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

摘要 轴突变性是脊髓损伤后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(IPSCs)的祖细胞是一种很有前途的策略 建立神经元中继以使受损的长束与其失神经神经元重新连接并促进 功能恢复。我们推测，联合移植人iPSC来源的神经胶质细胞限制的祖细胞 (GRP)和神经元限制性前体细胞(NRP)将协同工作，形成神经元中继，为 损伤束和多神经营养因子D15A将指导移植神经元形成功能性突触 颈部撕裂伤和挫伤的靶神经元失神经和促进更大的功能恢复 脊髓损伤动物模型。在这项提案中，我们将测试(1)联合移植人类IPSC来源的GRP和NRP 将协同作用，为损伤的上升背柱束(DCT)和 下行皮质脊髓束(CST)，促进C3背索撕裂后功能恢复； 如果背核和尾侧腹角内的梯度多神经营养因子D15A会引导移植神经元延伸 轴突朝向DCT和CST失神经支配的靶神经元并与之形成功能性突触，并促进 更大的功能恢复；以及(3)如果移植的NRP和GRP将整合到备用电路中，以及 促进临床相关的颈椎挫伤后功能恢复。从建议的 在开发安全有效的以IPSC为基础的恢复性疗法方面，方法将是关键 SCI在不久的将来。

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.