Center of Excellence for Aging & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
Cell Transplant. 2020 Jan-Dec;29:963689720913494. doi: 10.1177/0963689720913494.
Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.
肌萎缩侧索硬化症（ALS）是一种致命的脑和脊髓运动神经元退行性疾病。膈肌和其他呼吸肌的进行性瘫痪导致呼吸功能障碍和衰竭，是 ALS 患者最常见的死亡原因。ALS 动物模型也显示出呼吸损伤。血管病理学是 ALS 发病机制中另一个最近被认识到的标志。中枢神经系统（CNS）毛细血管损伤是 ALS 啮齿动物模型和 ALS 患者的共同疾病要素。CNS 以外的微血管损伤，如肺部，可能发生在 ALS 中，引发肺部损伤并影响呼吸功能。干细胞治疗是 ALS 的一种有前途的治疗方法。然而，这种治疗策略主要针对退化的运动神经元的拯救。我们通过静脉内给予人骨髓（hBM）干细胞，显示出对 ALS 超氧化物歧化酶 1（SOD1）小鼠模型中 CNS 毛细血管完整性的恢复有功能益处。由于通过这种途径广泛分布移植细胞，给予的细胞可能进入肺部，并有效地恢复呼吸器官中的微血管。在这里，我们提供了初步证据，证明微血管功能障碍在促使肺部损伤和 ALS 呼吸功能修复治疗方法中的潜在作用。我们的初步研究表明，ALS 小鼠的微血管损伤导致疾病晚期肺部出现瘀点，并且主要来源于 hBM 的内皮祖细胞的全身移植具有通过重建血管完整性促进肺部恢复的潜力。我们对这种疾病中以前未充分探索的肺部功能的新认识可能有助于针对恢复 ALS 呼吸功能的治疗。
