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, 62 (6-7-8), 491-505

Wound Healing, Cellular Regeneration and Plasticity: The Elegans Way


Wound Healing, Cellular Regeneration and Plasticity: The Elegans Way

Laura Vibert et al. Int J Dev Biol.


Regeneration and wound healing are complex processes that allow organs and tissues to regain their integrity and functionality after injury. Wound healing, a key property of epithelia, involves tissue closure that in some cases leads to scar formation. Regeneration, a process rather limited in mammals, is the capacity to regrow (parts of) an organ or a tissue, after damage or amputation. What are the properties of organs and the features of tissue permitting functional regrowth and repair? What are the cellular and molecular mechanisms underlying these processes? These questions are crucial both in fundamental and applied contexts, with important medical implications. The mechanisms and cells underlying tissue repair have thus been the focus of intense investigation. The last decades have seen rapid progress in the domain and new models emerging. Here, we review the fundamental advances and the perspectives that the use of C. elegans as a model have brought to the mechanisms of wound healing and cellular plasticity, axon regeneration and transdifferentiation in vivo.


Fig. 1
Fig. 1. Hypothetical model for the worm molecular response to epidermal wounding.
Left: epidermal wounding initiates a first influx of Ca2+ within the cells through the TRPM channel Gtl-2. A subsequent molecular cascade involving the phospholipase Cβ Egl-8 and its regulatory Gαq protein Egl-30 leads to the release of Ca2+ stored in the endoplasmic reticulum through the IP3 receptor Itr-1, increasing the intracellular concentration in Ca2+. The Cdc-42 GTPase could be activated by the increase in intracellular Ca2+ concentration and promotes wound closure by actin polymerization through the regulation of actin nucleation factors (Wsp-1/WASP and Arx-2/Arp2/3). On the contrary, Ca2+ mediated Rho-1 GTPase activation could inhibit F-actin polymerization, either by directly inactivating Cdc-42, or by promoting actomyosin cable formation by the intermediary of non-muscle myosin regulation. The increase in intracellular Ca2+ level also activates ROS production by the Bli-3 dual oxydase. The increase in ROS and the Cst-1/MST1 protein are responsible for the translocation of the Daf-16/FOXO transcription factor in the nucleus where it will regulate the expression of innate immunity genes. The released Ca2+ also enters the mitochondria via the mitochondrial Ca2+ uniporter Mcu-1 and triggers the mtROS release by opening the mitochondrial permeability transition pore mPTP. The released mtROS inhibits the Rho-1 GTPase, thereby promoting the F-actin mediated wound closure. Right: Following damage to the cuticle, an increase in the HPLA ligand triggers the activation of the G-protein coupled receptor Dcar-1. The Gα protein Gap-12 and Rack-1 and the Egl-8 and Plc-3 C-type phospholipases subsequently activate a signal transduction pathway consisting of the two protein kinases C Tpa-1 and Pkc-3, the Tir-1/SARM protein, and the Pmk-1/p38 MAP kinase cascade. The Snf-12 and Sta-2 transcription factors act downstream of this pathway to activate the AMPs genes. The Dapk-1 calcium-calmodulin kinase is an inhibitor of the molecular response to epidermal wounding, acting upstream of the Tir-1/p38 signaling cascade and on the the F-actin mediated wound closure pathway. Based on Couillault et al., 2004; Dierking et al., 2011; Pujol et al., 2008a; Pujol et al., 2008b; Tong et al., 2009; Xu and Chisholm, 2011; Xu and Chisholm, 2014a; Ziegler et al., 2009; Zou et al., 2013a; Zugasti et al., 2014.
Fig. 2
Fig. 2. Growth cone formation, axon fusion and key signalling pathways for axon regeneration.
(A) Injury first causes release of calcium (Ca2+) via 1) membrane release (orange), 2) voltage-gated calcium channel opening (EGL-19 (VGCC a1)) causing a bidirectional membrane propagation (orange arrow) of Ca2+ (blue), 3) Activation of Ca2+-dependent Ca2+ release from internal storages leading to transient Ca2+ waves (blue). Ca2+ dependent activation of cAMP and DLK-1 regeneration-dependent pathway lead to three key steps of axon regeneration: 1) growth cone formation, 2) axon extension and guidance and 3) fusion to target when it occurs. (B) Growth cone formation: Increased calcium levels activate 1) production of cAMP and activation of the PKA pathway, 2) the DLK-1 pathway which is also activated by microtubule (MT) disruption after injury. MT-associated proteins, such as the N-terminal EFA-6 factor, polymerisation and depolymerisation factors such as the depolymerizing kinesin-13 family member KLP-7 factor, act downstream DLK-1 whereas the tubulin posttranslational modifiers Patronin PTRN- acts in parallel. The Notch/lin-12 signalling prevents growth cone formation in a cellular-autonomous and DLK-1 independent manner (El Bejjani and Hammarlund, 2012). Ca2+-dependent activation of apoptotic factors CED3 and CED4 allows maintenance of the distal fragment, via DLK-1 (Pinan-Lucarre et al., 2012). (C) Injury triggers relocalisation of key proteins from soma to injured membranes for axon fusion. After injury, 1) u61569 PSR-1 relocalises from mitochondria and nuclei to axon tip (yellow dotted arrow) and axotomy-triggered flipping of the phosphatidylserine lipid (PS) (blue square). TTR-52 (red circle) relocates from PLM axonal soma to both the distal and proximal membrane (red dotted arrow) and could bind exposed PS for fusion. u61570 epithelial fusion failure-1 EFF-1 (green) relocalises from soma to distal tip of the severed membranes (green doted arrow) after injury. PSR-1/PS binding and relocalisation of the secreted PS binding protein TTR-52/transthyretin allowed the recruitment of u61571 apoptotic clearance molecules (NRF-5, CED-7, or CED-6) which are required upstream of EFF-1 for 2) the EFF-1 dependent fusion process of both axonal ends.
Fig. 3
Fig. 3. Time course of Y-to-PDA transdifferentiation and dynamic expression of some key factors throughout the process.
(A) Schematics showing cellular dynamics during transdifferentiation. (1) Focus on the rectum at the embryonic 1.5-fold stage showing the position with respect to the rectum of ABprpppaaaa (purple), which becomes the rectal Y cell; this cell is born at 290 minutes after fertilisation (Horvitz and Sulston, 1983). (2) The rectum in early L1 larva, composed of the six rectal cells known as: Y (purple), B, U, F, K and K’. The rectal slit is the visualisation of the lumen. (3) Transdifferentiation initiation starts at the end of the L1 stage, Y migrates anteriorly and dorsally (purple arrow) whereas a cell named replaces Y in the rectum (dark grey cell, grey arrow for migration). (4) In the L3 larval stage, the PDA motoneuron (green cell) with its characteristic axon is observed and P12. pa has replaced Y in the rectum. (B-E) Microscope images of embryos and blow ups of the rectum area throughout transdifferentiation. (B) Blow up of the rectal area of a 1.5-fold embryo expressing a Y-specific marker (green cell, red arrow). (C) DIC picture of the rectal area of an early L1 larva before the initiation of transdifferentiation; the nuclei of the six rectal cells are circled in white, and the Y cell is indicated by a red arrow. (D) L2 larva, ventral to dorsal: the, migrating Y (red arrow) and U nuclei are circled in white. (E) L3 transgenic larva expressing GFP in the PDA motoneuron (green cell, red arrow - adapted from Richard et al., 2011). The yellow arrows show the rectum in embryos or the rectal slit in larval stages; anterior is to the left and ventral to the bottom. (F) Timeline of transdifferentiation. At the end of the L1 larval stage, epithelial markers are lost and Y dedifferentiates (blue arrow) to becomes a unipotent transient cell, Y.0. Then, Y.0 redifferentiates step-wise into the PDA motoneuron, first by becoming an early neural cell Y.1. (G) Molecular players. Shortly after Y birth in the embryo, lin-12/Notch, ceh-6/OCT, egl-27/MTA1, sox-2, egl-5/HOX are expressed and required in the Y cell to promote its dedifferentiation; the LIN-12/NOTCH receptor is activated and is required until embryonic 2.2-fold for Y formation and transdifferentiation and sem-4/SALL4 is expressed from the embryonic 3-fold stage on (Kagias et al., 2012; T. Daniele & S. Jarriault personal communication). Redifferentiation requires the UNC-3/EBF transcription factor and the histone modifier JMJD-3.1. Perfect efficiency and robustness of the process is ensured via step-wise histone modifications involving H3K4 and H3K27 methylation (see WDR-5.1, JMJD-3.1, Zuryn et al., 2014).

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