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Understanding Gliosis to Improve Stem Cell Therapy for Visual Loss

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Review of “Molecular mechanisms mediating retinal reactive gliosis following mesenchymal stem cell (MSC) transplantation” from Stem Cells by Stuart P. Atkinson

Stem cell therapies for the treatment of retinal degeneration have met with some success [1, 2] although some obstacles to this mode of therapy still remain. One of these obstacles is reactive gliosis - the unwanted proliferation of astrocytes/Muller glia which occurs in the in the retina following damage or, importantly, in response to cell transplantation [3]. Unfortunately, this process inhibits synaptic plasticity, axonal remodeling, and donor cell integration and a means to disrupt or inhibit this process may mediate an improvement in stem cell based therapies. To assess the mechanisms mediating glial responses, the group of Keith Martin (University of Cambridge, UK) studied the response of the retina after intravitreal injection of bone marrow mesenchymal stem cells (BM-MSCs). Their findings, published in Stem Cells, now highlight the importance of inflammation and the activation of the MAPK and JAK/STAT3 cascades, and identify Lipocalin-2 (Lcn2) as a marker for reactive gliosis in Muller glia [4].

Following injection of BM-MSCs into the eye, the authors first noted that astrocytes/Muller glia upregulated the expression of the intermediate filament proteins (Gfap, Vimentin, Nestin – See figure), indicative of enhanced proliferation, and upregulated the level of Iba1, indicative of astrocytic activation. They also noted an increase in the retinal infiltration of blood-stream-derived macrophages in response to increases in chemokine and cytokine levels (CCL2, CCL3, CXCL10, and INFγ) and the structural disorganization of the retina.

To discover the controlling pathways, the authors generated mRNA expression profiles for treated and untreated retinas. This highlighted the importance of the Mapk/Erk and Jak/Stat signaling cascades, the P53-mediated apoptotic signaling pathway, and over-expression of the autocrine mediator of reactive astrocytosis Lipocalin-2 in graft-induced gliosis and inflammation. Protein analysis confirmed these findings, and also demonstrated that BM-MSC injection specifically enhanced Stat3 and Erk1/2 phosphorylation and activation, and greatly enhanced Lcn2 expression in Muller glia. Importantly, pharmacological inhibition of Stat3 downregulated Gfap expression in response to BM-MSCs and this allowed BM-MSCs to migrate and engraft into the retinal tissue.

This suggests that Stat3 inhibition may potentiate the therapeutic capacity of injected MSCs via inhibition of retinal gliosis, and may be important in other therapeutic strategies aiming to boost neuroprotection, replace cells, or enhance regeneration in the retina. Furthermore, the authors suggest the use of Lcn2 as a new marker for retinal reactive gliosis and its employment as an indicator for the effectiveness of a given retinal therapy. The authors note that Lcn2 has been previously linked to neuroinflammation [5], reactive gliosis [6], and neuronal death [5], and suggest that a greater understanding of the role for this protein may uncover a means to modulate its expression and inhibit any detrimental responses following stem cell transplant, further enhancing any therapeutic value.

References

  1. Johnson TV, Bull ND, Hunt DP, et al. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci 2010;51:2051-2059.
  2. Johnson TV, DeKorver NW, Levasseur VA, et al. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain 2014;137:503-519.
  3. Johnson TV, Bull ND, and Martin KR Identification of barriers to retinal engraftment of transplanted stem cells. Invest Ophthalmol Vis Sci 2010;51:960-970.
  4. Tassoni A, Gutteridge A, Barber AC, et al. Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation. Stem Cells 2015;33:3006-3016.
  5. Bi F, Huang C, Tong J, et al. Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci U S A 2013;110:4069-4074.
  6. Lee S, Park JY, Lee WH, et al. Lipocalin-2 is an autocrine mediator of reactive astrocytosis. J Neurosci 2009;29:234-249.