A recent Nature Communications study has shed light on a novel mechanism that could potentially enhance retinal regeneration in mammals suffering from various retinal diseases. The research focused on Müller glia, which have limited regenerative capabilities in mammals compared to their counterparts in species like zebrafish.
In the mammalian retina, Müller glia typically respond to injury by undergoing reactive gliosis – a process characterized by cellular hypertrophy and upregulation of glial fibrillary acidic protein (GFAP) – rather than by regenerating neurons. This gliotic response is a significant barrier to neuronal regeneration. The study explores the role of the transcription factor prospero-related homeobox 1 (Prox1), known for its involvement in cell fate determination during development, in regulating the regenerative potential of Müller glia.
The researchers discovered that Prox1 is transferred intercellularly between retinal cells, a process that appears to suppress the regenerative capacity of Müller glia. By disrupting this intercellular transfer of Prox1 using an antibody (CLZ001) that binds to the transcription factor, the authors observed a reactivation of neurogenic potential in Müller glia. Specifically, the inhibition of Prox1 transfer led to the upregulation of proneural genes such as Ascl1 and Ngn2, which are crucial for neuronal differentiation. This genetic reprogramming prompted Müller glia to adopt a progenitor-like state, enabling them to proliferate and differentiate into retinal neurons.
The findings align with previous research indicating that factors like Ascl1 can induce neurogenic potential in Müller glia. For instance, studies have shown that overexpression of Ascl1 in mouse Müller glia stimulates their reprogramming into retinal progenitors, facilitating the regeneration of retinal neurons. Additionally, the study complements research demonstrating that cell cycle progression is essential for the activation of proneural transcription factors in Müller glia, further supporting the notion that manipulating intrinsic cellular pathways can enhance retinal regeneration.
