NERVE ALLOTRANSPLANTATION FOR TRAUMATIC NERVE INJURY

描述（由申请人提供）：脱细胞神经同种异体移植物（ANA）正在迅速获得临床普及。ANA是经处理以去除抗原性细胞物质的尸体神经，提供了神经自体移植物的微观结构，而没有与自体神经收获相关的发病率或新鲜尸体神经同种异体移植物所需的宿主免疫抑制。这些“现成的”神经替代物目前在临床上用于长ga、大直径（大体积）神经重建。然而，它们仅被证明支持神经再生，类似于跨越短间隙（小体积）的小直径神经中的自体移植物。ANA不含雪旺细胞（SC），因此依赖于宿主SC增殖进入移植物以支持轴突再生。我们的初步研究结果表明，SC增殖是有限的，在大体积的ANA，并与有限的轴突再生跨越较大体积的ANA。大体积ANA的升高的增殖需求或者耗尽SC复制的能力，或者慢性地应激它们，诱导衰老状态。衰老细胞改变了它们分泌的蛋白质的程度和类型，采用衰老相关分泌表型（SASP）。SASP显著改变衰老细胞周围的组织微环境。我们推测，SASP的SC在ANA改变了环境，并产生负面影响轴突再生。我们已经表明，随着ANA体积的增加，移植物内衰老细胞的存在也增加，整个移植物的轴突再生减少。因此，我们推测，减少再生是由于衰老的SC的存在增加，改变了再生的微环境。神经管基底层（Endoneurial tube basal lamina，SC）及其分泌的生长因子为轴突再生提供了促再生的微环境. ANA中SC的缺乏限制了它们的最大再生长度，并且衰老SC的存在可能对再生微环境产生负面影响。目前的建议调查再生限制的ANA（目的1），并确定衰老的SC在限制再生通过大体积ANA（目的2）的机制作用。

DESCRIPTION (provided by applicant): Acellularized nerve allografts (ANAs) are rapidly gaining clinical popularity. ANAs, cadaveric nerves processed to remove antigenic cellular material, provide the microstructure of a nerve autograft without the morbidity associated with autologous nerve harvest or the host immunosuppression required with fresh cadaveric nerve allografts. These "off the shelf" nerve substitutes are currently being used clinically for long ga, large diameter (large volume) nerve reconstruction. However, they have only been shown to support nerve regeneration similar to autografts in small diameter nerves across short gaps (small volume). ANAs do not contain Schwann cells (SCs) and therefore depend on proliferation of host SCs into the graft to support axonal regeneration. Our preliminary results demonstrate that SC proliferation is limited in large volume ANAs and is associated with limited axonal regeneration across larger volume ANAs. The elevated proliferative requirement of large volume ANAs either exhausts the SCs ability to replicate or chronically stresses them inducing a senescent state. Senescent cells change the extent and types of proteins they secrete, adopting a senescent-associated secretion phenotype (SASP). The SASP drastically alters the tissue microenvironment surrounding senescent cells. We hypothesize that the SASP of SCs in ANAs alters the environment and negatively affects axonal regeneration. We have shown that as the volume of ANAs increases, the presence of senescent cells within the graft also increases and axonal regeneration across the graft decreases. Thus we postulate that decreased regeneration is due to the increased presence of senescent SCs altering the regenerative microenvironment. Endoneurial tube basal lamina, SCs, and their secreted growth factors, provide a pro- regenerative microenvironment for regenerating axons. The absence of SCs in ANAs limits their maximum regenerative length and the presence of senescent SCs may negatively affect the regenerative microenvironment. The current proposal investigates the regenerative limits of ANAs (Aim 1), and determines the mechanistic role of senescent SCs in limiting regeneration through large volume ANAs (Aim 2).