TY - JOUR
AU1 - Cigliola, Valentina
AU2 - Ghila, Luiza
AU3 - Chera, Simona
AU4 - Herrera, Pedro L.
AB - Abstract To date, most attention on tissue regeneration has focused on the exploration of positive cues promoting or allowing the engagement of natural cellular restoration upon injury. In contrast, the signals fostering cell identity maintenance in the vertebrate body have been poorly investigated; yet they are crucial, for their counteraction could become a powerful method to induce and modulate regeneration. Here we review the mechanisms inhibiting pro-regenerative spontaneous adaptive cell responses in different model organisms and organs. The pharmacological or genetic/epigenetic modulation of such regenerative brakes could release a dormant but innate adaptive competence of certain cell types and therefore boost tissue regeneration in different situations. Significance statement The state of differentiation of a given cell is not carved in stone. Cell identity, at all stages of life, is modulated by inhibitory signals from the close cellular environment. Cell identity maintenance is therefore an active process of inhibition of a natural trend to change and not an intrinsic or passive state of differentiation. The present study reviews some of the published knowledge regarding the brakes to these changes of cell identity, and thus to tissue regeneration, as described in different experimental models. The modulation of these inhibitory signals, by helping specialized cells to change their function, that is, by fostering regeneration, could prove crucial for treating pathologies due to massive or inappropriate cell death. Cell identity maintenance, at all stages of life, is modulated by inhibitory signals from the surrounding cellular environment. Stress-mediated suppression of these signals, such as after a lesion, may lead fully mature differentiated specialized cells to change their function, thus fostering regeneration of injured tissue. Controlling this cellular plasticity could prove crucial to developing new therapies to treat degenerative diseases. Open in new tabDownload slide Open in new tabDownload slide liver regeneration, pancreas, plasticity, proliferation, reprogramming, transdifferentiation INTRODUCTION Regeneration is defined as the ability to replace lost structures (cells, tissues, or body parts) following injury after birth. Its study has captured the attention of generations of biologists who have long studied the cellular and molecular basis of this fascinating phenomenon. The capacity of regeneration is heterogeneously distributed among the different phyla of the animal kingdom and is, in general, inversely correlated with increased evolutionary complexity.1-3 For instance, recent evidence from the fossil record suggests that limb regeneration is an ancient feature of all Tetrapoda, which was definitely lost in a common ancestor of the Amniota (ie, reptiles, birds, and mammals).4 Along this line, organisms such as polyps and flatworms, and even vertebrates such as bony fish and amphibians, have revealed an impressive natural regenerative capacity after injury, which is nearly lost in mammals. What are the molecular mechanisms and factors leading to cell and tissue regeneration? How is their activity controlled, both spatially and temporally? In other words, how is this activity targeted to the injured area, and how it ceases once regeneration is completed? Are these mechanisms irreversibly lost or just “blocked” or latent in higher vertebrates? Many intriguing questions remain unanswered, even after many years of scientific research. Solving these issues is of crucial importance, with consequences reaching beyond the regeneration field and impacting our fundamental knowledge of the cellular and molecular basis of organ homeostasis, adult cell fate maintenance, and cell-cell interaction signaling. The difficulty in addressing these questions is caused by the intrinsic complexity of the systems studied. In most cases, several cell types and molecular processes define the regeneration program; in addition, their cooperation is rigorously controlled by an intricate network of stringent interactions. Studies with different experimental model organisms suggest that regeneration is generally controlled by local organ- and tissue-specific signals, with the final stages of the regeneration process usually recapitulating, at the cellular level, the ontogenetic differentiation sequence.5 Most common regenerative strategies include the formation of a blastema, that is, a bulk of undifferentiated cells formed in the proximity of the wound which, acting as progenitors, will subsequently proliferate and replace the missing structure. Other regenerative strategies involve proliferation of differentiated cells surrounding the injury area and, as recently discovered, changes in cell identity (transdifferentiation or natural reprogramming), either direct or indirect, of differentiated cells. Different tissues and organs may employ several of these mechanisms, either simultaneously or sequentially. This review integrates some of the dispersed information on the regenerative brakes described in different models. We propose a classification of these brakes according to the diverse cellular processes that are hindered in different conditions. We thus review the available knowledge regarding signals that prevent regeneration during (i) blastema formation, specifically in polyps, flatworms, and salamanders, as well as during mouse digit tip regeneration; (ii) proliferation, with or without transient cell dedifferentiation, as observed in heart, liver, skin, ear, and lung regeneration, and (iii) transdifferentiation, also termed cell conversion or reprogramming, that is, the adaptive change of cell identity, as observed in retina, lens, and pancreas. In addition, we comment on the inhibition of the reconstitution of lost parts of cells, such as axonal sprouting (neurite outgrowth), as described during spinal cord regeneration (Table S1). For the sake of space, we discuss only some of the published papers, yet we cite some reviews to minimize the lack of coverage. Modulation of blastema development The blastema is a mass of undifferentiated mesenchymal cells that are covered by a multilayered epithelium and give rise to various differentiated cell types. Its formation is critical for progression of regeneration in certain invertebrates among which polyps (Hydra), flatworms (Planaria), and in vertebrates, such as bony fish (Danio, zebrafish), and amphibia (Ambystoma, the axolotl). There are two types of signals (“brakes”) inhibiting blastema formation: those that are associated with structural information vs those that are true brakes in regeneration. The first kind is important to avoid the formation of unnatural/ectopic structures. Blastema formation can occur through stem cell recruitment or dedifferentiation of mature cells located in the vicinity of the injury plane, or a combination of both (Figure 1, magenta sector). The first mechanism is typical of Planaria. Planarians are tiny flatworms able to regrow the entire body thanks to the abundance of pluripotent adult stem cells, named neoblasts, representing approximately 25%-30% of the organism's entire cell population.6,, 7 Following injury, neoblasts migrate and accumulate to form the blastema and, subsequently, convert into the required cell types.8 Due to their impressive regeneration potential, planarians do not seem to have natural regenerative brakes, yet RNAi screenings identified a number of genes involved in regulating neoblast proliferation capacity.9 Inhibition of these genes revealed increased mitoses, suggesting their function as cell proliferation brakes after injury. Additional RNAi studies have led to the identification of signals inhibiting the formation of misplaced structures during regeneration. One example is notum, a key regulator that displays a polarized pattern of expression (to the anterior pole) and inhibits the formation of a tail instead of a head by inhibiting Wnt signaling during regeneration.10 By extension, Wnt signaling inhibits head regeneration in planarians, while promoting a tail fate.11 Wnt signaling is therefore a key player in establishing the head/tail axis in regenerative halves (Table S2). Figure 1 Open in new tabDownload slide Cartoon depicting different natural cell regeneration strategies, according to the utilized cellular mechanism. C, conversion; dD, dedifferentiation; M, mitosis; O, outgrowth; P, proliferation; R, recruiting and migration Figure 1 Open in new tabDownload slide Cartoon depicting different natural cell regeneration strategies, according to the utilized cellular mechanism. C, conversion; dD, dedifferentiation; M, mitosis; O, outgrowth; P, proliferation; R, recruiting and migration The Wnt pathway has been shown to establish proper homeostatic and regenerative polarity also in Hydra, a freshwater polyp (cnidarian) with outstanding regenerative potential. Hydra has a very simple architecture, with a polarized tube-shaped body presenting a mouth opening surrounded by tentacles at one pole and a basal disc used to attach to the surfaces at the opposite one. During head regeneration, the SP5 transcription factor is a head inhibitor by repressing the activity of Wnt3 promoter.12 Animals in which SP5 is knocked-down by RNAi regenerate multiple heads, a phenotype which phenocopies to the one exhibited by Wnt signaling ectopic activation.13,, 14 These examples illustrate that, in organisms with extremely high regenerative potential, such as cnidarians and planarians, brakes are important to avoid the formation of misplaced or supernumerary structures. The axolotl (a salamander-like amphibian) displays an astonishing capacity of regeneration,15 and for this reason is one of the favorite organisms used in regeneration studies. Upon limb amputation, epidermal cells migrate to cover the wound surface and then start proliferating, forming a multilayered apical epidermal cap. This is required to form the blastema that allows regrowth of missing structures.16 Dedifferentiation of mature cells into blastema cells depends upon several wound-related signals. Bryant et al assessed the persistence of the axolotl's limb regenerative capacity and found that it declines after multiple consecutive amputations at the same plane. Transcriptomic analyses of regeneration-incompetent and competent limbs revealed that persistent high levels of amphiregulin antagonize limb regeneration, and thus function as regenerative roadblocks.17 Signals blocking blastema formation and thus regeneration are also found in zebrafish, a widely used regeneration model due to its remarkable ability to spontaneously regenerate amputated parts of different organs, such as after fin amputation, heart resection, or spinal cord transection.18 Fins consist of segmented bony rays separated by inter-ray mesenchymal tissue, all enclosed by the epidermis; the blastema that forms after fin amputation allows a complete regeneration within 2 weeks.19 Studies by Kang et al showed that dkk1b acts as a negative signal impeding pectoral fin regeneration, in a Wnt-dependent manner.20 Likewise, the chemokine Sdf1 regulates blastema formation by inhibiting cell proliferation, thus preventing fin regeneration.21 Taken together these findings suggest that tight control of blastema formation in lower vertebrates is essential for functional recovery upon injury, and avoidance of ectopic tissue re-growth. Therefore, discovering signals impeding blastema formation may be the key to stimulating successful regeneration where it does not naturally occur. In juvenile mice there is also blastema formation after fingertip amputation, and its cell composition/dynamics is remarkably similar to that of regenerating fins and limbs of fish and salamanders, respectively.22-24 Signals inhibiting regeneration in mice might come from inflammatory cells. Indeed, PU.1 null mice, lacking macrophages and functional neutrophils, are capable of scar-free wound healing.25 This result, which is against the accepted consensus according to which depletion of inflammatory cells inhibits regeneration,26,, 27 suggests that blocking signals exist in mammals too. Accordingly, digit tip blastema is avascular and its formation correlates with downregulation of pro-angiogenic factors. Thus, enhancing angiogenesis with exogenous VEGFA or BMP9, an inducer of VEGFA expression, is inhibitory for digit tip regeneration.28 A negative impact of inflammation on wound healing has also been reported by Geesala et al, who transplanted bone marrow-derived stem cells beside a wound site. Administration of celecoxib, a common anti-inflammatory drug blocking the proinflammatory enzyme COX-2 secreted by macrophages, improved stem cell survival and proliferation, boosting wound healing.29 Combined, these studies suggest that modulation of inflammation represents a promising approach to foster regeneration. Proliferation brakes Heart regeneration Adult mammals do not regenerate lost cardiac muscle. In stark contrast, the zebrafish has, again, a remarkable regeneration capacity after resection of 20% of the ventricular apex, after cryoinjury, or upon massive (60%) genetic ablation of ventricular cardiomyocytes (CMs).30-32 Intriguingly, the neonatal mouse heart also displays some regeneration.33 In both, zebrafish and newborn mice, CMs are newly formed after injury through proliferation of the ones escaping damage34 (Figure 1, orange sector). Different CM proliferation inhibitors have been identified to date. Yin et al35 demonstrated in zebrafish that CM injury is followed by a decrease in mi-RNA133, which restricts CM proliferation by targeting cell cycle factors (mps1, cdc37, and PA2G4) and cell junction components (cx43 and cldn5). Similarly, in newborn mice, miRNAs are also implicated in heart regeneration. For instance, overexpression of miRNA195 in neonatal CMs impairs their regenerative response, whereas its inhibition in adults increases CM proliferation after myocardial infarction.36 miRNA195 belongs to the miR-15 family and, interestingly, miRNA15s levels steadily increase in CMs from birth to adulthood.37 In addition to miRNAs, p38 mitogen-activated protein kinase also regulates CM proliferation. In zebrafish, adult CM proliferation requires p38α μΑPK inactivation38; in mouse, p38 effects have not been tested after injury, yet it is a negative regulator of mammalian CM proliferation during homeostasis: its targeted disruption increases neonatal CM mitoses and its inhibition along with specific growth factors induces cytokinesis in adult CMs.39 Also, the cell cycle inhibitor p21 inhibits mouse CM proliferation: its REST-mediated suppression is required for cardiac development and regeneration.40 Intriguing observations suggest that the Hippo pathway hampers adult CM renewal and heart regeneration in mice: blockade of the Hippo signaling components Salv and Lats1/2 allowed adult CM renewal after myocardial infarction.41 Finally, the transcription factor Meis1, a critical regulator of CM cell cycle, represents a proliferation brake in homeostatic and regenerative conditions: its inactivation extends the postnatal regeneration window and leads to reactivation of mitosis in the adult heart. Conversely, Meis1 overexpression in neonatal CMs decreases proliferation and inhibits heart regeneration.42 Skeletal muscle regeneration Skeletal muscle fibers are damaged and repaired continuously during life. In muscles, resident satellite cells (SCs) are activated and proliferate upon injury,43 yet SC-guided regeneration is severely inhibited through various mechanisms. It is thought that myostatin, a member of the TGF-β superfamily also known as growth differentiation factor 8, inhibits SC activation and is increased during muscle disuse. Mice lacking myostatin have more activated SCs and greater SC self-renewal capacity.44 Acting in a similar manner, GDF11 limits SC expansion and muscle regeneration in mice.45 Osteopontin, a pleiotropic cytokine, negatively influences muscle regeneration in an age-dependent manner: in injured aged mice, its levels increase in macrophages infiltrating the injured muscle as well as systemically, and its neutralization improves regeneration.46 Another negative regulator of muscle regeneration is CD163, a scavenger receptor expressed on cells of the monocyte/macrophage lineage that acts as a receptor for the tumor necrosis factor-like weak inducer of apoptosis (TWEAK). TWEAK stimulates SC proliferation and thus regeneration. In CD163 KO mice, femoral artery ligation leads to TWEAK upregulation, activation of canonical NF-κB and Notch signaling, thus improving skeletal muscle regeneration.47 Liver regeneration The liver has the highest natural regeneration capacity in the mammalian body. After resection, the amount of lost tissue determines the regenerative response: 1/3 removal of the total mass triggers hepatocyte hypertrophy, whereas higher ablation induces proliferation. Massive (70%-80%) liver ablation induces biliary epithelial cell dedifferentiation and proliferation, leading to regeneration.48 This is, however, compromised in chronic liver diseases, such as nonalcoholic fatty liver disease, alcoholic liver disease, and chronic exposure to toxins. In liver, TGF-β as well as other cytokines like TNF-α, IL-1, and IL-6 function as inhibitors of regeneration (reviewed in Liu et al49). Likewise, p53 inhibition with antisense oligonucleotides or in p53−/− mice, leads to increased hepatocyte proliferation,50 although p53 function in other organs might be different.51 Along this line, other oncogenes such as p21, Bcl-2, and NDRG2 have been shown to inhibit liver regeneration (reviewed in Liu et al49). Additional studies have shown that the dual-specific kinase MKK4 inhibits hepatocyte proliferation: notably, its suppression accelerates cell cycle entry through compensatory upregulation of MKK7 and activation of ATF2 and ELK1 dependent on JNK1.52 Another kinase, Map3k14, has recently been identified as a suppressor of mouse hepatocyte proliferation; it acts, at least in part, by repressing the JAK2/STAT3 pathway.53 Protein tyrosine phosphatases 1A and 1B (PTP1A and PTP1B) also affect hepatocyte proliferation: PTP1B null mice have increased PCNA and cyclin D1 and E levels upon liver injury, like cultured hepatic cells upon PPM1A inhibition. More studies are needed to fully understand the role of the latter in liver regeneration.54 The Hippo pathway, regulating organ size in several injury models, also participates in liver regeneration: its components are dynamically regulated upon 70% hepatectomy, with Mst1/2 and Lats1/2 activation being decreased at early stages upon injury and returning to normal levels when regeneration has completed, in quiescent hepatocytes.55 For an extensive review on negative regulators of hepatocyte proliferation see Liu et al. 49 Skin regeneration Although vertebrates such as fish and amphibians do regenerate the skin upon damage, this capability is lost in mammals.56 In wild-type mice, a punch piercing in the ear pavilion, which damages the epidermis and dermis with its hair follicles, sebaceous glands, adipose cells, cartilage, and so on, cannot be repaired. The proliferative brake impeding skin regeneration has been spotted now: mice missing cdkn1a (p21), a potent cyclin-dependent kinase inhibitor, can heal without scarring. In the wounded epidermis of p21−/− mice, the normal activation in of the stromal-derived factor 1 (Sdf1) and the recruitment of leukocytes expressing Cxcr4, the canonical receptor for Sdf1, are strongly impeded, whereas proliferation is increased. This suggests that the Sdf-Cxcr4 axis functions as a proliferative regeneration brake.57 As a rule, the capacity of regeneration is more pronounced in juveniles, because cell proliferation rates decrease with aging.58 This is due to increased DNA damage linked to oxidative stress, telomere shortening, and changes in gene expression that impair the self-renewing ability of adult stem cells.59 Decreased skin re-epithelialization and wound repair in aged individuals epitomize this phenomenon.60,, 61 However, some studies and clinical observations suggest that skin regeneration is more effective in the elderly, where wounds close with thinner scars.62 By comparing ear hole closure and back skin wound repair in young and aged mice, Nishiguchi et al have recently confirmed that Sdf1 inhibits skin regeneration, as its genetic deletion in young mice improves ear punch closure.63 Indeed, in adult mice, EZH2 and histone H3 lysine 27 trimethylation are recruited to the Sdf1 promoter, and EZH2 pharmacologic inhibition leads to Sdf1 induction, which prevents regeneration.63 Using the same experimental murine model (ear punching), Bastakoty et al identified the Wnt/β-catenin pathway as a regeneration inhibitor, naturally activated in the wounded dermis 2 days after injury, and reaching baseline levels by day 10. Topical application of a small-molecule inhibiting Wnt pathway (either a tankyrase inhibitor or a casein kinase activator, pyrvinium) led to improved wound closure.64 Dipeptidyl peptidase 4 inhibitors (DPP-4is), hypoglycemic agents used for treating type 2 diabetics, improve skin wound healing in mice made diabetic with streptozotocin, through a mechanism involving a Sdf1α-dependent keratinocyte epithelial-mesenchymal transition.65 Similarly, the angiotensin II inhibitor losartan accelerates stromal responses in diabetic wound healing.66 Inner ear regeneration Several laboratories have explored the molecular mechanisms of cochlea regeneration in the inner ear. The hair cells (HC) form the auditory epithelium of the cochlea, named organ of Corti, together with the supporting cells (SC). Although in mammals HC loss is in principle irreversible, in fish and birds these cells can regenerate from SCs,67 by either proliferation (fish68,, 69) or direct reprogramming (chick,70 axolotl71). Following injury, zebrafish robustly regenerates HCs in the lateral line through a mechanism involving SC proliferation (Figure 1, orange sector). At a molecular level, during the early stages of regeneration, the downregulation of FGF and Notch is coupled with the activation of Jak1/Stat3 pathway and leads to increased proliferation, followed by subsequent Wnt pathway activation.72 The regeneration efficiency in the lateral line appears to rely upon a tight modulation of Notch signaling.73 The prompt downregulation of Notch signaling after injury is missing in mammals, thus suggesting that it could be a regeneration brake.72 This is supported by the successful induction of SC transdifferentiation upon Notch inhibition by either administrating γ-secretase inhibitors or knocking-out RBP-J, a key player of the Notch Pathway.74-76 HC regeneration in the chick utricle also involves modulation of the Notch pathway; however, in this case it was reported an initial upregulation followed by a transient downregulation, when there is increased cell proliferation and conversion.77 Of interest, and consistent with zebrafish lateral line data, FGF signaling was postulated as a negative regulator of proliferation after utricle injury in chicks: Fgf20 and Fgf3 levels decrease when SCs proliferate, indicating that they might act as putative proliferative brakes.77 In 2014, Li et al showed that Notch signaling is a negative regulator of neonatal cochlear cell regeneration in mammals. Indeed, inhibition of Notch removes a brake, thus allowing the proliferation of Wnt-responsive Lgr5+ progenitor cells, the SCs, to generate new HCs, whose demise is the major cause of hearing loss and balance disorder.78 Lung regeneration Regeneration of the injured lung, an architecturally complex organ containing several epithelial and mesenchymal lineages, is also hampered by regenerative brakes.79 Studies have shown that hedgehog signaling is transiently downregulated upon injury in the lung epithelium, allowing proliferation of mesenchymal cells. Subsequently, its levels rise as injury is resolved and quiescence is restored.80 This suggests that active Hedgehog signaling during normal homeostasis may block proliferation. In summary, a tight control of the regeneration-inducing proliferation is essential for the proper structural and functional recovery, avoiding oncogenic transformation. Among others, components of Notch, Hippo, and FGF signaling pathways have now been identified as common proliferation brakes (Table S2). Neurite growth brakes Axon regeneration upon injury has been extensively studied in different model organisms. In mammals, damage to neurons of the central nervous system (CNS) is irreparable. By contrast, organisms such as the nematode Caenorhabditis elegans, and vertebrates like lamprey (jawless fish), zebrafish, and the salamander have a great ability to regenerate severed axons (Figure 1, blue sector). In nematodes, gamma-aminobutyric acid motoneuronal axon regrowth upon injury is inversely correlated with age. This ageing-related decline in regeneration is regulated by the insulin/insulin-like growth factor 1 signaling pathway. Similarly, regeneration is inhibited by daf-18/phosphatase and tensin homolog, and the transcription factor daf16/forkhead box protein O is also inhibitory through target of rapamycin signaling.81 Extensive studies over the past decades have identified innate negative cues preventing axon regeneration in CNS neurons of vertebrates. Studies in lampreys have revealed that serotonin is a negative modulator of axon regeneration after spinal cord transection, through serotonin 1A receptor signaling.82 In adult mice, myelin-mediated inhibition of axon growth has been extensively studied. Myelin-associated glycoprotein (MAG) was the first molecule identified as inhibiting axonal regeneration.83,, 84 Nogo-A, a membrane-associated protein mostly expressed in oligodendrocytes and some neurons in the developing and adult CNS, was also identified as a neurite growth inhibitor.85 Finally, Omgp (oligodendrocyte myelin glycoprotein), also blocks neurite outgrowth.86 Interfering with Omgp, Nogo-A, as well as MAG may improve axon regeneration after injury in vivo.87 Other examples of regenerative brakes have been reported in the CNS. For instance, it is known that that chondroitin sulfate proteoglycans (CSPGs) are dramatically upregulated upon neural injury and have a regeneration inhibitory role.88 Digestion of the chondroitin sulfate side chains by chondroitin ABC lyase promotes axon regeneration and sprouting of axon fibers.89 Supporting an inhibitory role for CSPGs, in 2009, Shen et al disrupted in mice the transmembrane protein tyrosine phosphatase PTPσ, which binds to CSPGs, and showed that axon extension upon spinal cord injury was significantly improved.90 Brakes to adaptive cell identity changes (natural reprogramming or conversion) Retina and lens regeneration Following injury, fish and amphibians can readily regenerate the retina from Müller glia (MG), a type of retinal glial cells proliferating and yielding the various neuronal types91 (Figure 1, green sector). This process requires the upregulation of the transcription factor Ascl1, a change which is not observed in mammals.92 Interestingly, experimental Ascl1 activation in MG cells of newborn mice promotes their neurogenic capacity, both in vivo and in vitro.93 Nevertheless, this competence is restricted to the first 2 weeks of life; after this window, Ascl1 expression is ineffective.94 Yet a recent study95 shows that combining Ascl1 induction with histone deacetylase inhibition (using trichostatin-A) extends the regenerative competence to adulthood, thus highlighting that the brakes to regeneration have epigenetic components. Retinal regeneration after surgical removal has been described in the chick embryo. This occurs through transdifferentiation of the retinal pigmented epithelium (RPE) or from proliferating stem/progenitor cells located in the anterior margin of the eye. Hedgehog signaling mediates RPE fate maintenance by inhibiting transdifferentiation and favoring regeneration through proliferation, involving FGFR-2 signaling upstream of the ERK pathway.96 Another eye structure undergoing rapid and efficient regeneration in both fish and amphibians is the crystalline lens. In salamanders, lens regeneration is based on an indirect transdifferentiation process, where pigment epithelium cells (PEC) from the dorsal iris dedifferentiate, proliferate, and re-differentiate, reconstituting the missing crystalline.97 Interestingly, the in vivo conversion is restricted only to this particular cell type, whereas in vitro all cell types of the neural pigment epithelium exhibit plasticity (reviewed in Tsonis97). This in vitro cell plasticity has also been observed in mammals, including humans, suggesting that an inhibitory mechanism blocks the conserved innate plasticity observed in vitro. One of such brakes is the BMP pathway: its inhibition has an unlocking effect, suggesting it is one of the main brakes stopping the PEC-driven regeneration in the ventral iris.98 Pancreas Regeneration brakes have also been identified in the endocrine pancreas, where the insulin-producing β-cells reside and whose loss leads to diabetes onset. In our laboratory, we showed that a small fraction (1%-2%) of the other endocrine non-β-cell types of the pancreatic islets in mice have the astonishing capacity of spontaneously reprogramming and engage insulin production and secretion after β-cell loss induction099,, 100 (Figure 1, green sector). This is a direct cell conversion process, namely an adaptive change of cell identity/functionality and, remarkably, it can also be induced in human α- and PP cells.101 In an attempt at identifying the inhibitors of insulin-producing cell regeneration, we investigated the mechanisms making most non-β-cells resistant or refractory to fate change and thus opposing regeneration. We focused on the glucagon-producing α-cells, and our study revealed that the identity change displayed by some of them is constrained by signals derived from the other islet endocrine neighbor cells. We found that local intra-islet blockade of Insulin and Hedgehog signaling pathways leads to improved reprogramming efficiency. Hence, Hedgehog and Insulin signaling are, together with other pathways not yet identified, natural brakes making α-cells to preserve their identity.102 By using a wide range of genetic tools, recent studies have revealed that α-to-β transdifferentiation can be artificially potentiated by the concomitant inhibition of the key α-cell-specific transcription factor Arx and the epigenetic modifier DNMT1.103 This suggests that α-cells are epigenetically locked, and that these brakes can be released. Interestingly, when β-cell loss is induced in prepubescent juvenile mice, another islet cell-type, the somatostatin-producing δ-cells, undergo an indirect reprogramming, whereby they de-differentiate, replicate, and ultimately re-differentiate into new insulin-expressing β-like cells.100 A direct comparison between juvenile and adult δ-cells suggests a role for the FoxO1/p21 axis in this process. Indeed, transient pharmacological inhibition of FoxO1 in regenerating adults revealed a low, nevertheless significant, number of β-like cells with δ-cell origin, suggesting that FoxO1-mediated mechanisms might act as cell conversion brakes in the pancreas.100 CONCLUSION Signals inhibiting regeneration in mammals are still poorly understood but appear to be evolutionarily conserved. Cumulating evidence points toward a number of players, such as the Notch pathway, acting as brake to proliferation and identity conversion. FGFs, IRs, P16, and insulin also seem to function as regeneration brakes (Figure 2, Table S2). SDF1 has a prominent role in this respect as well: aside from its involvement in skin and fin regeneration, it could also mediate regeneration in organs such as liver and lung.104,, 105 Injury-induced inflammatory responses, a key component of regeneration processes in mammals and other organisms, might also play a crucial role as modulators/inhibitors of cellular, tissue or organ regeneration. Further investigation of inflammation is therefore needed to understand the mechanisms through which inflammatory signals negatively modulate the capacity for epimorphic regeneration. Such knowledge could lead to the development of anti-inflammatory therapies to promote regeneration in the future. Figure 2 Open in new tabDownload slide Scheme briefly summarizing the signaling pathways exhibiting the widest usage as regenerative breaks amongst the various models of regeneration discussed herein Figure 2 Open in new tabDownload slide Scheme briefly summarizing the signaling pathways exhibiting the widest usage as regenerative breaks amongst the various models of regeneration discussed herein Deciphering the signals that block regeneration is a formidable task. In addition, in some cases the molecular brakes are expressed both in physiological conditions and upon injury. Their identification as regeneration modulators through gene profiling analyses will be cumbersome. As mentioned above, we have found, for instance, that insulin and hedgehog signaling in pancreatic islets are such players.102 It is tempting to think that the inhibition of regeneration brakes could be employed to promote cell and tissue reconstitution in future therapies to treat degenerative diseases. Yet it is intriguing that multiple mechanisms appear to block regeneration in mammals, such as axonal regrowth, for instance. Whether unlocking cell conversion events or promoting the formation of blastema and cell proliferation will be beneficial, or, on the contrary, could lead to uncontrolled growth and cancer development, will have to be carefully determined in each situation. These are challenging questions, but the identification of signaling pathways blocking mammalian regeneration and the development of tools allowing their pharmacological/epigenetic modulation represent a promising avenue for the development of innovative cell replacement therapies. ACKNOWLEDGMENTS S.C. was supported by grants from the Research Council of Norway and the Novo Nordisk Foundation. V.C. was supported by a Swiss National Science Foundation and a Regeneration Next Postdoctoral Fellowship. P.L.H. was supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease, the Juvenile Diabetes Research Foundation International, the Innovative Medicines Initiative Joint Undertaking, the Fondation privée des Hôpitaux Universitaires de Genève, and the Swiss National Science Foundation. CONFLICT OF INTEREST The authors indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS V.C., L.G., S.C.: wrote the manuscript; P.L.H.: wrote, edited, and approved the final version of the manuscript. DATA AVILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. REFERENCES 1 Bely AE , Nyberg KG. Evolution of animal regeneration: re-emergence of a field . Trends Ecol Evol . 2010 ; 25 ( 3 ): 161 - 170 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Tsonis PA . Regeneration in vertebrates . Dev Biol . 2000 ; 221 ( 2 ): 273 - 284 . 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Google Scholar Crossref Search ADS PubMed WorldCat Author notes Funding information Fondation privée des Hôpitaux Universitaires de Genève; Innovative Medicines Initiative; Juvenile Diabetes Research Foundation International; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease; Regeneration Next Postdoctoral Fellowship; Swiss National Science Foundation; Novo Nordisk Foundation; the Research Council ©AlphaMed Press 2019 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Tissue repair brakes: A common paradigm in the biology of regeneration
JF - Stem Cells
DO - 10.1002/stem.3118
DA - 2020-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/tissue-repair-brakes-a-common-paradigm-in-the-biology-of-regeneration-Vk2ll99vrf
SP - 330
EP - 339
VL - 38
IS - 3
DP - DeepDyve
ER -