Combinatory strategies to functional remyelination after spinal cord injury

脱髓鞘是创伤性脊髓损伤（SCI）后功能丧失的重要原因。脱髓鞘 轴突长期存在于受损的脊髓中，并且脱髓鞘的，但其他方面完整的轴突的髓鞘再生， 是促进SCI后功能恢复的重要修复策略。成年人的脊髓 自发髓鞘再生的能力，尽管事实上，少突胶质细胞前体细胞（OPCs）， 髓鞘再生的能力，对损伤的反应变得活跃和增殖。的区别，以及 内源性OPCs的髓鞘再生在受损的脊髓中受到抑制。神经干细胞移植 神经干细胞或神经胶质祖细胞也被证明有效地增加SCI后的髓鞘再生，但程度不同。 成功的大多数移植的NSC分化成星形胶质细胞，并且它们分化成星形胶质细胞。 在损伤的脊髓中，少突胶质细胞（OL）或神经元的表达受到抑制。同样，从移植的胶质细胞分化 在损伤的脊髓中，神经胶质祖细胞也受到限制，许多移植的神经胶质祖细胞仍然存在， 未分化或分化成星形胶质细胞。了解限制不同性别之间差异的机制 损伤脊髓中内源性和移植的NSC或OPCs的髓鞘再生应该导致新的神经再生。 治疗策略来修复SCI。损伤微环境中抑制因子的存在可能 有助于限制少突胶质细胞的分化和髓鞘再生。我们的初步数据显示 来自损伤脊髓的反应性星形胶质细胞通过增加成骨前体细胞的分化抑制了成骨前体细胞的OL分化。 骨形态发生蛋白（BMP）的表达。缺乏足够的信号刺激分化 损伤脊髓中OPCs和成熟OLs的髓鞘形成也可能有助于有限的髓鞘再生 SCI之后我们的初步数据显示，生长因子如多- 神经营养因子D15 A或CNTF促进移植OPCs在损伤脊髓中的髓鞘再生。我们 假设阻断抑制性BMP信号传导以促进OPC分化和 增加生长因子的表达以促进其成熟和髓鞘再生可能起作用 协同地促进更广泛的髓鞘再生，并导致更大的电生理和运动 SCI后的行为恢复在本申请中，我们将使用客观和敏感的电生理和 行为分析，以测试这一假设，在一个良好的表征化学脱髓鞘模型， 临床相关的挫伤性SCI模型。根据我们公布的和初步的数据，四个具体的 提出了以下目标：1.为了确定来自损伤脊髓的星形胶质细胞是否抑制 通过增加BMP的分泌，由成体OPCs进行髓鞘再生。2.为了验证阻断抑制性的假设， BMP信号传导将促进移植的成体OPCs在脑内的分化、成熟和髓鞘再生。 脊髓脱髓鞘3.为了检验阻断抑制性BMP信号传导与抑制性BMP信号传导的组合对 促进分化和增加生长因子的表达，从而增强 OL的髓鞘化将协同作用，促进移植的神经元的分化、成熟和髓鞘再生。 成人OPCs与脱髓鞘脊髓功能恢复4.为了检验最优组合 在目标1-3中建立的策略将导致移植的OPCs更广泛的髓鞘再生， 在更临床相关的挫伤SCI模型中的功能恢复。

Demyelination is a significant contributor to functional loss after traumatic spinal cord injury (SCI). Demyelinated axons persist in the injured spinal cord chronically, and remyelination of demyelinated, but otherwise intact axons, represents an important repair strategy to facilitate functional recovery after SCI. Adult spinal cord has a limited capacity to spontaneously remyelinate, despite the fact that oligodendrocyte precursor cells (OPCs), which have the capacity to remyelinate, become active and proliferate in response to the injury. The differentiation of, and remyelination by endogenous OPCs is inhibited in the injured spinal cord. Transplantation of neural stem cells (NSCs) or glial progenitors has also proven effective to increase remyelination after SCI, but with varying degrees of success. The majority of grafted NSCs differentiate into astrocytes and their differentiation into oligodendrocytes (OLs) or neurons is inhibited in the injured spinal cord. Similarly, differentiation from grafted glial progenitors is also restricted in the injured spinal cord, and many transplanted glial progenitors remain undifferentiated or differentiate into astrocytes. Understanding the mechanism(s) that restrict the differentiation of and remyelination by the endogenous and grafted NSC or OPCs in the injured spinal cord should lead to new therapeutic strategies to repair SCI. The presence of inhibitory factors in the injury microenvironment may contribute to the restriction of the oligodendrocyte differentiation and remyelination. Our preliminary data showed that reactive astrocytes from the injured spinal cord inhibit OL differentiation of adult OPCs by increasing expression of bone morphogenetic proteins (BMPs). The absence of sufficient signals to stimulate differentiation of OPCs and myelination by mature OLs in the injured spinal cord may also contribute to the limited remyelination after SCI. Our preliminary data showed that increasing expression of growth factors such as the multi- neurotrophin D15A or CNTF promoted the remyelination by grafted OPCs in the injured spinal cord. We hypothesize that the combination of blocking inhibitory BMP signaling to promote OPC differentiation and increasing the expression of growth factors to enhance their maturation and remyelination may work synergistically to promote more extensive remyelination, and lead to greater electrophysiological and locomotor behavioral recovery after SCI. In this application, we will use objective and sensitive electrophysiological and behavioral analyses to test this hypothesis in a well characterized chemically demyelinated model and also clinically-relevant contusive SCI model in adult rats. Based on our published and preliminary data, four specific aims are proposed: 1. To determine whether astrocytes from the injured spinal cord inhibit differentiation of and remyelination by adult OPCs by increased secretion of BMPs. 2. To test the hypothesis that blocking inhibitory BMP signaling will promote the differentiation, maturation, and remyelination of grafted adult OPCs in the demyelinated spinal cord. 3. To test the hypothesis that combination of blocking inhibitory BMP signaling to promote the differentiation and increasing the expression of growth factors that enhance the maturation of and myelination by OLs will work synergistically to promote the differentiation, maturation, and remyelination of grafted adult OPCs and functional recovery in the demyelinated spinal cord. 4. To test whether the optimal combinatorial strategies, established in Aims 1-3, will lead to more extensive remyelination by transplanted OPCs and further functional recovery in the more clinically relevant contusion SCI model.