MST2 Acts via AKT Activity to Promote Neurite Outgrowth and Functional Recovery after Spinal Cord Injury in Mice.

Spinal cord injury (SCI) constitutes a significant clinical challenge, and there is extensive research focused on identifying molecular activities that can facilitate the repair of spinal cord injuries. Mammalian sterile 20-like kinase 2 (MST2), a core component of the Hippo signaling pathway, plays a key role in apoptosis and cell growth. However, its role in neurite outgrowth after spinal cord injury remains unknown. Through comprehensive in vitro and in vivo experiments, we demonstrated that MST2, predominantly expressed in neurons, actively participated in the natural development of the CNS. Post-SCI, MST2 expression significantly increased, indicating its activation and potential role in the early stages of neural recovery. Detailed analyses showed that MST2 knockdown impaired neurite outgrowth and motor function recovery, whereas MST2 overexpression led to the opposite effects, underscoring MST2's neuroprotective role in enhancing neural repair. Further, we elucidated the mechanism underlying MST2's action, revealing its interaction with AKT and positive regulation of AKT activity, a well-established promoter of neurite outgrowth. Notably, MST2's promotion of neurite outgrowth and motor functional recovery was diminished by AKT inhibitors, highlighting the dependency of MST2's neuroprotective effects on AKT signaling. In conclusion, our findings affirmed MST2's pivotal role in fostering neuronal neurite outgrowth and facilitating functional recovery after SCI, mediated through its positive modulation of AKT activity. In conclusion, our findings confirmed MST2's crucial role in neural protection, promoting neurite outgrowth and functional recovery after SCI through positive AKT activity modulation. These results position MST2 as a potential therapeutic target for SCI, offering new insights into strategies for enhancing neuroregeneration and functional restoration.

Neuron-Derived Exosomes Promote the Recovery of Spinal Cord Injury by Modulating Nerve Cells in the Cellular Microenvironment of the Lesion Area.

During spinal cord injury (SCI), the homeostasis of the cellular microenvironment in the injured area is seriously disrupted, which makes it extremely difficult for injured neurons with regenerative ability to repair, emphasizing the importance of restoring the cellular microenvironment at the injury site. Neurons interact closely with other nerve cells in the central nervous system (CNS) and regulate these cells. However, the specific mechanisms by which neurons modulate the cellular microenvironment remain unclear. Exosomes were isolated from the primary neurons, and their effects on astrocytes, microglia, oligodendrocyte progenitor cells (OPCs), neurons, and neural stem cells were investigated by quantifying the expression of related proteins and mRNA. A mouse SCI model was established, and neuron-derived exosomes were injected into the mice by the caudal vein to observe the recovery of motor function in mice and the changes in the nerve cells in the lesion area. Neuron-derived exosomes could reverse the activation of microglia and astrocytes and promote the maturation of OPCs in vivo and in vitro. In addition, neuron-derived exosomes promoted neurite outgrowth of neurons and the differentiation of neural stem cells into neurons. Moreover, our experiments showed that neuron-derived exosomes enhanced motor function recovery and nerve regeneration in mice with SCI. Our findings highlight that neuron-derived exosomes could promote the repair of the injured spinal cord by regulating the cellular microenvironment of neurons and could be a promising treatment for spinal cord injury.