A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current
therapies may delay RGC loss, they do not restore visual function or completely halt
disease progression. Regenerative medicine has recently focused on stem cell
therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long-term impact of reactive
gliosis occurring in the host retina in response to transplanted stem cells. The aim of this work was to investigate
retinal glial responses to intravitreally transplanted bone marrow mesenchymal stem cells (BM-MSCs) to help identify factors able to modulate graft-induced reactive
gliosis. We found in vivo that intravitreal BM-MSC
transplantation is associated with
gliosis-mediated
retinal folding, upregulation of intermediate filaments, and recruitment of macrophages. These responses were accompanied by significant JAK/STAT3 and MAPK (ERK1/2 and JNK) cascade activation in
retinal Muller glia.
Lipocalin-2 (Lcn-2) was identified as a potential new
indicator of graft-induced reactive
gliosis. Pharmacological inhibition of STAT3 in BM-MSC cocultured
retinal explants successfully reduced
glial fibrillary acidic protein expression in
retinal Muller glia and increased BM-MSC
retinal engraftment. Inhibition of stem cell-induced reactive
gliosis is critical for successful
transplantation-based strategies for neuroprotection, replacement, and regeneration of the optic nerve.