Cell-based therapies for traumatic optic neuropathy: Recent advances, challenges, and perspectives.

Traumatic optic neuropathy is a form of optic neuropathy resulting from trauma. Its pathophysiological mechanisms involve primary and secondary injury phases, leading to progressive retinal ganglion cell loss and axonal degeneration. Contributing factors such as physical trauma, oxidative stress, neuroinflammation, and glial scar formation exacerbate disease progression and retinal ganglion cell death. Multiple forms of cell death-including apoptosis, pyroptosis, necroptosis, and ferroptosis- are involved at different disease stages. Although current treatments, such as corticosteroid therapy and surgical interventions, have limited efficacy, cell-based therapies have emerged as a promising approach that simultaneously promotes neuroprotection and retinal ganglion cell regeneration. This review summarizes recent advances in cell-based therapies for traumatic optic neuropathy. In the context of cell replacement therapy, retinal ganglion cell-like cells derived from embryonic stem cells and induced pluripotent stem cells-via chemical induction or direct reprogramming-have demonstrated the ability to integrate into the host retina and survive for weeks to months, potentially improving visual function. Mesenchymal stem cells derived from various sources, including bone marrow, umbilical cord, placenta, and adipose tissue, have been shown to enhance retinal ganglion cell survival, stimulate axonal regeneration, and support partial functional recovery. Additionally, neural stem/progenitor cells derived from human embryonic stem cells offer neuroprotective effects and function as "neuronal relays," facilitating reconnection between damaged regions of the optic nerve and the visual pathway. Beyond direct cell transplantation, cell-derived products, such as extracellular vesicles and cell-extracted solutions, have demonstrated promising neuroprotective effects in traumatic optic neuropathy. Despite significant progress, several challenges remain, including limited integration of transplanted cells, suboptimal functional vision recovery, the need for precise timing and delivery methods, and an incomplete understanding of the role of the retinal microenvironment and glial cell activation in neuroprotection and neuroregeneration. Furthermore, studies with longer observation periods and deeper mechanistic insights into the therapeutic effects of cell-based therapies remain scarce. Two Phase I clinical trials have confirmed the safety and potential benefits of cell-based therapy for traumatic optic neuropathy, with reported improvements in visual acuity. However, further studies are needed to validate these findings and establish significant therapeutic outcomes. In conclusion, cell-based therapies hold great promise for treating traumatic optic neuropathy, but critical obstacles must be overcome to achieve functional optic nerve regeneration. Emerging bioengineering strategies, such as scaffold-based transplantation, may improve cell survival and axonal guidance. Successful clinical translation will require rigorous preclinical validation, standardized protocols, and the integration of advanced imaging techniques to optimize therapeutic efficacy.