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.
Chapter 1: Identifying MANF in flies
In a paper published today in the journal Science, Buck researchers report that they have identified a natural immune system modulator called MANF that improved the success of retinal repair in both fly and mouse models of eye diseases, and enhanced retinal cell transplantation in mouse models of photoreceptor degeneration.
The story of MANF starts with Drosophila fruit flies grown in the lab of Buck Professor Dr. Heinrich Jasper. His lab studies hemocytes, the fly equivalent of blood cells, and the repair factors that they secrete in response to injury. To model retinal damage, Jasper and his lab exposed photoreceptors in the retina of flies to UV light and then screened for secreted proteins that were released by hemocytes in response to UV damage.
They identified a protein called a secreted protein called MANF and hypothesized that this factor could promote tissue regeneration and act as a neuroprotective, “retinal repair factor”.
In a Buck Institute news release, Jasper explained how further experiments showed that MANF was secreted by hemocytes in response to UV induced damage in the retina, and that it shifted these immune cells from promoting inflammation to reducing inflammation and promoting retinal regeneration.
Chapter 2: MANF is neuroprotective in mice
Part two of the story involved determining whether MANF had similar neuroprotective and anti-inflammatory properties in mammalian models. Dr. Deepak Lamba, Buck Professor and co-senior author on the study, took the lead and first tested whether MANF could reduce light-induced damage of photoreceptors in mouse models of retinal degeneration.
Injecting MANF protein into the eyes of these mice significantly reduced cell death caused by light exposure. Similarly, injection of fibroblast cells that secreted MANF also had a neuroprotective effect in the damaged retina by recruiting innate immune cells to promote the body’s natural repair mechanisms.
Chapter 3: MANF improves cell transplantation in mice
The final chapter involved testing whether MANF could improve the outcome of transplanted photoreceptor cells in blind mice genetically engineered to have retinal damage. The addition of MANF improved the survival and integration of the transplanted cells in the retinas of the mice and also improved the animals’ visual function.
Lamba concluded in a Buck news release that, “MANF promotes healing and helps create a microenvironment conducive to successful transplantation.”
These preliminary results in flies and mice are encouraging and Jasper believes that the neuroprotective effects of MANF could potentially be applied to other diseases of aging at an early stage that could prevent disease progression.
“Our hope is that MANF will be useful for treatment of inflammatory conditions in many disease contexts,” Jasper explained. “Focusing on immune modulation to promote a healthy repair response to tissue damage rather than a deleterious inflammatory response is a new frontier in aging research.”