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WIREs Dev Biol
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Direct cellular reprogramming in Caenorhabditis elegans: facts, models, and promises for regenerative medicine

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Abstract In vitro systems of cellular reprogramming [induced pluripotent stem (iPS) cells and direct reprogramming or transdifferentiation] are rapidly improving our repertoire of molecular techniques that can force cells in culture to change into a desired identity. However, the new frontier for regenerative medicine is in vivo cellular reprogramming, which in light of concerns about the safety of in vitro cell manipulations, is an increasingly attractive approach for regenerative medicine. Powerful in vivo approaches are currently being undertaken in the genetic model Caenorhabditis elegans. Several very distinct cell types have been induced to change or have been discovered to transform naturally, into altogether different cell types. These examples have improved our understanding of the fundamental molecular and cellular mechanisms that permit cell identity changes in live animals. In addition, the combination of a stereotyped lineage with single cell analyses allows dissection of the early and intermediate mechanisms of reprogramming, as well as their kinetics. As a result, several important concepts on in vivo cellular reprogramming have been recently developed. WIREs Dev Biol 2012, 1:138–152. doi: 10.1002/wdev.7 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Nuclear Reprogramming Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Invertebrate Organogenesis > Worms Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion

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Germ cell conversion. (a) Schematic layout of the Caenorhabditis elegans adult gonad. The distal tip cell (DTC) creates a niche in which mitotic germ cells reside. The proximal gonad, where gametogenesis occurs, is separated from the mitotic region by germ cells undergoing meiosis. (b) Ectopic expression of somatic marker genes (represented in blue) in the germline precursor cell, P2, in pie‐1 mutant 4‐cells embryos. (c) Conversion of germ cells into ASE neurons after lin‐53 RNA interference (RNAi) and ectopic expression of che‐1. The Differential interference contrast (DIC) photograph shows an abnormal looking nucleus in the mitotic region of the gonad. The fluorescent photograph shows coexpression of two different ASE specific markers in these same cells. (Reprinted with permission from Ref 21. Copyright 2011 AAAS) (d) Conversion of germ cells into both neuron and muscle cells within the meiotic region of mex‐3 gld‐1 double mutant gonads. (Reprinted with permission from Ref 12. Copyright 2006 AAAS)

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Postembryonic somatic cell conversion. (a) Conversion of intestinal cells into germ‐like cells that express the P‐granule proteins PGL‐1, GLH‐2, and GLH‐3 after mep‐1 RNAi. (Reprinted with permission from Ref 8. Copyright 2002 Elsevier) (b) Natural conversion of an rectal epithelial cell named Y (marked by egl‐5p::mCherry) into a motoneuron named PDA (marked by exp‐1p::GFP) during the second larval stage. Fluorescent image of PDA is taken from Ref 55. (c) Y‐to‐PDA transdifferentiation occurs in a stepwise manner whereby Y first loses all of its differentiated epithelial characteristics (Y.0, dedifferentiation) and then begins to acquire PDA neural characteristics (Y.1, redifferentiation), before becoming a fully differentiated motoneuron. LIN‐12, SEM‐4, and EGL‐5, as well as UNC‐3, are all required at different steps of the process.

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Blastomere conversion. (a) Endodermal (E) cell lineage in the embryo; (nE), number of E descendants, followed by the total number of embryonic cells; the time scale starts at the first embryonic cleavage. (b) Competence windows for widespread blastomere conversion following ectopic expression of the indicated transgenes. Widespread conversion of blastomeres into muscle cells, hlh‐1heat‐shock; intestinal cells, end‐1heatshock; epithelial cells, lin‐26heatshock; and epidermal cells, elt‐1heatshock and elt‐3heatshock is shown. Both hlh‐1heat‐shock and end‐1heatshock induced reprogramming of blastomeres can be extended in a mes‐2 mutant background (different color shade). The widest section of each window represents the embryonic stage where the efficiency of reprogramming is the highest. Data are compiled from Refs 29, 32, 34, 35, and 45. (c) 1–3: Comparison of WT embryos versus embryos carrying either (1) hsp::hlh‐1, or (2) hsp::end‐1, or (3) hsp::lin‐26 transgenes and induced under heat shock conditions. (1) Muscle cell identity is observed with an antibody against MHCa. (Reprinted with permission from Ref 29. Copyright 2005 Company of Biologists) (2) Intestinal cell identity is observed through expression of elt‐2p::gfp. (Reprinted with permission from Ref 32. Copyright 1998 Cold Spring Harbor Laboratory Press) (3) Epithelial identity is observed through expression of dlg‐1::gfp. (Reprinted with permission from Ref 34. Copyright 2001 Elsevier)

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Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion
Gene Expression and Transcriptional Hierarchies > Nuclear Reprogramming
Gene Expression and Transcriptional Hierarchies > Cellular Differentiation
Invertebrate Organogenesis > Worms