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）后功能丧失。 来自患者自身诱导多能干细胞 (iPSC) 的祖细胞是一种有前途的策略 建立神经元中继，将受伤的长束与其去神经的神经元重新连接起来，并促进 我们在共同移植人类 iPSC 来源的神经胶质细胞的限制性祖细胞方面遇到了困难。 （GRP）和限制性神经元祖细胞（NRP）将协同工作，形成神经元中继 损伤的纤维束，多神经营养蛋白 D15A 将指导移植的神经元形成功能性突触 去神经靶标神经元并促进颈椎撕裂伤和挫伤的更大功能恢复 在本提案中，我们将测试 (1) 是否共移植人类 iPSC 衍生的 GRP 和 NRP。 将协同作用，为受伤的上行背柱束（DCT）形成神经中继， 皮质脊髓下降束 (CST)，促进 C3 背索撕裂后的功能恢复 (2) 背核和尾侧腹角中的梯度多神经营养蛋白 D15A 是否会引导移植神经元延伸 轴突朝向 DCT 和 CST 的去神经靶神经元并与其形成功能性突触，并促进 更好的功能恢复；(3) 移植的 NRP 和 GRP 是否会整合到备用电路中，并且 促进临床相关颈挫伤 SCI 后的功能恢复 从拟议的数据中获得。 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 近期SCI。