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Neuroscience Bulletin Feb 2023Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors - the glial scar is triggered by...
Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors - the glial scar is triggered by injury and inhibits or promotes regeneration. Recent technological advances in spatial transcriptomics (ST) provide a unique opportunity to decipher most genes systematically throughout scar formation, which remains poorly understood. Here, we first constructed the tissue-wide gene expression patterns of mouse spinal cords over the course of scar formation using ST after spinal cord injury from 32 samples. Locally, we profiled gene expression gradients from the leading edge to the core of the scar areas to further understand the scar microenvironment, such as neurotransmitter disorders, activation of the pro-inflammatory response, neurotoxic saturated lipids, angiogenesis, obstructed axon extension, and extracellular structure re-organization. In addition, we described 21 cell transcriptional states during scar formation and delineated the origins, functional diversity, and possible trajectories of subpopulations of fibroblasts, glia, and immune cells. Specifically, we found some regulators in special cell types, such as Thbs1 and Col1a2 in macrophages, CD36 and Postn in fibroblasts, Plxnb2 and Nxpe3 in microglia, Clu in astrocytes, and CD74 in oligodendrocytes. Furthermore, salvianolic acid B, a blood-brain barrier permeation and CD36 inhibitor, was administered after surgery and found to remedy fibrosis. Subsequently, we described the extent of the scar boundary and profiled the bidirectional ligand-receptor interactions at the neighboring cluster boundary, contributing to maintain scar architecture during gliosis and fibrosis, and found that GPR37L1_PSAP, and GPR37_PSAP were the most significant gene-pairs among microglia, fibroblasts, and astrocytes. Last, we quantified the fraction of scar-resident cells and proposed four possible phases of scar formation: macrophage infiltration, proliferation and differentiation of scar-resident cells, scar emergence, and scar stationary. Together, these profiles delineated the spatial heterogeneity of the scar, confirmed the previous concepts about scar architecture, provided some new clues for scar formation, and served as a valuable resource for the treatment of central nervous system injury.
Topics: Mice; Animals; Gliosis; Cicatrix; Spinal Cord Injuries; Astrocytes; Spinal Cord; Fibrosis; Mammals; Receptors, G-Protein-Coupled
PubMed: 35788904
DOI: 10.1007/s12264-022-00897-8 -
Nature Neuroscience Jan 2018Injury or disease to the CNS results in multifaceted cellular and molecular responses. One such response, the glial scar, is a structural formation of reactive glia... (Review)
Review
Injury or disease to the CNS results in multifaceted cellular and molecular responses. One such response, the glial scar, is a structural formation of reactive glia around an area of severe tissue damage. While traditionally viewed as a barrier to axon regeneration, beneficial functions of the glial scar have also been recently identified. In this Perspective, we discuss the divergent roles of the glial scar during CNS regeneration and explore the possibility that these disparities are due to functional heterogeneity within the cells of the glial scar-specifically, astrocytes, NG2 glia and microglia.
Topics: Animals; Central Nervous System Diseases; Cicatrix; Humans; Neuroglia; Regeneration
PubMed: 29269757
DOI: 10.1038/s41593-017-0033-9 -
JACC. Clinical Electrophysiology Aug 2022
Topics: Arrhythmias, Cardiac; Cicatrix; Humans; Myocardium
PubMed: 35981801
DOI: 10.1016/j.jacep.2022.06.018 -
European Heart Journal Mar 2019The pathological processes leading to heart failure are characterized by the formation of fibrosis and scar, yet the dynamics of scar production and removal are... (Review)
Review
The pathological processes leading to heart failure are characterized by the formation of fibrosis and scar, yet the dynamics of scar production and removal are incompletely understood. Spontaneous disappearance of myocardial collagen is reported in infancy but doubted in adulthood where scar volume constitutes a better prognostic indicator than the conventional parameters of ventricular function. Whilst certain drugs are known to attenuate myocardial fibrosis evidence is emerging that stem cell therapy also has the potential to reduce scar size and improve myocardial viability. Both animal studies and clinical trials support the concept that, as in infancy, cellular processes can be triggered to remove collagen and regenerate injured myocardium. The molecular mechanisms likely involve anti-fibrotic cytokines growth factors and matrix-metalloproteinases. Autologous cardiac, bone-marrow and adipose tissue derived stem cells have each shown efficacy. Specific immune privileged mesenchymal stem cells and genetically modified immunomodulatory progenitor cells may in turn provide an allogenic source for the paracrine effects. Thus autologous and allogenic cells both have the potential through paracrine action to reduce scar volume, boost angiogenesis and improve ventricular morphology. The potential benefit of myocardial cell therapy for routine treatment of heart failure is an area that requires further study.
Topics: Adipose Tissue; Adult; Angiogenesis Inducing Agents; Animals; Cell- and Tissue-Based Therapy; Cicatrix; Clinical Trials as Topic; Collagen; Fibrosis; Heart Failure; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myocardium; Regenerative Medicine; Stem Cells; Ventricular Function
PubMed: 30203057
DOI: 10.1093/eurheartj/ehy503 -
European Journal of Medical Research Nov 2023Wound healing is a tandem process involving inflammation, proliferation, and remodeling, through which damage is repaired and ultimately scar tissue is formed. This... (Review)
Review
Wound healing is a tandem process involving inflammation, proliferation, and remodeling, through which damage is repaired and ultimately scar tissue is formed. This process mainly relies on the complex and extensive interaction of growth factors and cytokines, which coordinate the synthesis of various cell types. The loss of normal regulation in any part of this process can lead to excessive scarring or unhealed wounds. Recent studies have shown that it is possible to improve wound healing and even achieve scar-free wound healing through proper regulation of cytokines and molecules in this process. In recent years, many studies have focused on accelerating wound healing and reducing scar size by regulating the molecular mechanisms related to wound healing and scar formation. We summarized the role of these factors in wound healing and scar formation, to provide a new idea for clinical scar-free healing treatment of uterine incisions.
Topics: Humans; Cicatrix; Wound Healing; Cytokines
PubMed: 37941058
DOI: 10.1186/s40001-023-01485-w -
Molecules (Basel, Switzerland) Oct 2021Scars, as the result of abnormal wound-healing response after skin injury, may lead to loss of aesthetics and physical dysfunction. Current clinical strategies, such as... (Review)
Review
Scars, as the result of abnormal wound-healing response after skin injury, may lead to loss of aesthetics and physical dysfunction. Current clinical strategies, such as surgical excision, laser treatment, and drug application, provide late remedies for scarring, yet it is difficult to eliminate scars. In this review, the functions, roles of multiple polymer scaffolds in wound healing and scar inhibition are explored. Polysaccharide and protein scaffolds, an analog of extracellular matrix, act as templates for cell adhesion and migration, differentiation to facilitate wound reconstruction and limit scarring. Stem cell-seeded scaffolds and growth factors-loaded scaffolds offer significant bioactive substances to improve the wound healing process. Special emphasis is placed on scaffolds that continuously release oxygen, which greatly accelerates the vascularization process and ensures graft survival, providing convincing theoretical support and great promise for scarless healing.
Topics: Animals; Cell Proliferation; Cicatrix; Humans; Oxygen; Polymers; Skin; Tissue Scaffolds; Wound Healing
PubMed: 34684690
DOI: 10.3390/molecules26206110 -
Anatomical Record (Hoboken, N.J. : 2007) Oct 2012Many lizards are able to undergo scar-free wound healing and regeneration following loss of the tail. In most instances, lizard tail loss is facilitated by autotomy, an...
Many lizards are able to undergo scar-free wound healing and regeneration following loss of the tail. In most instances, lizard tail loss is facilitated by autotomy, an evolved mechanism that permits the tail to be self-detached at pre-existing fracture planes. However, it has also been reported that the tail can regenerate following surgical amputation outside the fracture plane. In this study, we used the leopard gecko, Eublepharis macularius, to investigate and compare wound healing and regeneration following autotomy at a fracture plane and amputation outside the fracture plane. Both forms of tail loss undergo a nearly identical sequence of events leading to scar-free wound healing and regeneration. Early wound healing is characterized by transient myofibroblasts and the formation of a highly proliferative wound epithelium immunoreactive for the wound keratin marker WE6. The new tail forms from what is commonly referred to as a blastema, a mass of proliferating mesenchymal-like cells. Blastema cells express the protease matrix metalloproteinase-9. Apoptosis (demonstrated by activated caspase 3 immunostaining) is largely restricted to isolated cells of the original and regenerating tail tissues, although cell death also occurs within dermal structures at the original-regenerated tissue interface and among clusters of newly formed myocytes. Furthermore, the autotomized tail is unique in demonstrating apoptosis among cells adjacent to the fracture planes. Unlike mammals, transforming growth factor-β3 is not involved in wound healing. We demonstrate that scar-free wound healing and regeneration are intrinsic properties of the tail, unrelated to the location or mode of tail detachment.
Topics: Amputation, Surgical; Animals; Cicatrix; Lizards; Random Allocation; Regeneration; Tail; Wound Healing
PubMed: 22933425
DOI: 10.1002/ar.22490 -
Current Opinion in Neurobiology Aug 2018Recent years have seen cytoskeleton dynamics emerging as a key player in axon regeneration. The cytoskeleton, in particular microtubules and actin, ensures the growth of... (Review)
Review
Recent years have seen cytoskeleton dynamics emerging as a key player in axon regeneration. The cytoskeleton, in particular microtubules and actin, ensures the growth of neuronal processes and maintains the singular, highly polarized shape of neurons. Following injury, adult central axons are tipped by a dystrophic structure, the retraction bulb, which prevents their regeneration. Abnormal cytoskeleton dynamics are responsible for the formation of this growth-incompetent structure but pharmacologically modulating cytoskeleton dynamics of injured axons can transform this structure into a growth-competent growth cone. The cytoskeleton also drives the migration of scar-forming cells after an injury. Targeting its dynamics modifies the composition of the inhibitory environment formed by scar tissue and renders it more permissive for regenerating axons. Hence, cytoskeleton dynamics represent an appealing target to promote axon regeneration. As some of cytoskeleton-targeting drugs are used in the clinics for other purposes, they hold the promise to be used as a basis for a regenerative therapy after a spinal cord injury.
Topics: Animals; Axons; Cell Movement; Cicatrix; Cytoskeleton; Growth Cones; Humans; Nerve Regeneration
PubMed: 29544200
DOI: 10.1016/j.conb.2018.02.024 -
Comprehensive Physiology Sep 2015Once myocardium dies during a heart attack, it is replaced by scar tissue over the course of several weeks. The size, location, composition, structure, and mechanical... (Review)
Review
Once myocardium dies during a heart attack, it is replaced by scar tissue over the course of several weeks. The size, location, composition, structure, and mechanical properties of the healing scar are all critical determinants of the fate of patients who survive the initial infarction. While the central importance of scar structure in determining pump function and remodeling has long been recognized, it has proven remarkably difficult to design therapies that improve heart function or limit remodeling by modifying scar structure. Many exciting new therapies are under development, but predicting their long-term effects requires a detailed understanding of how infarct scar forms, how its properties impact left ventricular function and remodeling, and how changes in scar structure and properties feed back to affect not only heart mechanics but also electrical conduction, reflex hemodynamic compensations, and the ongoing process of scar formation itself. In this article, we outline the scar formation process following a myocardial infarction, discuss interpretation of standard measures of heart function in the setting of a healing infarct, then present implications of infarct scar geometry and structure for both mechanical and electrical function of the heart and summarize experiences to date with therapeutic interventions that aim to modify scar geometry and structure. One important conclusion that emerges from the studies reviewed here is that computational modeling is an essential tool for integrating the wealth of information required to understand this complex system and predict the impact of novel therapies on scar healing, heart function, and remodeling following myocardial infarction.
Topics: Action Potentials; Animals; Cicatrix; Collagen; Humans; Myocardial Infarction; Myocytes, Cardiac; Ventricular Function
PubMed: 26426470
DOI: 10.1002/cphy.c140067 -
Scientific Reports Jan 2020The spiny mouse, Acomys cahirinus displays a unique wound healing ability with regeneration of all skin components in a scar-free manner. To identify orchestrators of... (Comparative Study)
Comparative Study
The spiny mouse, Acomys cahirinus displays a unique wound healing ability with regeneration of all skin components in a scar-free manner. To identify orchestrators of this regenerative response we have performed proteomic analyses of skin from Acomys and Mus musculus before and after wounding. Of the ~2000 proteins identified many are expressed at similar levels in Acomys and Mus, but there are significant differences. Following wounding in Mus the complement and coagulation cascades, PPAR signaling pathway and ECM-receptor interactions predominate. In Acomys, other pathways predominate including the Wnt, MAPK, the ribosome, proteasome, endocytosis and tight junction pathways. Notable among Acomys specific proteins are several ubiquitin-associated enzymes and kinases, whereas in Mus immuno-modulation proteins characteristic of inflammatory response are unique or more prominent. ECM proteins such as collagens are more highly expressed in Mus, but likely more important is the higher expression of matrix remodeling proteases in Acomys. Another distinctive difference between Acomys and Mus lies in the macrophage-produced arginase 1 is found in Mus whereas arginase 2 is found in Acomys. Thus, we have identified several avenues for experimental approaches whose aim is to reduce the fibrotic response that the typical mammal displays in response to wounding.
Topics: Animals; Cicatrix; Mice; Murinae; Proteome; Regeneration; Skin; Wound Healing
PubMed: 31932597
DOI: 10.1038/s41598-019-56823-y