Regenerating the retina or not: inflammation is the key.
Unlike mammals, some vertebrates use their Müller glia as stem cells for retinal regeneration after injury. Identifying the underlying molecular mechanisms may help foreseeing regenerative medicine strategies for patients suffering from degenerative diseases of the retina, such as AMD or retinitis pigmentosa. We have developed a Xenopus model of retinitis pigmentosa and demonstrated that despite the robust cell cycle re-entry of Müller cells following photoreceptor degeneration in pre-metamorphic tadpoles, their proliferative response is remarkably limited in younger counterparts.
This unique stage-dependency allowed us to unveil some intriguing findings: this variable response does not result from Müller cell intrinsic properties but rather from disparities in the inflammatory microenvironment, which evolves alongside tadpole aging. Indeed, the poor reactivation of Müller cells in young tadpoles stems from the scarcity of microglia (the resident immune cells) at these developmental stages, resulting in an inadequate inflammatory milieu. Thus, pro-inflammatory treatments are sufficient to strongly stimulate Müller cell proliferation at these refractory stages. Expanding on this exciting discovery, we found in the mouse that an immune challenge can also activate quiescent Müller cells in retinal explants (an ex vivo model of degeneration). This finding contradicts the current dogma, according to which neuroinflammation favors regeneration in non-mammalian vertebrates, while hindering it in mammals.
By uncoupling the proliferative and neurogenic responses of Müller cells, we here bring new conceptual insights by showing that (i) the beneficial effects of inflammatory signaling on Müller glia proliferation are shared by both regenerative and non-regenerative vertebrates and (ii) the adverse effects of microglial signaling on mammalian Müller cells seem to be limited to their neurogenic engagement. We further highlight these properties by showing that sequential pro- and anti-inflammatory treatments creates a “regenerative-friendly” microenvironment, which promotes mouse Müller glia cell cycle re-entry while preserving their neurogenic potential.
Overall, this study significantly advances our understanding of the microenvironment promoting retinal regeneration, a critical step for the design of efficient cellular therapies in the new era of regenerative medicine.
Neuroinflammation as a cause of differential Müller cell regenerative responses to retinal injury. Diana García-García, Lorena Vidal-Gil, Karine Parain, Jingxian Lun, Yann Audic, Albert Chesneau, Léa Siron, Demi Van Westendorp, Sophie Lourdel, Xavier Sánchez-Sáez, Despoina Kazani, Julien Ricard, Solène Pottin, Alicia Donval, Odile Bronchain, Morgane Locker, Jérôme E Roger, Caroline Borday, Patrick Pla, Juliette Bitard, Muriel Perron
Article published in Science Advances – Access to the manuscript
