Cellular Dedifferentiation and Regenerative Medicine by Xiaobing Fu Andong Zhao & Tian Hu

Author:Xiaobing Fu, Andong Zhao & Tian Hu
Language: eng
Format: epub
Publisher: Springer Berlin Heidelberg, Berlin, Heidelberg

1.4.4 Molecular Mechanism Underlying the MG Dedifferentiation

Injury-Induced Secreted Growth Factors and Cytokines

It has been shown that the extent of retinal damage or cell death is associated with the regenerative responses of MG, reflecting on the number of proliferating MG-derived progenitors. This suggests that signals from dying neurons, reactive microglia, and MG will stimulate MG to undergo dedifferentiation and proliferation. After retinal injury, the inhibitory factors for regeneration, normally present in the uninjured retina, may be suppressed, while the positive factors for regeneration are induced, thereby stimulating MG to dedifferentiate and proliferate to replace the lost retinal neurons.

The inflammatory cytokine tumor necrosis factor (TNF) is complicated in proliferative gliosis of MG in the mammalian retina [62], although TNFα is expected for proliferation of MG throughout retinal regeneration in zebrafish [69]. After light lesion, TNFα, TNF receptors, and TNF receptor-associated protein-1 all increase in the injured retina, and further analysis revealed that the dying photoreceptors and inner retinal neurons produce TNFα [69]. Since morpholino-mediated knockdown of TNFα in either the dying neurons or the MG markedly attenuate the proliferation of MG as well as the expression of regenerative genes such as stat3 and ascl1a, TNFα is a critical factor for MG-dependent retinal regeneration [69].

Retinal progenitor cells and MG proliferate in vitro and in vivo in response to several growth factors, such as EGF and FGF. In human, rodents, and chick, FGF2 treatments have stimulated the dedifferentiation and proliferation of MG in culture and in vivo [21, 23, 24, 27, 67]. In zebrafish, FGF is important for both maintenance of mature photoreceptors and photoreceptor regeneration [70]. EGF is also essential for MG dedifferentiation and proliferation. Indeed, intraocular injection of EGF into mice with damaged retina enhances MG to express retinal progenitor markers and proliferate to regenerate amacrine cells in vivo [24]. When postnatal rat retina was damaged by intense light, increased EGF receptor expression was observed in MG, resulting in a renewed mitotic response to EGF [65]. In zebrafish, injury-released heparin-binding epidermal-like growth factor (HB-EGF) , an EGFR ligand, is necessary and sufficient to induce MG dedifferentiation and the generation of progenitors. In adult zebrafish, HB-EGF is upregulated in the whole retina within 1 h after stab lesions and is mainly expressed in MG. Excitingly, knockdown of HB-EGF dramatically reduces the number of proliferating MG progenitors in vivo [71]. However, in the light-damaged retinas of zebrafish, although HB-EGF expression also increases, knockdown of it does not decrease the number of MG-derived progenitors [69]. This suggests that other factors released in the light-damaged retinas may sufficiently activate MG and that the effects of HB-EGF on dedifferentiation and proliferation of MG may be context-dependent. In agreement, in patients with proliferative vitreoretinopathy, HB-EGF is highly expressed in the retina and promotes the reactive gliosis of MG, resulting glial scarring, rather than regeneration of retinal progenitors [72].

Transforming growth factor β (TGFβ) can inhibit the MG proliferation and generation of MG-derived progenitors. In rodents, TGFβ ligands are highly expressed in postnatal retina, and TGFβ receptors are also expressed in MG.

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