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Can the Pharmacological Reprogramming of Müller Glia Recover Vision Loss in Human Patients?

Review of “Chemical induction of neurogenic properties in mammalian Müller glia” from STEM CELLS by Stuart P. Atkinson

Müller glia serve as endogenous stem cells in the adult retina that can regenerate retinal neurons following injury [1, 2]; however, this mechanism does not readily occur in mammals. Interestingly, a range of studies have suggested that the perturbation of the Lin28‐Let‐7‐Ascl1 axis may unlock the neurogenic potential of mammalian Müller glia [3-5], a finding supported by the reprogramming of Müller glia in zebrafish via the cytokine-induced expression of Ascl1, a pro‐neural gene [6, 7].

With this knowledge in mind, researchers led by Iqbal Ahmad (University of Nebraska Medical Center, Omaha, NE, USA) now report on the development of a pharmacological approach to inducing neurogenic properties in mammalian Müller glia. The authors of this new STEM CELLS study hope that their findings could lead to the development of advanced retinal regeneration strategies and the mitigation of vision loss [8].

Xia et al. first evaluated the impact of small molecule combinations in enriched primary cultures of Müller glia – the team inhibited Notch signaling to activate Ascl1/Lin28 expression (I-bet151) and induced neuronal properties (Forskolin + the isoxazole ISX9) in the presence of a broad‐spectrum caspase inhibitor, an antioxidant, and several neurotrophins. After only two days of treatment, this combination prompted the previously flat Müller glia to develop into elongated neuronal-shaped cells with processes that increased in length and complexity with time.

Encouragingly, analyses of transcriptional profiles, protein marker expression profiles, and neuronal functionality all suggested that the small molecule combination effectively induced the dedifferentiation of Müller glia and the development of retinal neurons through a developmentally appropriate pathway, thereby providing evidence for the utility of this therapeutic regeneration approach.

The authors hope to optimize their strategy further to improve the physiological immaturity of the generated neurons and enhance neural differentiation efficiency as the next steps in this advanced Müller glia-targeting retinal regeneration strategy, which may represent an exciting means of restoring lost vision in human patients after injury.

For more on the pharmacological reprogramming of Müller glia as a treatment strategy for vision loss, stay tuned to the Stem Cells Portal!

References

  1. Goldman D, Müller glial cell reprogramming and retina regeneration. Nature Reviews Neuroscience 2014;15:431-442.
  2. Hoang T, Wang J, Boyd P, et al., Gene regulatory networks controlling vertebrate retinal regeneration. Science 2020;370:eabb8598.
  3. Xia X and Ahmad I, let-7 microRNA regulates neurogliogenesis in the mammalian retina through Hmga2. Developmental Biology 2016;410:70-85.
  4. Pollak J, Wilken MS, Ueki Y, et al., ASCL1 reprograms mouse Müller glia into neurogenic retinal progenitors. Development 2013;140:2619-2631.
  5. Yao K, Qiu S, Tian L, et al., Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas. Cell Reports 2016;17:165-178.
  6. Zhao X-F, Wan J, Powell C, et al., Leptin and IL-6 Family Cytokines Synergize to Stimulate Müller Glia Reprogramming and Retina Regeneration. Cell Reports 2014;9:272-284.
  7. Gorsuch RA and Hyde DR, Regulation of Müller glial dependent neuronal regeneration in the damaged adult zebrafish retina. Experimental Eye Research 2014;123:131-140.
  8. Xia X, Teotia P, Patel H, et al., Chemical induction of neurogenic properties in mammalian Müller glia. STEM CELLS 2021;39:1081-1090.