Reconnecting the injured cervical spinal cord by transplanted human iPSC-derived neural progenitors

通过移植人类 iPSC 衍生的神经祖细胞重新连接受损的颈脊髓

• 批准号: 10596787
• 负责人: Ying Liu
• 金额: $ 32.27万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596787
• 关键词: Ablation; Acute; Address; Anatomy; Animal Model; Astrocytes; Axon; Biological Assay; Cell Nucleus; Cell Therapy; Cells; Cervical; Cervical spinal cord injury; Cholera Toxin Protomer B; Contusions; Corticospinal Tracts; Data; Dorsal; Electron Microscopy; Electrophysiology (science); Food; Future; Generations; Horns; Human; Immunoelectron Microscopy; Label; Laceration; Locomotor Recovery; Mediating; Microscopy; Modeling; Molecular; Natural regeneration; Neurologic; Neurons; Patients; Phase; Phenotype; Protocols documentation; Recovery of Function; Role; Sensory; Somatosensory Evoked Potentials; Spinal Cord Contusions; Spinal Cord Lacerations; Spinal cord injury; Stem cell transplant; Synapses; System; Testing; Therapeutic; Time; Tissues; Transplantation; Vesicular stomatitis Indiana virus; Walking; Wheelchairs; Work; axon regeneration; axonal degeneration; axonal sprouting; base; behavior test; biotinylated dextran amine; cell type; clinically relevant; dorsal column; functional loss; graft function; gray matter; improved; induced pluripotent stem cell; injured; insight; interest; motor recovery; nerve stem cell; neural circuit; neural graft; neuroprotection; novel therapeutics; progenitor; relating to nervous system; remyelination; stem cell therapy; stem cells; tool; white matter

Abstract Axonal degeneration significantly contributes to functional loss after spinal cord injury (SCI). Grafting neural progenitors derived from patients’ own induced pluripotent stem cells (iPSCs) is a promising strategy to establish neuronal relay for reconnecting injured long tracts with their denervated neurons and promoting functional recovery. We hypothesize that co-transplanted human iPSC-derived glial restricted progenitors (GRPs) and neuronal restricted progenitors (NRPs) will work synergistically to form neuronal relays for the injured tracts and that multineurotrophin D15A will direct grafted neurons to form functional synapses with denervated target neurons and promote greater functional recovery in both laceration and contusion cervical SCI animal models. In this proposal, we will test (1) if co-transplanted human iPSC-derived GRPs and NRPs will work synergistically to form neuronal relays for the injured ascending dorsal column tract (DCT) and descending corticospinal tract (CST), and promote functional recovery after C3 dorsal funiculus laceration; (2) if gradient multineurotrophin D15A in dorsal nuclei and caudal ventral horn will direct grafted neurons to extend axons toward and form functional synapses with denervated target neurons of DCT and CST, and promote greater functional recovery; and (3) if grafted NRPs and GRPs will integrate into the spared circuits and promote functional recovery after clinically relevant cervical contusion SCI. Data obtained from the proposed approach will be critical in developing safe and effective patient-specific iPSC-based restorative therapies for SCI in the near future.

抽象的 轴突变性显着导致脊髓损伤（SCI）后的功能损失。嫁接中性 源自患者自身诱导的多能干细胞（IPSC）的祖细胞是一种有前途的策略 建立神经元继电器，以重新连接受伤的长片，其神经元并促进 功能恢复。我们假设共转移的人IPSC衍生的胶质限制祖细胞 （GRP）和神经元受限的祖细胞（NRP）将协同作用，形成神经元继电器 受伤的道和多尿营养蛋白D15A将指导移植神经元与 神经的靶神经元，并促进了裂缝和挫伤的更大功能恢复 SCI动物模型。在此提案中，如果共转移的人IPSC衍生的GRP和NRP，我们将测试（1） 将协同作用以形成受伤的升背柱（DCT）的神经元继电器和 降级皮质脊髓束（CST），并在C3背曲线裂缝后促进功能恢复； （2） 如果背侧核和尾腹角中的梯度多尿营养素D15A将导致移植神经元延伸 轴突朝向DCT和CST的已取代目标神经元的轴突和形成功能突触，并促进 更大的功能恢复； （3）如果嫁接的NRP和GRP将集成到蓄能的电路中，并且 临床相关的宫颈挫伤SCI后促进功能恢复。从提出的数据获得的数据 方法对于开发安全有效的患者特异性IPSC的修复疗法至关重要 SCI在不久的将来。