Stem cell therapies for degenerative eye diseases sound promising – inject retinal progenitor cells derived from human pluripotent stem cells into the eye where they will integrate and replace damaged retinal tissue to hopefully restore sight. However, a significant road block is preventing these stem cell transplants from doing their job: the transplanted cells are unable to survive and generate healthy retinal tissue due to the unhealthy, degenerative environment they find themselves in.
In patients with age-related macular degeneration or retinitis pigmentosa, retinal tissue in the eye is in a state of inflammation initiated by innate immune cells such as macrophage-derived microglia. When activated, microglia can either promote an inflammatory response or resolve inflammation and promote tissue repair and regeneration.
This balance between a pro-inflammation and tissue regeneration is something that scientists are looking to manipulate in order to develop new potential therapeutic strategies for degenerative eye diseases.
Identifying MANF in flies
In a paper published in Science, Buck researchers report that they have identified a natural immune system modulator called MANF. MANF improved the success of retinal repair in both fly and mouse models of eye diseases. It also enhanced retinal cell transplantation in mouse models of photoreceptor degeneration.
The story of MANF begins with Drosophila fruit flies in the lab of Buck Professor Dr. Heinrich Jasper. His team studies hemocytes—the fly equivalent of blood cells—and the repair factors they secrete after injury. To model retinal damage, the lab exposed fly photoreceptors to UV light and screened for proteins released by hemocytes in response.
They identified a secreted protein called MANF and hypothesized that it could promote tissue regeneration and act as a neuroprotective “retinal repair factor.”
In a Buck Institute news release, Jasper explained that further experiments confirmed MANF is released by hemocytes after UV‑induced retinal damage and shifts these immune cells from promoting inflammation to reducing it, helping drive retinal regeneration.
MANF is neuroprotective in mice
The study also tested whether MANF has similar neuroprotective and anti‑inflammatory effects in mammals. Dr. Deepak Lamba, Buck Professor and co‑senior author, led the work. He examined whether MANF could reduce light‑induced photoreceptor damage of mice.
Injecting MANF protein into the mice’s eyes significantly reduced cell death from light exposure. Injecting fibroblast cells that secrete MANF produced a similar neuroprotective effect. This occured by recruiting innate immune cells to support the retina’s natural repair processes.
MANF improves cell transplantation in mice
The final stage tested whether MANF could use transplanted photoreceptor cells in blind mice genetically engineered with retinal damage. Adding MANF boosted the survival and integration of the transplanted cells and improved the animals’ visual function.
In a Buck Institute news release, Lamba noted that “MANF promotes healing and helps create a microenvironment conducive to successful transplantation.”
These preliminary results in flies and mice are encouraging. Jasper believes MANF’s neuroprotective effects could apply to other age‑related diseases, potentially slowing or preventing progression if used early.
“Our hope is that MANF will be useful for treatment of inflammatory conditions in many disease contexts,” Jasper explained. “Focusing on immune modulation … is a new frontier in aging research.”
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http://www.patientsforstemcells.org/real-world-patient-evidence/