-
Physiological Reviews Oct 2015After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of... (Review)
Review
After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world.
Topics: Animals; Cell Differentiation; Heart; Heart Diseases; Humans; Myocytes, Cardiac; Regeneration; Stem Cells
PubMed: 26269526
DOI: 10.1152/physrev.00021.2014 -
Biochimie May 2022Musculoskeletal injuries are common in humans. The cascade of cellular and molecular events following such injuries results either in healing with functional recovery or... (Review)
Review
Musculoskeletal injuries are common in humans. The cascade of cellular and molecular events following such injuries results either in healing with functional recovery or scar formation. While fibrotic scar tissue serves to bridge between injured planes, it undermines functional integrity. Hence, faithful regeneration is the most desired outcome; however, the potential to regenerate is limited in humans. In contrast, various non-mammalian vertebrates have fascinating capabilities of regenerating even an entire appendage following amputation. Among them, zebrafish is an important and accessible laboratory model organism, sharing striking similarities with mammalian embryonic musculoskeletal development. Moreover, clinically relevant muscle and skeletal injury zebrafish models recapitulate mammalian regeneration. Upon muscle injury, quiescent stem cells - known as satellite cells - become activated, proliferate, differentiate and fuse to form new myofibres, while bone fracture results in a phased response involving hematoma formation, inflammation, fibrocartilaginous callus formation, bony callus formation and remodelling. These models are well suited to testing gene- or pharmaco-therapy for the benefit of conditions like muscle tears and fractures. Insights from further studies on whole body part regeneration, a hallmark of the zebrafish model, have the potential to complement regenerative strategies to achieve faster and desired healing following injuries without any scar formation and, in the longer run, drive progress towards the realisation of large-scale regeneration in mammals. Here, we provide an overview of the basic mechanisms of musculoskeletal regeneration, highlight the key features of zebrafish as a regenerative model and outline the relevant studies that have contributed to the advancement of this field.
Topics: Animals; Cicatrix; Mammals; Stem Cells; Wound Healing; Zebrafish
PubMed: 34715269
DOI: 10.1016/j.biochi.2021.10.014 -
The International Journal of... 2018This brief review considers the question of why some animals can regenerate and others cannot and elaborates the opposing views that have been expressed in the past on... (Review)
Review
This brief review considers the question of why some animals can regenerate and others cannot and elaborates the opposing views that have been expressed in the past on this topic, namely that regeneration is adaptive and has been gained or that it is a fundamental property of all organisms and has been lost. There is little empirical evidence to support either view, but some of the best comes from recent phylogenetic analyses of regenerative ability in Planarians which reveals that this property has been lost and gained several times in this group. In addition, a non-regenerating species has been induced to regenerate by altering only one signaling pathway. Extrapolating this to mammals it may be the case that there is more regenerative ability in mammals than has typically been thought to exist and that inducing regeneration in humans may not be as impossible as it may seem. The regenerative abilities of mammals is described and it turns out that there are several examples of classical epimorphic regeneration involving a blastema as exemplified by the regenerating Urodele limb that can be seen in mammals. Even the heart can regenerate in mammals which has long been considered to be a property unique to Urodeles and fish and several recent examples of regeneration have come from recent studies of the spiny mouse, Acomys, which are discussed here. It is suggested that a much more thorough phylogenetic analysis of mammalian regeneration would likely reveal some important insights into the evolution of regeneration.
Topics: Animals; Biological Evolution; Extremities; Humans; Mammals; Organogenesis; Phylogeny; Planarians; Regeneration
PubMed: 29938749
DOI: 10.1387/ijdb.180031mm -
Antioxidants & Redox Signaling Dec 2023Retinal neurons are vulnerable to disease and injury, which can result in neuronal death and degeneration leading to irreversible vision loss. The human retina does not... (Review)
Review
Retinal neurons are vulnerable to disease and injury, which can result in neuronal death and degeneration leading to irreversible vision loss. The human retina does not regenerate to replace neurons lost to disease or injury. However, cells within the retina of other animals are capable of regenerating neurons, and homologous cells within the mammalian retina could potentially be prompted to do the same. Activating evolutionarily silenced intrinsic regenerative capacity of the mammalian retina could slow, or even reverse, vision loss, leading to an improved quality of life for millions of people. During development, neurons in the retina are generated progressively by retinal progenitor cells, with distinct neuron types born over developmental time. Many genes function in this process to specify the identity of newly generated neuron types, and these appropriate states of gene expression inform recent regenerative work. When regeneration is initiated in other vertebrates, including birds and fish, specific signaling pathways control the efficiency of regeneration, and these conserved pathways are likely to be important in mammals as well. Using insights from development and from other animals, limited regeneration from intrinsic cell types has been demonstrated in the mammalian retina, but it is able only to generate a subset of partially differentiated retinal neuron types. Future studies should aim at increasing the efficiency of regeneration, activating regeneration in a targeted fashion across the retina, and improving the ability to generate specific types of retinal neurons to replace those lost to disease or injury. . 39, 1039-1052.
Topics: Animals; Humans; Quality of Life; Retina; Neurons; Regeneration; Mammals
PubMed: 37276181
DOI: 10.1089/ars.2023.0309 -
Frontiers in Bioscience : a Journal and... Jul 2002Unlike other vital organs, the liver typically regenerates after injury. Indeed, the very factors that cause liver injury initiate a reparative process in the residual... (Review)
Review
Unlike other vital organs, the liver typically regenerates after injury. Indeed, the very factors that cause liver injury initiate a reparative process in the residual liver that includes the induction of cytoprotective mechanisms, deletion of mortally wounded cells, repair of less damaged survivors, liver cell proliferation to replace the cells that died, the deposition of new matrix, and tissue remodeling to restore normal hepatic mass and architecture. During liver regeneration, the liver normally continues to perform vital, liver-specific functions. Unfortunately, the hepatic regenerative response sometimes becomes disrupted--either failing to occur or occurring in a disordered, or incomplete fashion. Abnormal regeneration contributes to the pathogenesis of fulminate liver failure, cirrhosis, and primary liver cancers. Research in the field of regenerative biology has identified several events that are required for liver regeneration. These include injury-induced changes in the hepatic microenvironment, the ability of surviving liver cells and/or their progenitors to proliferate, and a temporary suspension of homeostatic mechanisms that normally couple cell proliferation to programmed cell death. The signals that mediate these complex biologic responses are being detailed. A better understanding of the extra- and intracellular signals that prompt the injured liver to regenerate should suggest treatments to promote liver regeneration in patients with otherwise fatal liver diseases.
Topics: Animals; Humans; Liver Regeneration
PubMed: 12086922
DOI: 10.2741/A925 -
Advances in Wound Care Sep 2022Skin scarring poses a major biomedical burden for hundreds of millions of patients annually. However, this burden could be mitigated by therapies that promote wound... (Review)
Review
Skin scarring poses a major biomedical burden for hundreds of millions of patients annually. However, this burden could be mitigated by therapies that promote wound regeneration, with full recovery of skin's normal adnexa, matrix ultrastructure, and mechanical strength. The observation of wound regeneration in several mouse models suggests a retained capacity for postnatal mammalian skin to regenerate under the right conditions. Mechanical forces are a major contributor to skin fibrosis and a prime target for devices and therapeutics that could promote skin regeneration. Wound-induced hair neogenesis, "spiny" mice, Murphy Roths Large mice, and mice treated with mechanotransduction inhibitors all show various degrees of wound regeneration. Comparison of regenerating wounds in these models against scarring wounds reveals differences in extracellular matrix interactions and in mechanosensitive activation of key signaling pathways, including Wnt, Sonic hedgehog, focal adhesion kinase, and Yes-associated protein. The advent of single-cell "omics" technologies has deepened this understanding and revealed that regeneration may recapitulate development in certain contexts, although it is unknown whether these mechanisms are relevant to healing in tight-skinned animals such as humans. While early findings in mice are promising, comparison across model systems is needed to resolve conflicting mechanisms and to identify conserved master regulators of skin regeneration. There also remains a dire need for studies on mechanomodulation of wounds in large, tight-skinned animals, such as red Duroc pigs, which better approximate human wound healing.
Topics: Animals; Cicatrix; Hedgehog Proteins; Humans; Mammals; Mechanotransduction, Cellular; Regeneration; Swine; Wound Healing
PubMed: 34465219
DOI: 10.1089/wound.2021.0040 -
Current Opinion in Ophthalmology Nov 2017Recent advances in experimental studies of optic nerve regeneration to better understand the pathophysiology of axon regrowth and provide insights into the future... (Review)
Review
PURPOSE OF REVIEW
Recent advances in experimental studies of optic nerve regeneration to better understand the pathophysiology of axon regrowth and provide insights into the future treatment of numerous optic neuropathies.
RECENT FINDINGS
The optic nerve is part of the central nervous system and cannot regenerate if injured. There are several steps that regenerating axons of retinal ganglion cells (RGCs) must take following optic nerve injury that include: maximizing the intrinsic growth capacity of RGCs, overcoming the extrinsic growth-inhibitory environment of the optic nerve, and optimizing the reinnervation of regenerated axons to their targets in the brain. Recently, some degree of experimental optic nerve regeneration has been achieved by factors associated with inducing intraocular inflammation, providing exogenous neurotrophic factors, reactivating intrinsic growth capacity of mature RGCs, or by modifying the extrinsic growth-inhibitory environment of the optic nerve. In some experiments, regenerating axons have been shown to reinnervate their central targets in the brain.
SUMMARY
Further approaches to the combination of aforementioned treatments will be necessary to develop future therapeutic strategy to promote ultimate regeneration of the optic nerve and functional vision recovery after optic nerve injury.
Topics: Animals; Axons; Disease Models, Animal; Humans; Nerve Regeneration; Optic Nerve; Optic Nerve Injuries; Retinal Ganglion Cells
PubMed: 28795960
DOI: 10.1097/ICU.0000000000000417 -
Experimental Neurology Oct 2017Intraorbital optic nerve crush in rodents is widely used as a model to study axon regeneration in the adult mammalian central nervous system. Recent studies using... (Review)
Review
Intraorbital optic nerve crush in rodents is widely used as a model to study axon regeneration in the adult mammalian central nervous system. Recent studies using appropriate genetic manipulations have revealed remarkable abilities of mature retinal ganglion cell (RGC) axons to regenerate after optic nerve injury, with some studies demonstrating that axons can then go on to re-innervate a number of central visual targets with partial functional restoration. However, one confounding factor inherent to optic nerve crush injury is the potential incompleteness of the initial lesion, leaving spared axons that later on could erroneously be interpreted as regenerating distal to the injury site. Careful examination of axonal projection pattern and morphology may facilitate separating spared from regenerating RGC axons. Here we discuss morphological criteria and strategies that may be used to differentiate spared versus regenerated axons in the injured mammalian optic nerve.
Topics: Animals; Humans; Nerve Regeneration; Optic Nerve Injuries; Retinal Ganglion Cells
PubMed: 28716559
DOI: 10.1016/j.expneurol.2017.07.008 -
Stem Cell Research & Therapy Feb 2022Structural regeneration of amputated appendages by blastema-mediated, epimorphic regeneration is a process whose mechanisms are beginning to be employed for inducing...
BACKGROUND
Structural regeneration of amputated appendages by blastema-mediated, epimorphic regeneration is a process whose mechanisms are beginning to be employed for inducing regeneration. While epimorphic regeneration is classically studied in non-amniote vertebrates such as salamanders, mammals also possess a limited ability for epimorphic regeneration, best exemplified by the regeneration of the distal mouse digit tip. A fundamental, but still unresolved question is whether epimorphic regeneration and blastema formation is exhaustible, similar to the finite limits of stem-cell mediated tissue regeneration.
METHODS
In this study, distal mouse digits were amputated, allowed to regenerate and then repeatedly amputated. To quantify the extent and patterning of the regenerated digit, the digit bone as the most prominent regenerating element in the mouse digit was followed by in vivo µCT.
RESULTS
Analyses revealed that digit regeneration is indeed progressively attenuated, beginning after the second regeneration cycle, but that the pattern is faithfully restored until the end of the fourth regeneration cycle. Surprisingly, when unamputated digits in the vicinity of repeatedly amputated digits were themselves amputated, these new amputations also exhibited a similarly attenuated regeneration response, suggesting a systemic component to the amputation injury response.
CONCLUSIONS
In sum, these data suggest that epimorphic regeneration in mammals is finite and due to the exhaustion of the proliferation and differentiation capacity of the blastema cell source.
Topics: Amputation, Surgical; Animals; Cell Differentiation; Extremities; Mammals; Mice; Wound Healing
PubMed: 35130972
DOI: 10.1186/s13287-022-02741-2 -
Development, Growth & Differentiation Feb 2007Urodele amphibians are highly regenerative animals. After partial removal of the brain in urodeles, ependymal cells around the wound surface proliferate, differentiate... (Review)
Review
Urodele amphibians are highly regenerative animals. After partial removal of the brain in urodeles, ependymal cells around the wound surface proliferate, differentiate into neurons and glias and finally regenerate the lost tissue. In contrast to urodeles, this type of brain regeneration is restricted only to the larval stages in anuran amphibians (frogs). In adult frogs, whereas ependymal cells proliferate in response to brain injury, they cannot migrate and close the wound surface, resulting in the failure of regeneration. Therefore frogs, in particular Xenopus, provide us with at least two modes to study brain regeneration. One is to study normal regeneration by using regenerative larvae. In this type of study, the requirement of reconnection between a regenerating brain and sensory neurons was demonstrated. Functional restoration of a regenerated telencephalon was also easily evaluated because Xenopus shows simple responses to the stimulus of a food odor. The other mode is to compare regenerative larvae and non-regenerative adults. By using this mode, it is suggested that there are regeneration-competent cells even in the non-regenerative adult brain, and that immobility of those cells might cause the failure of regeneration. Here we review studies that have led to these conclusions.
Topics: Animals; Brain; Regeneration; Xenopus laevis
PubMed: 17335433
DOI: 10.1111/j.1440-169X.2007.00914.x