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Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration.

Haynes T, Luz-Madrigal A, Reis ES, Echeverri Ruiz NP, Grajales-Esquivel E, Tzekou A, Tsonis PA, Lambris JD, Del Rio-Tsonis K - Nat Commun (2013)

Bottom Line: Identifying the initiation signals for tissue regeneration in vertebrates is one of the major challenges in regenerative biology.Much of the research thus far has indicated that certain growth factors have key roles.This activation sets forth regulation of Wnt2b, Six3 and Sox2, genes associated with retina stem and progenitor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Miami University, Oxford, Ohio 45056, USA.

ABSTRACT
Identifying the initiation signals for tissue regeneration in vertebrates is one of the major challenges in regenerative biology. Much of the research thus far has indicated that certain growth factors have key roles. Here we show that complement fragment C3a is sufficient to induce complete regeneration of the embryonic chick retina from stem/progenitor cells present in the eye, independent of fibroblast growth factor receptor signaling. Instead, C3a induces retina regeneration via STAT3 activation, which in turn activates the injury- and inflammation-responsive factors, IL-6, IL-8 and TNF-α. This activation sets forth regulation of Wnt2b, Six3 and Sox2, genes associated with retina stem and progenitor cells. Thus, our results establish a mechanism for retina regeneration based on injury and inflammation signals. Furthermore, our results indicate a unique function for complement anaphylatoxins that implicate these molecules in the induction and complete regeneration of the retina, opening new avenues of experimentation in the field.

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A model for the induction of chick retina regeneration by C3a.A model depicting the mechanism of induction of retina regeneration by C3a. C3a binds its receptor, C3aR, which leads to the activation of MAPK and subsequent phosphorylation of S727 STAT3. In the presence of active pS727 STAT3, expression of injury-responsive genes, IL-6, TNF-α and IL-8 is increased followed by a decrease in the expression of the retinal stem cell gene, Wnt2b, and an increase in expression of the retinal progenitor genes, Six3 and Sox2.
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f7: A model for the induction of chick retina regeneration by C3a.A model depicting the mechanism of induction of retina regeneration by C3a. C3a binds its receptor, C3aR, which leads to the activation of MAPK and subsequent phosphorylation of S727 STAT3. In the presence of active pS727 STAT3, expression of injury-responsive genes, IL-6, TNF-α and IL-8 is increased followed by a decrease in the expression of the retinal stem cell gene, Wnt2b, and an increase in expression of the retinal progenitor genes, Six3 and Sox2.

Mentions: To determine whether C3a regulates any retina-specific genes necessary for regeneration through STAT3 activation, we performed RT–qPCR at 2 and 6 h PR using RNA isolated from the CM. Interestingly, Wnt2b, a stem cell maintenance factor in the retina39 with a binding site for STAT3 (ref. 37), was downregulated in the CM at 6 h PR (Fig. 6a). The addition of PD98059, Stattic or C3aR-Ab reversed this downregulation (Fig. 6a). Addition of the pharmacological agent CHIR 99021, an activator of the Wnt pathway that we show increases Wnt2b and Axin2 mRNA (two downstream targets of the Wnt pathway) in the CM after retinectomy, (Supplementary Fig. S8) also reduced the ability of C3a-p to induce regeneration as shown by histological analysis at 3 days PR (Fig. 6f,h,i). At the same time, we saw an increase in the expression of Six3 (ref. 40) and Sox2 (ref. 41), which are retinal progenitor genes containing STAT3-binding sites3742. This change was dependent on a functional MAPK and STAT3 pathway as well as C3aR activity, as inhibition at any of these levels resulted in a significant decrease in Six3 and Sox 2 expression (Fig. 6a). Together, these results demonstrate that, initially, C3a induces injury-responsive genes as expected, but then downregulates the expression of stem cell maintenance genes while inducing the expression of progenitor-specific genes, thereby setting the stage for regeneration (Fig. 7).


Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration.

Haynes T, Luz-Madrigal A, Reis ES, Echeverri Ruiz NP, Grajales-Esquivel E, Tzekou A, Tsonis PA, Lambris JD, Del Rio-Tsonis K - Nat Commun (2013)

A model for the induction of chick retina regeneration by C3a.A model depicting the mechanism of induction of retina regeneration by C3a. C3a binds its receptor, C3aR, which leads to the activation of MAPK and subsequent phosphorylation of S727 STAT3. In the presence of active pS727 STAT3, expression of injury-responsive genes, IL-6, TNF-α and IL-8 is increased followed by a decrease in the expression of the retinal stem cell gene, Wnt2b, and an increase in expression of the retinal progenitor genes, Six3 and Sox2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753547&req=5

f7: A model for the induction of chick retina regeneration by C3a.A model depicting the mechanism of induction of retina regeneration by C3a. C3a binds its receptor, C3aR, which leads to the activation of MAPK and subsequent phosphorylation of S727 STAT3. In the presence of active pS727 STAT3, expression of injury-responsive genes, IL-6, TNF-α and IL-8 is increased followed by a decrease in the expression of the retinal stem cell gene, Wnt2b, and an increase in expression of the retinal progenitor genes, Six3 and Sox2.
Mentions: To determine whether C3a regulates any retina-specific genes necessary for regeneration through STAT3 activation, we performed RT–qPCR at 2 and 6 h PR using RNA isolated from the CM. Interestingly, Wnt2b, a stem cell maintenance factor in the retina39 with a binding site for STAT3 (ref. 37), was downregulated in the CM at 6 h PR (Fig. 6a). The addition of PD98059, Stattic or C3aR-Ab reversed this downregulation (Fig. 6a). Addition of the pharmacological agent CHIR 99021, an activator of the Wnt pathway that we show increases Wnt2b and Axin2 mRNA (two downstream targets of the Wnt pathway) in the CM after retinectomy, (Supplementary Fig. S8) also reduced the ability of C3a-p to induce regeneration as shown by histological analysis at 3 days PR (Fig. 6f,h,i). At the same time, we saw an increase in the expression of Six3 (ref. 40) and Sox2 (ref. 41), which are retinal progenitor genes containing STAT3-binding sites3742. This change was dependent on a functional MAPK and STAT3 pathway as well as C3aR activity, as inhibition at any of these levels resulted in a significant decrease in Six3 and Sox 2 expression (Fig. 6a). Together, these results demonstrate that, initially, C3a induces injury-responsive genes as expected, but then downregulates the expression of stem cell maintenance genes while inducing the expression of progenitor-specific genes, thereby setting the stage for regeneration (Fig. 7).

Bottom Line: Identifying the initiation signals for tissue regeneration in vertebrates is one of the major challenges in regenerative biology.Much of the research thus far has indicated that certain growth factors have key roles.This activation sets forth regulation of Wnt2b, Six3 and Sox2, genes associated with retina stem and progenitor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Miami University, Oxford, Ohio 45056, USA.

ABSTRACT
Identifying the initiation signals for tissue regeneration in vertebrates is one of the major challenges in regenerative biology. Much of the research thus far has indicated that certain growth factors have key roles. Here we show that complement fragment C3a is sufficient to induce complete regeneration of the embryonic chick retina from stem/progenitor cells present in the eye, independent of fibroblast growth factor receptor signaling. Instead, C3a induces retina regeneration via STAT3 activation, which in turn activates the injury- and inflammation-responsive factors, IL-6, IL-8 and TNF-α. This activation sets forth regulation of Wnt2b, Six3 and Sox2, genes associated with retina stem and progenitor cells. Thus, our results establish a mechanism for retina regeneration based on injury and inflammation signals. Furthermore, our results indicate a unique function for complement anaphylatoxins that implicate these molecules in the induction and complete regeneration of the retina, opening new avenues of experimentation in the field.

Show MeSH
Related in: MedlinePlus