Reprogramming of the chick retinal pigmented epithelium
after retinal injury
Agustin Luz-Madrigal, Erika Grajales-Esquivel, Alexander
McCorkle, Ashley M DiLorenzo, Karla Barbosa-Sabanero, Panagiotis A Tsonis and
Katia Del Rio-Tsonis
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BMC Biology 2014, 12:28
doi:10.1186/1741-7007-12-28
Published: 17 April 2014
Abstract (provisional)
One of the promises in regenerative medicine is to
regenerate or replace damaged tissues. The embryonic chick can regenerate its
retina by transdifferentiation of the retinal pigmented epithelium (RPE) and by
activation of stem/progenitor cells present in the ciliary margin. These two
ways of regeneration occur concomitantly when an external source of fibroblast
growth factor 2 (FGF2) is present after injury (retinectomy). During the
process of transdifferentiation, the RPE loses its pigmentation and is
reprogrammed to become neuroepithelium which differentiates to reconstitute the
different cell types of the neural retina. Somatic mammalian cells can be
reprogrammed to become induced pluripotent stem cells (iPSCs) by ectopic
expression of pluripotency inducing factors such as Oct4, Sox2, Klf4, c-Myc and
in some cases Nanog and Lin-28. However, there is limited information
concerning the expression of these factors during natural regenerative
processes. Organisms that are able to regenerate their organs, could share
similar mechanisms and factors with the reprogramming process of somatic cells.
Herein, we investigate the expression of pluripotency inducing factors in the
RPE after retinectomy (injury) and during transdifferentiation in the presence
of FGF2.
Results
We present evidence that upon injury, the quiescent
(p27Kip1+/BrdU-) RPE cells transiently dedifferentiate and express sox2, klf4
and c-Myc along with eye field transcriptional factors and display a
differential up-regulation of alternative splice variants of pax6. However,
this transient process of dedifferentiation is not sustained unless FGF2 is present.
We have identified lin-28 as a downstream target of FGF2 during the process of
retina regeneration. Moreover, we show that overexpression of lin-28 after
retinectomy was sufficient to induce transdifferentiation of the RPE in the
absence of FGF2.
Conclusion
These findings delineate in detail the molecular changes
that take place in the RPE during the process of transdifferentiation in the
embryonic chick, and specifically identify Lin-28 as an important factor in
this process. We propose a novel model in which injury signals initiate RPE
dedifferentiation, while FGF2 up-regulates Lin-28, allowing for RPE
transdifferentiation to proceed. TOMADO DE ENVIO DE BCM
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