Heterozygous modulation of TGF-β signaling does not influence Müller glia cell reactivity or proliferation following NMDA-induced damage

Abstract

The stimulation of progenitor or stem cells proliferation in the retina could be a therapeutic avenue for the treatment of various ocular neurodegenerative disorders. Müller glia cells have been discussed to represent a progenitor cell population in the adult retina. In the brain, TGF-β signaling regulates the fate of stem cells; however, its role in the vertebrate retina is unclear. We therefore investigated whether manipulation of the TGF-β signaling pathway is sufficient to promote Müller glia cell proliferation and subsequently their trans-differentiation into retinal neurons. To this end, we used mice with heterozygous deficiency of the essential TGF-β receptor type II or of the inhibitory protein SMAD7, in order to down- or up-regulate the activity of TGF-β signaling, respectively. Excitotoxic damage was applied by intravitreal N-methyl-D-aspartate injection, and BrdU pulse experiments were used to label proliferative cells. Although we successfully stimulated Müller glia cell reactivity, our findings indicate that a moderate modulation of TGF-β signaling is not sufficient to provoke Müller glia cell proliferation. Hence, TGF-β signaling in the retina might not be the essential causative factor to maintain mammalian Müller cells in a quiescent, non-proliferative state that prevents a stem cell-like function.

Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage

“…The light exposed and control retinae were investigated following manufacturers’ instructions and protocols published previously (Braunger et al, 2013b, 2015; Kugler et al, 2015). For quantitative analysis, the number of TUNEL-positive nuclei in mid-horizontal sections throughout the entire retina was counted and normalized to the area of the ONL.…”

BMP‐ and TGFβ‐signaling regulate the formation of Müller glia‐derived progenitor cells in the avian retina

“…Taken together, these findings suggest that inhibiting the repressive role of TGFb/Smad2/3-signaling is a necessary step in promoting the formation of proliferating MGPCs in the vertebrate retina.Consistent with findings that TGFb/Smad2/3-signaling suppresses the reprogramming of mature M€ uller glia into proliferating MGPCs, this pathway may additionally suppress proliferation of late-stage progenitors and promote glial maturation during retinal development. The loss of one allele of TGFb-RII (loss-of-function) or inhibitory Smad7 (gain-of-function) resulted in no significant proliferation or reactivity of M€ uller glia in NMDA-induced damaged retinas(Kugler et al, 2015). By comparison, in postnatal rat retina, TGFb-signaling potently suppresses the proliferation of progenitors during the later stages of retinal development(Close et al, 2005), when there is a gradual acquisition of M€ uller glial phenotype coupled with a diminished ability of progenitors to proliferate(Nelson et al, 2011).…”

Müller glial cell‐dependent regeneration of the neural retina: An overview across vertebrate model systems

“…Regeneration of photoreceptors from rodent M€ uller glia has subsequently been reported in models of photoreceptor degeneration: following N-methyl-N-nitrosourea (MNU) administration (Wan et al, 2008) or in retinal explants (Osakada et al, 2007). However, this M€ uller cell potential remains controversial as other teams found no dedifferentiation nor proliferation following NMDA-induced damage (Kugler et al, 2015). Similarly, photoreceptor damage due to intense light exposure does not seem to promote M€ uller cell proliferation (Joly et al, 2011).…”