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Heparin-binding epidermal growth factor and fibroblast growth factor 2 rescue Müller glia-derived progenitor cell

Heithem M El-Hodiri1, James R Bentley1, Alana G Reske1

  • 1Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43221, USA.

Development (Cambridge, England)
|November 16, 2023
PubMed

Insights

Reactive microglia/macrophages are crucial for Müller glial-derived progenitor cell (MGPC) formation in the retina. These immune cells stimulate Müller glia (MG) via specific signaling pathways, promoting retinal regeneration.

Area of Science:

  • Retinal biology
  • Neuroimmunology
  • Cellular reprogramming

Background:

  • Pro-inflammatory signaling and reactive microglia/macrophages influence Müller glial-derived progenitor cell (MGPC) formation.
  • Microglia/macrophages play a critical role in chick retina MGPC generation; their absence prevents MGPC formation.
  • Single-cell RNA-sequencing reveals microglia/macrophages significantly alter the transcriptomic profile of Müller glia (MG).

Purpose of the Study:

  • To investigate the role of microglia/macrophages in regulating Müller glia (MG) signaling pathways.
  • To identify specific signaling molecules involved in microglia/macrophage-mediated MG reprogramming into MGPCs.
  • To understand how immune cell signals promote retinal progenitor cell generation.

Main Methods:

  • Analysis of single-cell RNA-sequencing data from chick retinal libraries.
  • Experimental manipulation of microglia/macrophage populations in damaged retinas.
  • Pharmacological inhibition/activation of specific signaling pathways (GSK3β, Wnt, HBEGF, FGF2, Smad3, retinoic acid receptors) in monocyte-depleted retinas.

Main Results:

  • Müller glia (MG) in damaged, monocyte-depleted retinas failed to upregulate key signaling pathway genes (Wnt, HBEGF, FGF, retinoic acid).
  • Inhibition of GSK3β did not rescue MGPC formation.
  • Application of heparin-binding epidermal growth factor (HBEGF) or fibroblast growth factor 2 (FGF2) fully rescued MGPC formation in depleted retinas.
  • Inhibition of Smad3 or activation of retinoic acid receptors partially rescued MGPC formation.

Conclusions:

  • Reactive microglia/macrophages in damaged retinas stimulate MG to upregulate HBEGF, FGF, and retinoic acid signaling.
  • These immune signals downregulate TGFβ/Smad3 signaling, promoting MG reprogramming into proliferating MGPCs.
  • Microglia/macrophage-derived signals are essential for initiating retinal progenitor cell formation through specific molecular pathways.
Keywords:
Cell signalingMicrogliaMüller gliaRetinal regenerationscRNA-seq

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