MANF in Retinal Therapies:Improving Regenerative T

MANF in Retinal Therapies:Improving Regenerative Therapies
by Promoting Tissue Repair
JOANA NEVES, Deepak A. Lamba, Heinrich Jasper.
Buck Institute
for Research on Aging, Novato, CA
.
Purpose:
Stem cell based therapies, have been shown to hold real
promise in the treatment of degenerative diseases of the retina.
However, the efficiency of such strategies is still considerably low.
Tissue repair mechanisms are conserved at the organism level and
enhance the regenerative process. We hypothesized that promoting
tissue repair may also enhance the efficiency of cell engraftment in
the retina. Key components of the retinal repair network have been
identified in Drosophila involving interactions between the damaged
retina and hemocytes. We have used the Drosophila to identify
hemocyte derived factors that can promote tissue repair in the retina
and have tested the conservation of their function in the mammalian
retina. Our work focused on Mesencephalic Astrocyte-derived
Neurotrophic Factor (MANF).
Methods:
We have used UV induced retinal damage in flies and light
induced retinal damage in mouse as model systems to test the effects
of MANF. MANF was overexpressed in flies using the UAS/Gal4
system. In mice, recombinant protein was delivered by intravitreal
injection.
Results:
We have identified MANF as a hemocyte derived protein
in Drosophila that can promote tissue repair in the fly retina, using
RNAseq. We show that MANF is expressed in hemocytes of
Drosophila larvae, it is secreted to the hemolymph and induced in
response to stress in a Pvf-1/PvR dependent manner. Hemocyte
specific MANF expression is sufficient to reduce tissue loss after
UV and genetically-induced photoreceptor apoptosis. Moreover,
stress induced MANF results in changes in the hemocyte population
correlating with increased lamellocyte differentiation. We have tested
the conservation of the pathway in mammalian retinal repair. As in
flies, MANF is induced in microglia/macrophages invading the retina
following light damage and this correlates with reduced tissue loss.
Importantly, intravitreal delivery of MANF recombinant protein is
sufficient to limit cell death following light damage and promotes
alterations in macrophages/microglia.
Conclusions:
MANF is a conserved neuroprotective factor in the
retina. MANF acts as an immune-modifying factor to limit cell loss
following acute damage. . This work will serve as a proof of concept
to the use of tissue repair promoting factors as co-adjutants in stem
cell regenerative therapies.
Commercial Relationships:
JOANA NEVES
, None;
Deepak A.
Lamba
, None;
Heinrich Jasper
, None
Support:
Glenn Foundation Postdoctoral fellowship to JN, NIH