L-DOPA enhances iRPE differentiation via Wnt signaling and improves cytotherapy for retinal degradation

Transplantation of stem cell-derived Retinal Pigment Epithelium (RPE) cells offers significant therapeutic potential for treating retinal degenerative diseases (RDDs). To enhance the efficacy and safety of such cell replacement therapies, it is essential to efficiently generate high-quality RPE donor cells. The crosstalk between dopamine signalling and the Wnt pathway provides an important mechanism underlying RPE cell fate determination during eye development.

We present a protocol for RPE differentiation from iPSCs with L-DOPA supplementation. The effect of L-DOPA is attributed to the activation of Wnt signalling, mediated through the dopamine D1 receptor, which triggers the downstream cAMP/PKA signalling cascade. Subsequent phosphorylation of GSK3β and β-catenin by PKA facilitates the stabilization and nuclear translocation of β-catenin.

L-DOPA supplementation significantly enhances the efficiency of RPE induction, as well as the maturity and functionality of iRPE. Moreover, L-DOPA-treated iRPE cells demonstrated robust resistance to oxidative stress and exhibited improved therapeutic effects in RCS rats after transplantation, alleviating retinal degeneration and preserving retinal function.

These findings highlight the potential of L-DOPA as a promising adjunct for iRPE differentiation and stem cell-based therapies for RDDs.