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

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)

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.

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‐1^heat‐shock; intestinal cells, end‐1^heat‐shock; epithelial cells, lin‐26^heat‐shock; and epidermal cells, elt‐1^heat‐shock and elt‐3^heat‐shock is shown. Both hlh‐1^heat‐shock and end‐1^heat‐shock 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)