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Chemically Induced Photoreceptors as a New Therapeutic Option for Vision Loss

Review of “Pharmacologic fibroblast reprogramming into photoreceptors restores vision” from Nature by Stuart P. Atkinson

The differentiation of pluripotent stem cells into retinal photoreceptor cells has the potential to restore vision in patients suffering from conditions such as age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa [1, 2]; however, the cumbersome and time-consuming nature of currently described differentiation approaches have led many to explore alternative, more clinically relevant means to generate retinal cells. Direct reprogramming of somatic cells into photoreceptors via the ectopic transcription factors and/or chemical induction represents an exciting strategy, and now, researchers led by Sai H. Chavala (University of North Texas Health Science Center, Fort Worth, TX, USA) report on the administration of a small molecule cocktail that can induce the transformation of fibroblasts into rod photoreceptor-like cells with the potential to restore vision loss [3].

Mahato et al. discovered that the treatment of both mouse embryonic and human adult dermal fibroblasts with the Wnt/β-catenin pathway inhibitor IWR1, valproic acid, the GSK3 inhibitor CHIR99021, RepSox, forskolin, and Sonic hedgehog/taurine/retinoic acid efficiently induced their conversion into “chemically-induced” photoreceptor-like cells that expressed specific markers such as CRX, rhodopsin, and recoverin. In search of mechanistic insight, the authors studied AXIN2, which forms part of the Wnt signaling pathway, given reports suggesting that CHIR and IWR1 treatment stabilized AXIN2 [4] and that XAV939 treatment (an IWR1 analog) translocated AXIN2 to the mitochondria [5]. They discovered that treatment with the small molecule cocktail prompted the translocation of AXIN2 to the mitochondria and induced the production of reactive oxygen species, the activation of NF-κB, and the upregulation of Ascl1, a proneural transcription factor that can reprogram both fibroblasts into neurons [6, 7] and Müller glia into rod photoreceptor-like cells [8, 9]. 

Finally and encouragingly, chemically-induced photoreceptor-like cells transplanted into the subretinal space of rd1 mice (a model of retinal degeneration) survived, functioned, and connected with the inner retinal neurons and prompted long-term improvements in pupillary light reflex and the restoration of normal visual behavior in a light aversion test.

Overall, the authors establish the transplantation of chemically-induced photoreceptor-like cells as a promising therapeutic approach for the restoration of vision and highlight the mitochondria as a signaling hub during cell fate conversion. The ongoing development of their protocol currently aims to further increase the conversion efficiency to generate the large numbers of cells required for translational applications. 

For more on the future of chemically-induced photoreceptor-like cells and their therapeutic potential, stay tuned to the Stem Cells Portal!

References

  1. Wright AF, Chakarova CF, Abd El-Aziz MM, et al., Photoreceptor Degeneration: Genetic and Mechanistic Dissection of a Complex Trait. Nature Reviews Genetics 2010;11:273-284.
  2. Bramall AN, Wright AF, Jacobson SG, et al., The Genomic, Biochemical, and Cellular Responses of the Retina in Inherited Photoreceptor Degenerations and Prospects for the Treatment of These Disorders. Annual Review of Neuroscience 2010;33:441-472.
  3. Mahato B, Kaya KD, Fan Y, et al., Pharmacologic Fibroblast Reprogramming into Photoreceptors Restores Vision. Nature 2020;581:83-88.
  4. Kim H, Wu J, Ye S, et al., Modulation of β-catenin Function Maintains Mouse Epiblast Stem Cell and Human Embryonic Stem Cell Self-renewal. Nature Communications 2013;4:2403.
  5. Shin J-H, Kim H-w, Rhyu IJ, et al., Axin is Expressed in Mitochondria and Suppresses Mitochondrial ATP Synthesis in HeLa cells. Experimental Cell Research 2016;340:12-21.
  6. Pang ZP, Yang N, Vierbuchen T, et al., Induction of Human Neuronal Cells by Defined Transcription Factors. Nature 2011;476:220-223.
  7. Vierbuchen T, Ostermeier A, Pang ZP, et al., Direct Conversion of Fibroblasts to Functional Neurons by Defined Factors. Nature 2010;463:1035-1041.
  8. Ueki Y, Wilken MS, Cox KE, et al., Transgenic Expression of the Proneural Transcription Factor Ascl1 in Müller Glia Stimulates Retinal Regeneration in Young Mice. Proceedings of the National Academy of Sciences 2015;112:13717.
  9. Jorstad NL, Wilken MS, Grimes WN, et al., Stimulation of Functional Neuronal Regeneration from Müller Glia in Adult Mice. Nature 2017;548:103-107.