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  • Wound healing without blastema formation causes partial rest

    2024-02-07

    Wound healing without blastema formation causes partial restoration of lost tissue, and gives rise to fibrotic scars. Healing by fibrotic scarring rather than by regeneration leads to tissue dysfunction, and can place a huge burden for the health of the animal [4]. Therefore, understanding the molecular and cellular basis of regenerative growth has been an area of intense investigation during the past decades. Mammals show restrictive regeneration, and for this reason several different model organisms that show a high degree of regenerative capacity, like hydra, planaria, Drosophila, Xenopus, salamander or zebrafish, are being used with the goal to identify the mechanisms that underlie injury-induced cellular plasticity and regeneration [4]. Studying regeneration in various model organisms can provide insight into why mammals have lost the capacity to regenerate, and whether it is possible to restore regeneration in mammals, forming the basis for regenerative medicine.
    Apoptosis-induced compensatory proliferation (AiP) Compensatory proliferation is one of the mechanisms by which a regenerative response is initiated post injury. In this mechanism, the uninjured Schaftoside increase proliferation to replace the damaged cells, and thus maintain tissue homeostasis [6] (Fig. 1A). Studies in several model organisms have revealed that apoptotic cells are one of the driving forces for compensatory proliferation through secretion of mitogenic signals, hence this phenomenon was termed “apoptosis-induced compensatory proliferation” (AiP) [7], [8]. Active caspases are the main inducers of AiP. Caspases are conserved cysteine proteases present in cells as inactive zymogens. They are divided into initiator caspases and effector caspases based on the length of their prodomains and their activation process. Initiator caspases like Caspase-2, −8, −9, −10, and Drosophila Dronc have long prodomains, and are activated by incorporation into large apoptotic protein complexes called the apoptosome (Fig. 2A,B). Effector caspases like Caspase-3, −6, −7, and Drosophila DrICE and Dcp-1 are characterized by short prodomains, and are activated upon cleavage by upstream initiator caspases [9]. After apoptosis induction, caspases are activated in a sequential cascade that culminates in the death of the cell (Fig. 2A,B). Recent studies have shown that caspases also function independently of their role in apoptosis, and are involved in inflammation and immunity, cell migration, neurite pruning, cellular remodeling and differentiation, as well as AiP (reviewed in [10], [11]). AiP initiated by caspases is seen in a variety of model organisms like Hydra, planarians, newts, Drosophila, Xenopus and mice [12]. In Hydra, activation of effector caspases in apoptotic cells after mid-gastric amputation triggers release of the mitogen Wnt3, which stimulates proliferation and head regeneration [13]. Similarly, in Xenopus tadpoles, tail amputation induces caspase activity at the site of injury, which is essential for regeneration [14]. In mice, in an AiP-dependent process termed “Phoenix Rising”, caspases are important for epithelial wound healing, liver regeneration after partial hepatectomy, and tumor repopulation following chemotherapy or radiation. During Phoenix Rising, Caspase-3-induced activation of calcium-independent Phospholipase A2 (iPLA2) and prostaglandin E2 (PGE2) is required for compensatory proliferation [15], [16]. Pioneering work performed in Drosophila over the past decade have helped to identify the mechanisms and signaling events involved in AiP (reviewed in [12], [17], [18]). These genetic models of AiP take advantage of the high regenerative capacity of larval imaginal discs, developing epithelial primordia that give rise to adult structures such as eyes and wings. In these studies apoptotic wounds are induced in eye or wing imaginal discs, either genetically by over-expressing IAP antagonists (like hid or reaper) (Fig. 2B,C) [19], or by irradiation, to study the role of active caspases for AiP. However, due to the transient nature of the apoptotic process, studying the non-apoptotic signaling events initiated by caspases is difficult. To overcome this limitation, the “undead” models of AiP were developed [20]. In these models, apoptotic signaling is induced by expressing IAP antagonists, but cells are kept alive by co-expressing the baculovirus protein P35 that specifically inhibits the effector caspases DrICE and Dcp-1, but not the initiator caspase Dronc (Fig. 2C) [21]. Rendering cells in an undead state allows uncoupling of the apoptotic and non-apoptotic functions of Dronc, which can now persistently signal to induce compensatory proliferation leading to hyperplastic overgrowth (Fig. 1B) [20], [22], [23], [24], [25]. For example, if hid and p35 are simultaneously expressed in the developing eye imaginal disc, hyperplastic tissue overgrowth is induced, and adult flies are characterized by enlarged head cuticles with several patterning defects (Fig. 1C). The overgrowth phenotype of undead fly heads has been used for genetic screens aimed at identifying genes and mechanisms involved in AiP [26], [27].