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.

摘要 脊髓损伤（SCI）后，轴突变性是导致脊髓功能丧失的重要原因.移植神经 来源于患者自身的诱导多能干细胞（iPSC）的祖细胞是一种有前途的策略， 建立神经元中继，用于将损伤的长神经束与其失神经元重新连接， 功能恢复我们假设共移植的人iPSC衍生的胶质限制性祖细胞 （GRP）和神经元限制性祖细胞（NRP）将协同工作以形成用于神经元的神经元中继。 多神经营养因子D15 A将指导移植的神经元与受损的神经束形成功能性突触， 失神经的靶神经元，并促进更大的功能恢复在两个撕裂和挫伤的颈部 SCI动物模型。在该提议中，我们将测试（1）共移植的人iPSC衍生的GRP和NRP是否与人iPSC衍生的GRP和NRP共移植。 将协同工作，为受伤的上行背柱束（DCT）形成神经元中继， 皮质脊髓下行束（CST），促进C3背索损伤后的功能恢复; 如果背核和尾侧腹角的多神经营养因子D15 A梯度将指导移植神经元延伸 轴突朝向DCT和CST的失神经靶神经元并与之形成功能性突触，并促进 更大的功能恢复;和（3）如果移植的NRPs和GRP将整合到备用电路中， 促进临床相关颈挫伤SCI后的功能恢复。从拟议的 这种方法对于开发安全有效的基于患者特异性iPSC的恢复疗法至关重要， SCI在不久的将来