Friday, May 9, 2025
5/9/2025
Enhancement of RGC survival and Optic Nerve Regeneration by Cytokine Polarized Myeloid Cells - Abstract A significant percent of individuals with optic nerve (ON) injuries, secondary to trauma or glaucoma, suffer permanent visual loss. The adult mammalian visual system has a limited capacity for self-repair, making it vulnerable to damage and degenerative processes. Mature retinal ganglion cells (RGCs, the projection neurons of the eye) do not replicate, and severed ON axons have a limited capacity to regrow, increasing the likelihood of poor visual outcomes. Various strategies, such as genetic reprogramming of RGC, blockade of endogenous axon growth inhibitors, and biomaterial transplantation, have been attempted in animal studies to promote axon regeneration, but none have been curative. Successful outcomes in the clinical setting will likely require personalized, multimodal approaches using synergistic therapeutic agents. A promising strategy for restoring the integrity of injured tissue is to deploy natural immune driven healing pathways. Immune-drive healing has been convincingly demonstrated in animal models of cutaneous wounds and myocardial ischemia. There is an increasing recognition of the potential for immune responses to drive repair in the eye as well. However, the specific immune cell populations involved, and their mechanisms of action, are poorly understood. In preliminary experiments, we showed that immature bone marrow neutrophils (BMN), harvested from naïve mice, express markers of alternative activation and acquire neuroprotective pro-regenerative properties following short term polarization with interleukin (IL)-4 and granulocyte-colony stimulating factor (G-CSF). These novel cells promote RGC survival and drive RGC axon regrowth, both in vitro and in animal models of optic neuropathy, at least partially through the secretion of soluble factors. Similarly, IL-4/G-CSF polarized human BM myeloid cells, as well as their conditioned media, promoted neurite outgrowth of human iPSC derived RGCs. A major goal of the current proposal is to elucidate the factors secreted by the IL-4/G-CSF polarized murine BMN that contribute to their reparative effects. Additionally, we will investigate how these BMN modulate glial cells in the eye to promote a neuroprotective phenotype. Lastly, we will characterize pro- regenerative human BM myeloid cells in depth, explore their mechanisms of action, and develop protocols to expand them in vitro, in a manner that preserves their reparative properties. We are hopeful that, collectively, the results of these experiments will inform the development of the first autologous myeloid cell therapies that promote visual recovery in individuals with optic neuropathy. Furthermore, this line of research could lead to the development of therapeutic cocktails of pharmaceutical agents, nanoparticle-based therapies, and/ or gene therapies, that mimic the mechanism of action of the IL-4/G-CSF polarized myeloid cells.
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