Heparin-binding epidermal growth factor (HBEGF) and fibroblast growth factor 2 (FGF2) rescue the deficit in the formation of Müller glia-derived progenitor cells in retinas missing microglia and macrophage.

Recent studies have demonstrated the impact of pro-inflammatory signaling and reactive microglia/macrophage on the formation of Müller glial-derived progenitor cells (MGPCs) in the retina. In chick retina, the ablation of microglia/macrophage prevents the formation of MGPCs. Analyses of scRNA-seq chick retinal libraries revealed that quiescent and activated microglia/macrophage have a significant impact upon the transcriptomic profile of Müller glia (MG). In the damaged monocyte-depleted retinas, MG fail to upregulate genes related to different cell signaling pathways including those related to Wnt, Heparin binding epidermal growth factor (HBEGF), Fibroblast growth factor (FGF), and retinoic acid receptors. Inhibition of GSK3β, to simulate Wnt-signaling, failed to rescue the deficit in the formation of MGPCs, whereas application of HBEGF or FGF2 completely rescued the formation of MGPCs in monocyte-depleted retinas. Inhibition of Smad3 or activation of retinoic acid receptors partially rescued the formation of MGPCs in monocyte-depleted retinas. We conclude that signals produced by reactive microglia/macrophage in damaged retinas stimulate MG to upregulate cell signaling through HBEGF, FGF and retinoic acid, and downregulate signaling through TGFβ/Smad3 to promote the reprogramming on MG into proliferating MGPCs.