Unlocking the Neurogenic Potential of Mammalian Müller Glia

Xia, Xiaohuan; Ahmad, Iqbal

doi:10.15283/ijsc16020

Cited by 19 publications

(7 citation statements)

References 39 publications

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“…However, this protective effect is opposed by the fact that the α 2 M*/LRP1 interaction also causes MGC activation during the proliferative stage inducing the up-regulation of GFAP 13 , which contribute to retinal function loss and neuronal cell death 42 . In this complex scenario, MGCs become particularly relevant due to their latent stem cell potential, positioning MGCs as excellent targets for regenerative therapies 43–45 . In this regard, MGCs cultured under appropriate circumstances in vitro 46,47 can, when transplanted in vivo 46,47 , display an improved ability to migrate towards retinal injured sites.…”

Section: Discussionmentioning

confidence: 99%

Activated α2-Macroglobulin Regulates LRP1 Levels at the Plasma Membrane through the Activation of a Rab10-dependent Exocytic Pathway in Retinal Müller Glial Cells

Jaldín-Fincati

Dato

Díaz

et al. 2019

Sci Rep

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Activated α2-macroglobulin (α2M*) and its receptor, low-density lipoprotein receptor-related protein 1 (LRP1), have been linked to proliferative retinal diseases. In Müller glial cells (MGCs), the α2M*/LRP1 interaction induces cell signaling, cell migration, and extracellular matrix remodeling, processes closely associated with proliferative disorders. However, the mechanism whereby α2M* and LRP1 participate in the aforementioned pathologies remains incompletely elucidated. Here, we investigate whether α2M* regulates both the intracellular distribution and sorting of LRP1 to the plasma membrane (PM) and how this regulation is involved in the cell migration of MGCs. Using a human Müller glial-derived cell line, MIO-M1, we demonstrate that the α2M*/LRP1 complex is internalized and rapidly reaches early endosomes. Afterward, α2M* is routed to degradative compartments, while LRP1 is accumulated at the PM through a Rab10-dependent exocytic pathway regulated by PI3K/Akt. Interestingly, Rab10 knockdown reduces both LRP1 accumulation at the PM and cell migration of MIO-M1 cells induced by α2M*. Given the importance of MGCs in the maintenance of retinal homeostasis, unravelling this molecular mechanism can potentially provide new therapeutic targets for the treatment of proliferative retinopathies.

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Section: Discussionmentioning

confidence: 99%

Activated α2-Macroglobulin Regulates LRP1 Levels at the Plasma Membrane through the Activation of a Rab10-dependent Exocytic Pathway in Retinal Müller Glial Cells

Jaldín-Fincati

Dato

Díaz

et al. 2019

Sci Rep

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“…However, the substantial differences in the genetic setup of hiPSCs and mature MGC likely contribute to the incapacity of the latter to regenerate PHRs during retina degeneration. The inability of MGC to regenerate the retina has been suggested to result from either intrinsic features of mammalian MGC or extrinsic properties of their “niche,” which interfere with the reprograming process of these cells (Xia and Ahmad, 2016). Analysis of cultured MGC from rd1 retinas revealed that their cell cycle was downregulated, compared to wt MGC.…”

Section: Discussionmentioning

confidence: 99%

A Defective Crosstalk Between Neurons and Müller Glial Cells in the rd1 Retina Impairs the Regenerative Potential of Glial Stem Cells

Volonté

Vallese-Maurizi

Dibo

et al. 2019

Front. Cell. Neurosci.

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Müller glial cells (MGC) are stem cells in the retina. Although their regenerative capacity is very low in mammals, the use of MGC as stem cells to regenerate photoreceptors (PHRs) during retina degenerations, such as in retinitis pigmentosa, is being intensely studied. Changes affecting PHRs in diseased retinas have been thoroughly investigated; however, whether MGC are also affected is still unclear. We here investigated whether MGC in retinal degeneration 1 ( rd1 ) mouse, an animal model of retinitis pigmentosa, have impaired stem cell properties or structure. rd1 MGC showed an altered morphology, both in culture and in the whole retina. Using mixed neuron-glial cultures obtained from newborn mice retinas, we determined that proliferation was significantly lower in rd1 than in wild type (wt) MGC. Levels of stem cell markers, such as Nestin and Sox2 , were also markedly reduced in rd1 MGC compared to wt MGC in neuron-glial cultures and in retina cryosections, even before the onset of PHR degeneration. We then investigated whether neuron-glial crosstalk was involved in these changes. Noteworthy, Nestin expression was restored in rd1 MGC in co-culture with wt neurons. Conversely, Nestin expression decreased in wt MGC in co-culture with rd1 neurons, as occurred in rd1 MGC in rd1 neuron-glial mixed cultures. These results imply that MGC proliferation and stem cell markers are reduced in rd1 retinas and might be restored by their interaction with “healthy” PHRs, suggesting that alterations in rd1 PHRs lead to a disruption in neuron-glial crosstalk affecting the regenerative potential of MGC.

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“…Extrinsic and intrinsic factors participate in the activation process associated with Müller glial cells in retinal regeneration, including SHH ( 14 ), Notch ( 15 ), Wnt ( 16 , 17 ) and fibroblast growth factor ( 18 ) signaling pathways. Activation of these pathways, due to injury or exogenous ligands, induces a subset of Müller glial cells into the G1-S phase of the cell cycle ( 6 , 39 ). Our previous study indicated that SHH may promote the proliferation of Müller glial cells by increasing the expression of cyclin D1 and cyclin D3 ( 14 ).…”

Section: Discussionmentioning

confidence: 99%

Directed transdifferentiation of Müller glial cells to photoreceptors using the sonic hedgehog signaling pathway agonist purmorphamine

Wang

Zhang

et al. 2017

Molecular Medicine Reports

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Specification of distinct cell types from Müller glial cells is key to the potential application of endogenous repair in retinal regeneration. Sonic hedgehog (SHH) has been established as a potent mitogen for rat Müller glial cells, which also induces Müller glial cells to dedifferentiate and adopt the phenotype of rod photoreceptors. The present study investigated the effects of purmorphamine, a small molecule that activates the SHH-pathway, in the proliferation, dedifferentiation and transdifferentiation of Müller glial cells, as determined by several methods including immunofluorescence, polymerase chain reaction and western blotting. It was demonstrated that it may be able to replace SHH for the regeneration of retinal neurons. Purmorphamine was revealed to stimulate the proliferation of Müller glial cells by increasing the expression of cyclin D1 and cyclin D3. In addition, purmorphamine-treated Müller glial cells were induced to dedifferentiate by inducing the expression of progenitor-specific markers; subsequently differentiating into rod-like photoreceptors. Intraocular injection of purmorphamine promoted the activation of Müller glial cells, and in turn, the production of rod-like photoreceptors in acute damaged retina. These results suggested that the endogenous neurogenic capacity of retinal Müller glial cells may be enhanced by this small molecular agonist of the SHH signaling pathway.

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Unlocking the Neurogenic Potential of Mammalian Müller Glia

Cited by 19 publications

References 39 publications

Activated α2-Macroglobulin Regulates LRP1 Levels at the Plasma Membrane through the Activation of a Rab10-dependent Exocytic Pathway in Retinal Müller Glial Cells

Activated α2-Macroglobulin Regulates LRP1 Levels at the Plasma Membrane through the Activation of a Rab10-dependent Exocytic Pathway in Retinal Müller Glial Cells

A Defective Crosstalk Between Neurons and Müller Glial Cells in the rd1 Retina Impairs the Regenerative Potential of Glial Stem Cells

Directed transdifferentiation of Müller glial cells to photoreceptors using the sonic hedgehog signaling pathway agonist purmorphamine

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