytes, osteocytes, and neurons. SOD1G93A ALS mice were divided into three groups: sham, intravenous (IV), and intracerebroventricular (ICV) groups. Human ASCs were transplanted in the ALS mice at 70 postnatal days before the appearance of clinical symptoms. Behavior of transplanted animals was assessed by rotarod test, paw grip endurance (PaGE), and reflex index. Mice in every group were sacrificed after 4 weeks posttransplantation. Transplanted ASCs were identified in the lumbar spinal cords with an antihuman mitochondria antibody and cell type-specific markers for neurons or astrocytes. Delayed onset of clinical symptoms (26 days) and extended survival of animals (24 days) were observed in ALS mice transplanted with ASCs via ICV route. ASCs were found to secrete high levels of neurotrophic factors such as NGF, BDNF, IGF-1, and VEGF. Reduction of apoptotic cell death by these factors was confirmed in cultured CNS cells and in the ALS spinal cord. These results indicate that transplantation of ASCs in ALS mice provides neuroprotective effects by production of cytokines/growth factors, delays disease progression, and prolongs the life span of ALS mice.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，它选择性地影响大脑皮层、脑干和脊髓中的运动神经元。确切的致病机制仍然未知，目前也没有有效的治疗方法。我们在ALS动物模型中评估了人脂肪组织来源的干细胞（ASC）的治疗效果。通过简单的抽脂从供体获取人腹部皮下脂肪组织，并从脂肪基质血管成分中分离出ASC。发现ASC可分化为脂肪细胞、软骨细胞、骨细胞和神经元。将SOD1G93A ALS小鼠分为三组：假手术组、静脉注射（IV）组和脑室内（ICV）组。在出生后70天，即在临床症状出现之前，将人ASC移植到ALS小鼠体内。通过转棒试验、握力耐力（PaGE）和反射指数评估移植动物的行为。移植后4周处死每组小鼠。用抗人线粒体抗体以及神经元或星形胶质细胞的细胞类型特异性标记物在腰脊髓中鉴定移植的ASC。通过ICV途径将ASC移植到ALS小鼠中后，观察到临床症状出现延迟（26天）以及动物存活期延长（24天）。发现ASC分泌高水平的神经营养因子，如NGF、BDNF、IGF - 1和VEGF。在培养的中枢神经系统细胞和ALS脊髓中证实了这些因子可减少凋亡细胞死亡。这些结果表明，在ALS小鼠中移植ASC可通过产生细胞因子/生长因子提供神经保护作用，延缓疾病进展，并延长ALS小鼠的寿命。
