Vivinetto A L, Bernstein A, Soliman M, Cave J W, Hollis E
Burke Neurological Institute, White Plains, New York, USA.
In Vitro Cell Research LLC, Fort Lee, New Jersey, USA.
Glia. 2025 May;73(5):969-984. doi: 10.1002/glia.24667. Epub 2025 Jan 19.
Manipulating wound healing-associated signaling after SCI presents a promising avenue for increasing the recovery of function after injury. This study explores the potential of targeting molecular regulators of wound healing, initially identified in nonneural tissues, to enhance outcomes after SCI. Astrocytes, pivotal in central nervous system wound healing, play a crucial role in tissue remodeling and recovery. However, the optimal manipulation of astrogliosis for beneficial outcomes remains elusive. Previous research demonstrated a transcriptional response in astrocytes resembling epithelial-to-mesenchymal transitions (EMTs) after CNS injury. Here, we investigate the extrinsic manipulation of wound healing through the Receptor Activator of Nuclear-factor Kappa-Β (RANK) pathway, known for its involvement in nonneural tissue remodeling and linked to EMT pathway. Using a severe thoracic spinal cord contusion mouse model, we demonstrate that acute activation of the RANK pathway with RANK ligand (RANKL) adversely affects tissue remodeling, resulting in larger lesion volumes and delayed recovery of posture and locomotion. These findings suggest that early perturbations in the tight molecular regulation of tissue remodeling negatively impact the wound-healing process after SCI. The study provides a proof-of-concept demonstration that exogenous nonneural remodeling ligands can modify astrocyte responses and functional recovery after SCI, raising questions about the optimal time frame for beneficial remodeling interventions during injury progression. These insights open new avenues for therapeutic strategies aimed at improving functional outcomes following SCI.
脊髓损伤后调控与伤口愈合相关的信号传导为促进损伤后功能恢复提供了一条有前景的途径。本研究探索了靶向最初在非神经组织中发现的伤口愈合分子调节因子以改善脊髓损伤后结果的潜力。星形胶质细胞在中枢神经系统伤口愈合中起关键作用，在组织重塑和恢复中扮演重要角色。然而，对星形胶质细胞增生进行最佳调控以获得有益结果仍不明确。先前的研究表明，中枢神经系统损伤后星形胶质细胞会出现类似上皮-间充质转化（EMT）的转录反应。在此，我们通过核因子κB受体激活剂（RANK）途径研究伤口愈合的外在调控，该途径以参与非神经组织重塑并与EMT途径相关而闻名。使用严重胸段脊髓挫伤小鼠模型，我们证明用RANK配体（RANKL）急性激活RANK途径会对组织重塑产生不利影响，导致更大的损伤体积以及姿势和运动恢复延迟。这些发现表明，组织重塑严格分子调控的早期扰动会对脊髓损伤后的伤口愈合过程产生负面影响。该研究提供了一个概念验证，即外源性非神经重塑配体可改变脊髓损伤后星形胶质细胞反应和功能恢复，这引发了关于损伤进展过程中有益重塑干预最佳时间框架的问题。这些见解为旨在改善脊髓损伤后功能结果的治疗策略开辟了新途径。
