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Opposing Effects of Growth and Differentiation Factors in Cell-Fate Specification

Kun-Che Chang1, Catalina Sun1, Evan G Cameron1

  • 1Spencer Center for Vision Research, Byers Eye Institute, School of Medicine, Stanford University, Palo Alto, CA 94304, USA.

Current Biology : CB
|June 4, 2019
PubMed

Insights

Growth and Differentiation Factor-15 (GDF-15) promotes retinal ganglion cell (RGC) differentiation, unlike GDF-11. This discovery offers a new strategy for stem cell therapies to restore vision after RGC neuron loss.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Stem Cell Biology

Background:

  • Retinal ganglion cell (RGC) neuron death causes irreversible vision loss in conditions like glaucoma.
  • Current stem cell therapies face challenges as few differentiated stem cells become RGC-like neurons.
  • Understanding RGC differentiation mechanisms is crucial for improving cell transplantation outcomes.

Purpose of the Study:

  • To identify novel regulatory mechanisms governing RGC differentiation in vivo.
  • To investigate the opposing roles of GDF-15 and GDF-11 in RGC fate specification.
  • To explore potential therapeutic strategies for enhancing stem cell-based vision restoration.

Main Methods:

  • Utilized rodent retinal progenitor cells (RPCs) and human embryonic stem cells (hESCs).
  • Administered GDF-15 and GDF-11 to developing retinas in vivo.
  • Investigated the effects of GDF-15 and GDF-11 on Smad-2 and Smad-1 signaling pathways.
  • Examined the impact of GDF-11 knockout and Smad-2 blockade on RGC differentiation.

Main Results:

  • GDF-15 significantly promoted RGC differentiation in both RPCs and hESCs.
  • GDF-11 suppressed RGC fate specification, contrasting with GDF-15's effect.
  • GDF-15 specifically suppressed Smad-2 signaling induced by GDF-11.
  • Pharmacologic or genetic blockade of Smad-2 in vivo increased RGC specification.
  • GDF-11 knockout did not affect other retinal cell types; GDF-15 knockout slightly reduced photoreceptors.

Conclusions:

  • GDF-15 and GDF-11 exhibit opposing regulatory roles in RGC differentiation via differential Smad signaling.
  • This study reveals a novel mechanism controlling GDFs' effects on RGC development.
  • Findings suggest GDF-15 as a potential therapeutic agent to advance stem cell-to-RGC replacement therapies for vision restoration.
Keywords:
GDFsTGF-β signalingdifferentiationretinal developmentretinal ganglion cellstem cell

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