Heparin-binding epidermal growth factor and fibroblast growth factor 2 rescue Müller glia-derived progenitor cell formation in microglia- and macrophage-ablated chick retinas

Recent studies have demonstrated the impact of pro-inflammatory signaling and reactive microglia/macrophages on the formation of Müller glial-derived progenitor cells (MGPCs) in the retina. In chick retina, ablation of microglia/macrophages prevents the formation of MGPCs. Analyses of single-cell RN...

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Bibliographic Details
Published in:	Development (Cambridge) Vol. 150; no. 23
Main Authors:	El-Hodiri, Heithem M, Bentley, James R, Reske, Alana G, Taylor, Olivia B, Palazzo, Isabella, Campbell, Warren A, Halloy, Nicklaus R, Fischer, Andy J
Format:	Journal Article
Language:	English
Published:	England The Company of Biologists Ltd 01-12-2023
Subjects:	Animals Cell Proliferation - genetics Chickens EGF Family of Proteins - metabolism Ependymoglial Cells - metabolism Fibroblast Growth Factor 2 - metabolism Heparin - metabolism Heparin - pharmacology Macrophages Microglia - metabolism Neuroglia - metabolism Receptors, Retinoic Acid - metabolism Retina - metabolism Stem Cells Stem Cells and Regeneration Wnt Signaling Pathway scRNA-seq Müller glia Retinal regeneration Cell signaling Microglia
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Summary:	Recent studies have demonstrated the impact of pro-inflammatory signaling and reactive microglia/macrophages on the formation of Müller glial-derived progenitor cells (MGPCs) in the retina. In chick retina, ablation of microglia/macrophages prevents the formation of MGPCs. Analyses of single-cell RNA-sequencing chick retinal libraries revealed that quiescent and activated microglia/macrophages have a significant impact upon the transcriptomic profile of Müller glia (MG). In 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 MGPC formation, 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/macrophages 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 of MG into proliferating MGPCs.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work Competing interests Handling Editor: François Guillemot The authors declare no competing or financial interests.
ISSN:	0950-1991 1477-9129
DOI:	10.1242/dev.202070