Regeneration and reprogramming compared

Bea Christen,Marina Raya,Vanesa Robles,Ida Paramonov,Juan Carlos Izpisúa Belmonte

doi:10.1186/1741-7007-8-5

Abstract

BackgroundDedifferentiation occurs naturally in mature cell types during epimorphic regeneration in fish and some amphibians. Dedifferentiation also occurs in the induction of pluripotent stem cells when a set of transcription factors (Oct4, Sox2, Klf4 and c-Myc) is over expressed in mature cell types.ResultsWe hypothesised that there are parallels between dedifferentiation or reprogramming of somatic cells to induced pluripotent stem cells and the natural process of dedifferentiation during epimorphic regeneration. We analysed expression levels of the most commonly used pluripotency associated factors in regenerating and non-regenerating tissue and compared them with levels in a pluripotent reference cell. We found that some of the pluripotency associated factors (oct4/pou5f1, sox2, c-myc, klf4, tert, sall4, zic3, dppa2/4 and fut1, a homologue of ssea1) were expressed before and during regeneration and that at least two of these factors (oct4, sox2) were also required for normal fin regeneration in the zebrafish. However these factors were not upregulated during regeneration as would be expected if blastema cells acquired pluripotency.ConclusionsBy comparing cells from the regeneration blastema with embryonic pluripotent reference cells we found that induced pluripotent stem and blastema cells do not share pluripotency. However, during blastema formation some of the key reprogramming factors are both expressed and are also required for regeneration to take place. We therefore propose a link between partially reprogrammed induced pluripotent stem cells and the half way state of blastema cells and suggest that a common mechanism might be regulating these two processes.

Highlights

Dedifferentiation occurs naturally in mature cell types during epimorphic regeneration in fish and some amphibians
We focused on the studies of gene expression by quantitative real time polymerase chain reaction of regenerating and non-regenerating tissue compared to an embryonic, pluripotent reference cell type, analysis of the blastema cell cycle by fluorescence-activated cell sorting (FACS) and a functional approach by knocking down pou5f1/oct4 and sox2 with morpholinos in the zebrafish caudal fin demonstrating that some of the core factors needed for reprogramming are present and required during regeneration
We treated the blastema as a homogeneous population of cells, as would be predicted if they dedifferentiated to a pluripotent state and second, we expected overall levels of pluripotency associated factors to increase as abundance of blastema cells increases up to a comparable expression level of a pluripotent reference cell

Summary

Introduction

Dedifferentiation occurs naturally in mature cell types during epimorphic regeneration in fish and some amphibians. Dedifferentiation occurs in the induction of pluripotent stem cells when a set of transcription factors (Oct, Sox, Klf and c-Myc) is over expressed in mature cell types. Differentiation during development is normally viewed as a one way process from undifferentiated to more differentiated cells. Some lower vertebrates such as teleost fish and some amphibians are able to compensate for the loss of body parts by regenerating a nearly perfect copy of the original part by dedifferentiating cells in vivo to facilitate regeneration. After the loss of an appendage undifferentiated, plurior multipotent cells from different origins accumulate at the damaged surface to form a regeneration blastema. Despite the heterogeneous origin of the blastema cells, histologically they appear as a homogeneous population of cells and have been traditionally viewed as a

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