NERVE ALLOTRANSPLANTATION FOR TRAUMATIC NERVE INJURY

描述（申请人提供）：脱细胞神经同种异体移植（ANAs）在临床上迅速普及。ANAs，尸体神经处理去除抗原细胞物质，提供了自体神经移植物的微观结构，而没有自体神经移植相关的并发症或新鲜尸体神经移植物所需的宿主免疫抑制。这些“现成的”神经代用品目前在临床上用于长神经、大直径（大容量）神经重建。然而，它们只被证明支持神经再生，类似于小直径神经在短间隙（小体积）内的自体移植物。ANAs不含雪旺细胞（SCs），因此依赖于宿主SCs向移植物的增殖来支持轴突再生。我们的初步结果表明，SC增殖在大体积的ANAs中受到限制，并且与大体积ANAs的轴突再生有限有关。对大量ANAs的增殖需求的增加，要么耗尽了SCs的复制能力，要么使它们长期受到压力，从而导致衰老状态。衰老细胞改变其分泌蛋白质的程度和类型，采用衰老相关分泌表型（senescence associated分泌phenotype， SASP）。SASP极大地改变了衰老细胞周围的组织微环境。我们假设ANAs中SCs的SASP改变了环境并对轴突再生产生负面影响。我们已经证明，随着ANAs体积的增加，移植物中衰老细胞的存在也增加，移植物的轴突再生减少。因此，我们假设再生减少是由于衰老SCs的增加改变了再生微环境。内皮管基底层、SCs及其分泌的生长因子为轴突的再生提供了一个促进再生的微环境。ANAs中SCs的缺失限制了其最大再生长度，衰老SCs的存在可能对再生微环境产生负面影响。目前的提案研究了ANAs的再生极限（Aim 1），并确定了衰老sc通过大容量ANAs限制再生的机制作用（Aim 2）。

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).