XB-ART-52722Regeneration (Oxf) August 1, 2016; 3 (4): 198-208.
The cellular and molecular mechanisms of tissue repair and regeneration as revealed by studies in Xenopus.
Survival of any living organism critically depends on its ability to repair and regenerate damaged tissues and/or organs during its lifetime following injury, disease, or aging. Various animal models from invertebrates to vertebrates have been used to investigate the molecular and cellular mechanisms of wound healing and tissue regeneration. It is hoped that such studies will form the framework for identifying novel clinical treatments that will improve the healing and regenerative capacity of humans. Amongst these models, Xenopus stands out as a particularly versatile and powerful system. This review summarizes recent findings using this model, which have provided fundamental knowledge of the mechanisms responsible for efficient and perfect tissue repair and regeneration.
PubMed ID: 27800170
PMC ID: PMC5084359
Article link: Regeneration (Oxf)
Genes referenced: abr akt1 cdc42 rac1 rho rho.2 rhoa
Article Images: [+] show captions
|Figure 1. Single‐cell wound responses. (A) Immediate signals, including calcium, IP4, and others, are produced in a gradient at the wound edge, upstream of the cytoskeletal signaling. (B) From 30 sec post wounding onwards, small Rho GTPases Cdc42 and RhoA are activated at the wound edge. Spatial patterning of the circumferential rings of Cdc42 and RhoA is regulated by Abr, a dual‐functional GAP/GEF, which separates active Cdc42 and active RhoA into an outer ring and an inner ring, respectively. (C) Cytoskeletal machinery in single‐cell wound closure. Myosin‐2 and F‐actin also accumulate circumferentially at the wound edge, and the closure of this actomyosin ring is driven by a centripetal gradient of RhoA activity (box). Reciprocally, this RhoA activity is also regulated by treadmilling of the actin filaments at the wound edge|
|Figure 2. Stages of multicellular wound healing. (A) In an unwounded epithelium, calcium ions are stored in the network of smooth endoplasmic reticulum (ER) and cell shape is maintained by cortical actin. Blue beads, calcium ions. (B) At early stages post wounding, calcium ions are released from the ER storage through calcium channels. The opening of the calcium channels is promoted by both IP3 and the product of Itpkb, IP4. The wave of calcium release propagates planarly across several rows of epithelial cells, mobilizing a larger region of the epithelial sheet for reepithelialization. On the other hand, cortical actin in leading edge cells undergoes reorganization and forms a contractile actomyosin cable at the wound edge. Itpkb regulates the accumulation of F‐actin, whereas Erk signaling regulates myosin‐2 activation, mediated by active RhoA. PI3K activity is inhibited at this stage. (C) Closure of the wound at a later stage is driven by filopodial zippering at the leading edge. PI3K signaling is active, and through Rac and Cdc42 transforms early‐stage actomyosin cable to filopodial protrusions|
|Figure 3. Stages of tadpole tail regeneration. (A) A Xenopus tadpole tail is composed of a number of axial structures including the spinal cord, notochord, and somites. An unamputated tail is in a polarized state, sustained by V‐ATPase pumps in the skin. (B) After amputation, wounded tail is depolarized and simultaneously reactive oxygen species (ROS) are produced at the amputation site. Downstream targets of the ROS include Wnt and FGF, and a number of other signaling pathways are required for successful regeneration such as Shh, TGF‐β, BMP, Notch, and Hippo pathways. V‐ATPases are also upregulated at this stage to repolarize the skin. (C) A fully functional tail is regenerated 7 days after amputation. The growth and termination of a regenerating tail are regulated by PCP signaling. BMP, bone morphogenetic protein; FGF, fibroblast growth factor; TGF‐β, transforming growth factor β; PCP, planar cell polarity|
|Figure 4. Xenopus as a model to compare regenerative and non‐regenerative limbs. Before metamorphosis, Xenopus froglets are capable of regenerating amputated limbs. Listed are required genes and pathways in different processes of limb regeneration, including growth, patterning, joint and muscle development. Post‐metamorphic froglets enter a non‐permissive stage of limb regeneration when amputated limb can only grow into a spike instead of a restored limb. Many of the upregulated genes and activated pathways in the permissive stage are not properly expressed or activated at the non‐permissive stage|
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