Optic nerve atrophy (ONA) is the endpoint of numerous optic neuropathies, characterized by the degeneration of retinal ganglion cells (RGCs) and their axons, leading to partial or complete loss of vision.1 The optic neuropathy may be: ischemic, traumatic, glaucomatous,  inflammatory, toxic,  compression,  hereditary, or tumor-induced. Histopathologically, it manifests as axonal loss, gliosis, and pallor of the optic disc.1 Conventional treatments are focused on preventing progression rather than reversing neuronal damage, underscoring the urgent need for regenerative strategies aimed at restoring lost function.2,3

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Recent advancements in stem cell therapy include the development of RGC organoids, CRISPR-mediated gene editing in iPSCs for inherited conditions such as Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA), and intravitreal or subretinal injections of MSCs for their paracrine support.4-6 Beike Biotechnology reports positive anecdotal outcomes from the clinical use of umbilical cord-derived stem cells, indicating improvements in visual acuity and field in certain patients. However, thorough clinical trials are still needed to substantiate these claims.7 While no stem cell-based therapy has yet received widespread regulatory approval for ONA, ongoing trials and translational research continue to shed light on the safety and potential efficacy of these approaches.3,8 iPSCs, due to their patient-specific origin and versatility in differentiation, represent a cornerstone of personalized regenerative medicine for optic neuropathies.3,8  Future research should focus on refining transplantation methods to ensure long-term cell survival and integration, as well as minimizing immunogenicity and tumorigenic risks.8,9 These goals will likely be achieved through interdisciplinary collaborations that integrate stem cell biology, gene editing, biomaterials, and neuro-ophthalmology.

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Emerging therapies involving stem cells—particularly induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) - hold promise for neuroregeneration and neuroprotection in ONA. These cells demonstrate potential in differentiating into RGC-like phenotypes, integrating into host tissue, and secreting trophic factors essential for neuronal survival.2,3 Preclinical studies have shown that iPSCs can recapitulate disease phenotypes in vitro, providing a platform for modeling optic neuropathies and evaluating gene and cell therapies.2,3 Furthermore, MSCs possess immunomodulatory and neuroprotective capabilities, making them attractive candidates for halting optic nerve degeneration.4

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Stem cell therapy can replace damaged cells directly by implanting exogenous cells into the affected area, which are also capable of promoting the proliferation, differentiation, and restoration of tissue-resident cells. This is done by modifying their microenvironments via the activation of precursor cells.10,1 The nerve grafting is gold standard treatment for peripheral nerve injury for now, but this has issues such as donor site morbidity. New techniques focus on replacing these grafts with growth factors and/or stem cells (MSCs). Dental-MSCs may also be the potential sources of MSCs for nerve repair.11,12

Bone marrow-derived stromal cells (BM-MSCs) are gaining increasing importance in the field of regenerative medicine. Although the therapeutic value of MSCs is now being established through numerous clinical trials, concerns have been raised regarding their expansion under regulatory guidelines. Bone marrow-derived MSCs (BM-MSCs) account for approximately 0.001-0.01% of bone marrow mononuclear cells. Due to their low abundance, extensive in vitro culturing and expansion are necessary to obtain sufficient numbers for research or clinical applications. The properties of BM-MSCs - such as ease of isolation from bone marrow without causing an immunological problem, ability to expand in vitro within a short period, biopreservation for point-of-care delivery with minimal loss of potency, and the absence of reported severe adverse reactions during autologous or allogenic therapy - make them an essential tool in regenerative medicine.12

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While significant progress has been made in the field of optic nerve regeneration over the past few decades, it is essential to recognize that the process of axon regeneration is highly complex, and relying on a single factor may not be sufficient to facilitate complete regeneration. Providing a combinatorial treatment is almost certainly necessary to achieve successful regeneration of the optic nerve, and numerous studies investigating different combinations have demonstrated that combining treatments results in more regeneration compared to single therapies. While these treatments have shown promising results in experimental models, treatments focused solely on optic nerve regeneration are still in the early stages of preclinical development. Ultimately, the ability to regenerate the axons of the optic nerve would enable the development of successful therapies for the millions of people who suffer from optic neuropathies.13