Neural transplants to promote respiratory plasticity after spinal cord injury

呼吸障碍是颈髓损伤(SCI)的毁灭性后果，具有显著的 这增加了受伤人员的负担，增加了死亡风险。呼吸功能障碍及相关继发性 并发症仍然是颈椎脊髓损伤患者发病率和死亡率的主要原因。尤其是 令人担忧的是，有报告表明，近年来宫颈SCI的数量有所增加。趁有机会 越来越多的临床和实验证据表明呼吸的自发改善，恢复的程度 -或功能可塑性-仍然不完整。然而，可塑性依赖于备用的神经基质 不完全脊髓损伤(SCI)。因此，在没有治疗干预和解剖的情况下，恢复的程度 修复是有限的。为了解决这一限制，并增强以下呼吸的可塑性和恢复 颈部脊髓损伤，拟议的工作旨在使用一种新的细胞疗法来促进膈神经运动的修复 控制横隔肌功能的通路--横隔肌是呼吸所必需的呼吸肌。 我们最近的实验研究结果表明，富含中间神经元的移植 损伤部位的神经前体细胞可以促进解剖修复和改善呼吸功能 追随SCI。移植的神经前体细胞存活、增殖并与受损宿主整合 脊髓，有助于修复呼吸途径。这里提出的实验是建立在我们 对膈肌动系统有丰富的经验，测试一种新的移植改进策略 与膈功能相关的神经元间前体。使用临床相关的挫伤模型 颈脊髓损伤，我们将测试移植的神经前体细胞能否在解剖和功能上整合 利用这一横隔膜系统，促进横隔膜持续、持久的恢复。 这些实验不仅将测试一种创新和有前途的治疗方法，而且它们将 显著提高我们对多种神经元治疗潜力的理解 移植方法，包括目前正在测试的许多干细胞疗法 在实验和临床上。

Impaired breathing is a devastating consequence of cervical spinal cord injury (SCI), representing a significant burden to injured people and increasing the risk of mortality. Respiratory dysfunction and associated secondary complications remain the leading cause of morbidity and mortality in people with cervical SCI. Particularly concerning are reports indicating that the number of cervical SCIs has increased in recent years. While there is mounting clinical and experimental evidence for spontaneous improvements in respiration, the extent of recovery – or functional plasticity – remains incomplete. However, plasticity is reliant on spared neural substrates after incomplete spinal cord injury (SCI). Thus, the extent of recovery without therapeutic intervention and anatomical repair is limited. To address this limitation, and amplify plasticity and recovery of breathing following cervical SCI, the proposed work aims to use a novel cell therapy to promote repair of phrenic motor pathways that control function of the diaphragm – a respiratory muscle essential to breathing. Results from our recent experimental studies have demonstrated that transplantation of interneuron-rich neural progenitor cells at the site of injury can promote anatomical repair and improve respiratory function following SCI. Transplanted neural precursor cells survive, proliferate and become integrated with injured host spinal cord, contributing to repair of respiratory pathways. The experiments proposed here build upon our extensive experience with the phrenic motor system, to test a novel strategy for transplanting refined interneuronal precursors that are associated with phrenic function. Using a clinically relevant contusion model of cervical SCI, we will test whether transplanted neural progenitors can anatomically and functionally integrate with this phrenic system, and promote consistent, lasting recovery of diaphragm. Not only will these experiments test an innovative and promising treatment approach, but they will significantly improve our understanding of the therapeutic potential of a wide range of neuronal transplantation approaches, including many of the stem cell therapies currently being tested experimentally and clinically.