Review
Abstract
The ability to repair tissues is essential for the survival of organisms. In chronic settings, the failure of the repair process to terminate results in overproduction of collagen, a pathology known as fibrosis, which compromises organ recovery and impairs function. The origin of the collagen-overproducing cell has been debated for years. Here we review recent insights gained from the use of lineage tracing approaches in several organs. The resulting evidence points toward specific subsets of tissue-resident mesenchymal cells, mainly localized in a perivascular position, as the major source for collagen-producing cells after injury. We discuss these findings in view of the functional heterogeneity of mesenchymal cells of the perivascular niche, which have essential vascular, immune, and regenerative functions that need to be preserved for efficient repair.
Authors
Selene E. Di Carlo, Lucie Peduto
Abstract
Epithelial cell loss alters a tissue’s optimal function and awakens evolutionarily adapted healing mechanisms to reestablish homeostasis. Although adult mammalian organs have a limited regeneration potential, the liver stands out as one remarkable exception. Following injury, the liver mounts a dynamic multicellular response wherein stromal cells are activated in situ and/or recruited from the bloodstream, the extracellular matrix (ECM) is remodeled, and epithelial cells expand to replenish their lost numbers. Chronic damage makes this response persistent instead of transient, tipping the system into an abnormal steady state known as fibrosis, in which ECM accumulates excessively and tissue function degenerates. Here we explore the cellular and molecular switches that balance hepatic regeneration and fibrosis, with a focus on uncovering avenues of disease modeling and therapeutic intervention.
Authors
Lucía Cordero-Espinoza, Meritxell Huch
Abstract
Fibroblasts synthesize the extracellular matrix of connective tissue and play an essential role in maintaining the structural integrity of most tissues. Researchers have long suspected that fibroblasts exhibit functional specialization according to their organ of origin, body site, and spatial location. In recent years, a number of approaches have revealed the existence of fibroblast subtypes in mice. Here, we discuss fibroblast heterogeneity with a focus on the mammalian dermis, which has proven an accessible and tractable system for the dissection of these relationships. We begin by considering differences in fibroblast identity according to anatomical site of origin. Subsequently, we discuss new results relating to the existence of multiple fibroblast subtypes within the mouse dermis. We consider the developmental origin of fibroblasts and how this influences heterogeneity and lineage restriction. We discuss the mechanisms by which fibroblast heterogeneity arises, including intrinsic specification by transcriptional regulatory networks and epigenetic factors in combination with extrinsic effects of the spatial context within tissue. Finally, we discuss how fibroblast heterogeneity may provide insights into pathological states including wound healing, fibrotic diseases, and aging. Our evolving understanding suggests that ex vivo expansion or in vivo inhibition of specific fibroblast subtypes may have important therapeutic applications.
Authors
Magnus D. Lynch, Fiona M. Watt
Abstract
Fibrosis is the excessive accumulation of extracellular matrix that often occurs as a wound healing response to repeated or chronic tissue injury, and may lead to the disruption of organ architecture and loss of function. Although fibrosis was previously thought to be irreversible, recent evidence indicates that certain circumstances permit the resolution of fibrosis when the underlying causes of injury are eradicated. The mechanism of fibrosis resolution encompasses degradation of the fibrotic extracellular matrix as well as elimination of fibrogenic myofibroblasts through their adaptation of various cell fates, including apoptosis, senescence, dedifferentiation, and reprogramming. In this Review, we discuss the present knowledge and gaps in our understanding of how matrix degradation is regulated and how myofibroblast cell fates can be manipulated, areas that may identify potential therapeutic approaches for fibrosis.
Authors
Joon-Il Jun, Lester F. Lau
Abstract
There is an increasing recognition that inflammation plays a critical role in neurodegenerative diseases of the CNS, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and the prototypic neuroinflammatory disease multiple sclerosis (MS). Differential immune responses involving the adaptive versus the innate immune system are observed at various stages of neurodegenerative diseases, and may not only drive disease processes but could serve as therapeutic targets. Ongoing investigations into the specific inflammatory mechanisms that play roles in disease causation and progression have revealed lessons about inflammation-driven neurodegeneration that can be applied to other neurodegenerative diseases. An increasing number of immunotherapeutic strategies that have been successful in MS are now being applied to other neurodegenerative diseases. Some approaches suppress CNS immune mechanisms, while others harness the immune system to clear deleterious products and cells. This Review focuses on the mechanisms by which inflammation, mediated either by the peripheral immune response or by endogenous CNS immune mechanisms, can affect CNS neurodegeneration.
Authors
Tanuja Chitnis, Howard L. Weiner
Abstract
Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an “activated state”). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer’s disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed.
Authors
Heela Sarlus, Michael T. Heneka
Abstract
Oligodendrocytes are glial cells that populate the entire CNS after they have differentiated from oligodendrocyte progenitor cells. From birth onward, oligodendrocytes initiate wrapping of neuronal axons with a multilamellar lipid structure called myelin. Apart from their well-established function in action potential propagation, more recent data indicate that oligodendrocytes are essential for providing metabolic support to neurons. Oligodendrocytes transfer energy metabolites to neurons through cytoplasmic “myelinic” channels and monocarboxylate transporters, which allow for the fast delivery of short-carbon-chain energy metabolites like pyruvate and lactate to neurons. These substrates are metabolized and contribute to ATP synthesis in neurons. This Review will discuss our current understanding of this metabolic supportive function of oligodendrocytes and its potential impact in human neurodegenerative disease and related animal models.
Authors
Thomas Philips, Jeffrey D. Rothstein
Abstract
Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.
Authors
Antoine Louveau, Benjamin A. Plog, Salli Antila, Kari Alitalo, Maiken Nedergaard, Jonathan Kipnis
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease that causes severe loss of pancreatic β cells. Autoreactive T cells are key mediators of β cell destruction. Studies of organ donors with T1D that have examined T cells in pancreas, the diabetogenic insulitis lesion, and lymphoid tissues have revealed a broad repertoire of target antigens and T cell receptor (TCR) usage, with initial evidence of public TCR sequences that are shared by individuals with T1D. Neoepitopes derived from post-translational modifications of native antigens are emerging as novel targets that are more likely to evade self-tolerance. Further studies will determine whether T cell responses to neoepitopes are major disease drivers that could impact prediction, prevention, and therapy. This Review provides an overview of recent progress in our knowledge of autoreactive T cells that has emerged from experimental and clinical research as well as pathology investigations.
Authors
Alberto Pugliese
Abstract
Microglia are the main resident macrophage population of the CNS and perform numerous functions required for CNS development, homeostasis, immunity, and repair. Many lines of evidence also indicate that dysregulation of microglia contributes to the pathogenesis of neurodegenerative and behavioral diseases. These observations provide a compelling argument to more clearly define the mechanisms that control microglia identity and function in health and disease. In this Review, we present a conceptual framework for how different classes of transcription factors interact to select and activate regulatory elements that control microglia development and their responses to internal and external signals. We then describe functions of specific transcription factors in normal and pathological contexts and conclude with a consideration of open questions to be addressed in the future.
Authors
Inge R. Holtman, Dylan Skola, Christopher K. Glass
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