Combinatory strategies to functional remyelination after spinal cord injury

脊髓损伤后功能性髓鞘再生的组合策略

• 批准号: 8242791
• 负责人: QI LIN CAO
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242791
• 关键词: Adult; Astrocytes; Axon; BMP2 gene; Behavioral; Bone Morphogenetic Proteins; Cell Differentiation process; Cell Transplants; Ciliary Neurotrophic Factor; Coculture Techniques; Complex; Contusions; Data; Demyelinations; Development; Environment; Family; Growth Factor; Healthcare; In Vitro; Injection of therapeutic agent; Injury; Lead; Lesion; Modeling; Modification; Myelin; Neurons; Oligodendroglia; Patients; Process; Proliferating; Publishing; Quality of life; Rattus; Reactive Inhibition; Recovery; Recovery of Function; Severities; Signal Transduction; Societies; Spinal Cord; Spinal Ganglia; Spinal cord injury; Testing; Therapeutic Intervention; Time; Transplantation; Undifferentiated; Work; astrogliosis; base; behavior test; central nervous system injury; clinically relevant; combinatorial; functional loss; in vivo; inhibitor/antagonist; injured; irradiation; myelination; nerve stem cell; neurotrophic factor; novel therapeutics; oligodendrocyte precursor; overexpression; precursor cell; progenitor; remyelination; repaired; response to injury; success; transcription factor

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.

脱髓鞘是创伤性脊髓损伤(SCI)后功能丧失的重要因素。脱髓鞘 轴突在损伤的脊髓中长期存在，脱髓鞘的轴突重新髓鞘形成，但其他情况下完整的轴突， 是促进脊髓损伤后功能恢复的重要修复策略。成人脊髓有一个有限的 自发重新髓鞘形成的能力，尽管少突胶质前体细胞(OPC)具有 损伤后再生髓鞘、变得活跃和增殖的能力。、和的区别 在损伤的脊髓中，内源性OPC的再髓鞘形成受到抑制。神经干细胞移植 神经干细胞或神经胶质前体细胞也被证明能有效促进脊髓损伤后的髓鞘再生，但程度不同。 成功之路。大多数移植的神经干细胞分化为星形胶质细胞，并分化为 损伤脊髓中的少突胶质细胞(OLs)或神经元受到抑制。同样，与移植的神经胶质细胞的分化 祖细胞也被限制在损伤的脊髓中，许多移植的神经胶质祖细胞仍然存在 未分化或分化为星形胶质细胞。认识制约人的分化的机制(S) 而内源性和移植的神经干细胞或OPC在损伤的脊髓中的重新髓鞘形成应该会导致新的 修复脊髓损伤的治疗策略。损伤微环境中抑制因子的存在可能 有助于抑制少突胶质细胞的分化和再髓鞘形成。我们的初步数据显示 损伤脊髓中的反应性星形胶质细胞通过增加 骨形态发生蛋白的表达。缺乏足够的信号来刺激分化 损伤脊髓中OPC的表达和成熟OCs的髓鞘化也可能是有限的再髓鞘形成的原因 在SCI之后。我们的初步数据显示，生长因子的表达增加，如多个- 神经营养因子D15A或CNTF促进损伤脊髓内移植的OPC的再髓鞘形成。我们 假设联合阻断抑制BMP信号以促进OPC分化和 增加生长因子的表达以促进它们的成熟和再髓鞘形成可能会起作用 协同促进更广泛的髓鞘再生，并导致更大的电生理和运动性 脊髓损伤后的行为恢复。在这一应用中，我们将使用客观和灵敏的电生理和 在一个具有良好特征的化学脱髓鞘模型中进行行为分析来验证这一假说，而且 临床相关的成年大鼠脊髓挫伤模型。根据我们公布的和初步的数据，四个具体的 目的被提出：1.确定损伤脊髓的星形胶质细胞是否抑制分化 成体OPC通过增加BMPs的分泌而重新髓鞘形成。2.检验阻断抑制作用的假设 BMP信号将促进移植的成体OPC的分化、成熟和再髓鞘形成 脊髓脱髓鞘。3.验证以下假设：阻断抑制BMP信号的组合 促进分化和增加生长因子的表达，促进细胞的成熟 成骨细胞的髓鞘形成将协同作用促进移植的分化、成熟和再髓鞘形成。 成人OPC与脱髓鞘脊髓的功能恢复。4.检验最优组合是否 在目标1-3中建立的战略将导致移植的OPC更广泛的再髓鞘形成，并进一步 更具临床相关性的挫伤脊髓损伤模型的功能恢复。

项目成果

Effect of type-2 astrocytes on the viability of dorsal root ganglion neurons and length of neuronal processes.

• DOI: 10.4103/1673-5374.125339
• 发表时间: 2014-01-15
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Fan C;Wang H;Chen D;Cheng X;Xiong K;Luo X;Cao Q
• 通讯作者: Cao Q

Transplantation of Human Induced Pluripotent Stem Cell-Derived Neural Progenitor Cells Promotes Forelimb Functional Recovery after Cervical Spinal Cord Injury.

• DOI: 10.3390/cells11172765
• 发表时间: 2022-09-05
• 期刊: CELLS
• 影响因子: 6
• 作者: Zheng, Yiyan;Gallegos, Chrystine M.;Xue, Haipeng;Li, Shenglan;Kim, Dong H.;Zhou, Hongxia;Xia, Xugang;Liu, Ying;Cao, Qilin
• 通讯作者: Cao, Qilin

RNA-seq characterization of spinal cord injury transcriptome in acute/subacute phases: a resource for understanding the pathology at the systems level.

• DOI: 10.1371/journal.pone.0072567
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chen K;Deng S;Lu H;Zheng Y;Yang G;Kim D;Cao Q;Wu JQ
• 通讯作者: Wu JQ