Abstract
Purpose :
There is a current unmet need for regenerative therapies that restore vision and retinal ganglion cell (RGC) function in individuals that suffer from axonopathy, a pathological feature of a multitude of diseases and disorders including, glaucoma, optic neuritis, and traumatic optic nerve injury. Research in our lab has indicated that murine immature myeloid cells act in a regenerative capacity, rescuing damaged neurons from death, and stimulating axon regeneration in response to injury. In the current project, we sought to identify and isolate an immature human myeloid cell population that could induce neuro-protection/regeneration, thus creating a translational therapeutic treatment capable of reversing neurological damage.
Methods :
CD34+ Humanized NSG-SGM3 mice were subjected to optic nerve crush (ONC) injury with and without lens scratch (LS) injury. For functional studies, human umbilical cord blood (UCB) samples were collected and processed to isolate myeloid cell populations. Definable myeloid cell populations were isolated and co-cultured with explanted neurons ex vivo or adoptively transferred into the eyes of RAG1-/- mice immediately following ONC, and again three days later.
Results :
We discovered that LS of humanized mice yielded an increased population of immature CD33+ human myeloid cells that correlated with increased regeneration of optic nerve axons in vivo. This CD33+ cell subset also increased neurite outgrowth of explanted RGCs in co-culture ex vivo. To expand translational potential, we sought to identify a similar cell subset from human samples. Utilizing human UCB samples, we determined that a unique subset of CD33+ myeloid cells, similar to those identified in the humanized mouse, improved regeneration/outgrowth compared to control myeloid cells within the same patient sample. These UCB derived CD33+ cells increased survival of human motor neurons and increased neurite outgrowth in both human cortical neurons and mouse RGCs, when compared to control cells ex vivo. Further, following ONC, CD33+ UCB cells improved axon regeneration and RGC survival over same patient control cells.
Conclusions :
Our results indicate that we have successfully identified a unique pro-regenerative/neuroprotective human myeloid cell subset. These findings demonstrate the exciting potential of a translational immune cell-based therapy capable of ameliorating RGC loss and neurological disability.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.