Review
Abstract
Skeletal muscle damaged by injury or by degenerative diseases such as muscular dystrophy is able to regenerate new muscle fibers. Regeneration mainly depends upon satellite cells, myogenic progenitors localized between the basal lamina and the muscle fiber membrane. However, other cell types outside the basal lamina, such as pericytes, also have myogenic potency. Here, we discuss the main properties of satellite cells and other myogenic progenitors as well as recent efforts to obtain myogenic cells from pluripotent stem cells for patient-tailored cell therapy. Clinical trials utilizing these cells to treat muscular dystrophies, heart failure, and stress urinary incontinence are also briefly outlined.
Authors
Francesco Saverio Tedesco, Arianna Dellavalle, Jordi Diaz-Manera, Graziella Messina, Giulio Cossu
Abstract
Stem cell–based approaches have received much hype as potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are also potential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the pathological environment.
Authors
Olle Lindvall, Zaal Kokaia
Abstract
Enabling stem cell–targeted therapies requires an understanding of how to create local microenvironments (niches) that stimulate endogenous stem cells or serve as a platform to receive and guide the integration of transplanted stem cells and their derivatives. In vivo, the stem cell niche is a complex and dynamic unit. Although components of the in vivo niche continue to be described for many stem cell systems, how these components interact to modulate stem cell fate is only beginning to be understood. Using the HSC niche as a model, we discuss here microscale engineering strategies capable of systematically examining and reconstructing individual niche components. Synthetic stem cell–niche engineering may form a new foundation for regenerative therapies.
Authors
Raheem Peerani, Peter W. Zandstra
Abstract
Inflammation is the coordinated immune response to harmful stimuli that appear during infections or after tissue damage. Cells of the innate immune system are the central players in mediating inflammatory tissue responses. These cells are equipped with an array of signaling receptors that detect foreign molecular substances or altered endogenous molecules that appear under situations of stress. This review provides an overview of recent progress in elucidating the molecular mechanisms that lead to inflammatory reactions. We discuss the current knowledge of the mechanisms leading to the activation of cytoplasmic, multimolecular protein complexes, termed “inflammasomes,” which regulate the activity of caspase-1 and the maturation and release of IL-1β.
Authors
Andrea Stutz, Douglas T. Golenbock, Eicke Latz
Abstract
Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly — a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.
Authors
Shlomo Melmed
Abstract
Sepsis is characterized by a severe inflammatory response to infection, and its complications, including acute kidney injury, can be fatal. Animal models that correctly mimic human disease are extremely valuable because they hasten the development of clinically useful therapeutics. Too often, however, animal models do not properly mimic human disease. In this Review, we outline a bedside-to-bench-to-bedside approach that has resulted in improved animal models for the study of sepsis — a complex disease for which preventive and therapeutic strategies are unfortunately lacking. We also highlight a few of the promising avenues for therapeutic advances and biomarkers for sepsis and sepsis-induced acute kidney injury. Finally, we review how the study of drug targets and biomarkers are affected by and in turn have influenced these evolving animal models.
Authors
Kent Doi, Asada Leelahavanichkul, Peter S.T. Yuen, Robert A. Star
Abstract
DCs are specialized APCs that orchestrate innate and adaptive immune responses. The intestinal mucosa contains numerous DCs, which induce either protective immunity to infectious agents or tolerance to innocuous antigens, including food and commensal bacteria. Several subsets of mucosal DCs have been described that display unique functions, dictated in part by the local microenvironment. In this review, we summarize the distinct subtypes of DCs and their distribution in the gut; examine how DC dysfunction contributes to intestinal disease development, including inflammatory bowel disease and celiac disease; and discuss manipulation of DCs for therapy.
Authors
Maria Rescigno, Antonio Di Sabatino
Abstract
The observation that only a fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. As we discuss here, human predisposition to infectious diseases seems to cover a continuous spectrum from monogenic to polygenic inheritance. Although many studies have provided proof of principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. However, in the future, studies in human genetics are likely to establish a new paradigm for infectious diseases.
Authors
Alexandre Alcaïs, Laurent Abel, Jean-Laurent Casanova
Abstract
Malaria continues to exert a tremendous health burden on human populations, reflecting astonishingly successful adaptations of the causative Plasmodium parasites. We discuss here how this burden has driven the natural selection of numerous polymorphisms in the genes encoding hemoglobin and other erythrocyte proteins and some effectors of immunity. Plasmodium falciparum, the most deadly parasite species in humans, displays a vigorous system of antigen variation to counter host defenses and families of functionally redundant ligands to invade human cells. Advances in genetics and genomics are providing fresh insights into the nature of these evolutionary adaptations, processes of parasite transmission and infection, and the difficult challenges of malaria control.
Authors
Thomas E. Wellems, Karen Hayton, Rick M. Fairhurst
Abstract
Humans have been colonized by Helicobacter pylori for at least 50,000 years and probably throughout their evolution. H. pylori has adapted to humans, colonizing children and persisting throughout life. Most strains possess factors that subtly modulate the host environment, increasing the risk of peptic ulceration, gastric adenocarcinoma, and possibly other diseases. H. pylori genes encoding these and other factors rapidly evolve through mutation and recombination, changing the bacteria-host interaction. Although immune and physiologic responses to H. pylori also contribute to pathogenesis, humans have evolved in concert with the bacterium, and its recent absence throughout the life of many individuals has led to new human physiological changes. These may have contributed to recent increases in esophageal adenocarcinoma and, more speculatively, other modern diseases.
Authors
John C. Atherton, Martin J. Blaser
No posts were found with this tag.
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)