Wnt signaling activation: targets and therapeutic opportunities for stem cell therapy and regenerative medicine
05 Aug 2021-Vol. 2, Iss: 4, pp 1144-1157
TL;DR: Wnt proteins are secreted morphogens that play critical roles in embryonic development, stem cell proliferation, self-renewal, tissue regeneration and remodeling in adults, and their use to promote ex vivo expansion during tissue engineering is a promising application.
Abstract: Wnt proteins are secreted morphogens that play critical roles in embryonic development, stem cell proliferation, self-renewal, tissue regeneration and remodeling in adults. While aberrant Wnt signaling contributes to diseases such as cancer, activation of Wnt/β-catenin signaling is a target of interest in stem cell therapy and regenerative medicine. Recent high throughput screenings from chemical and biological libraries, combined with improved gene expression reporter assays of Wnt/β-catenin activation together with rational drug design, led to the development of a myriad of Wnt activators, with different mechanisms of actions. Among them, Wnt mimics, antibodies targeting Wnt inhibitors, glycogen-synthase-3β inhibitors, and indirubins and other natural product derivatives are emerging modalities to treat bone, neurodegenerative, eye, and metabolic disorders, as well as prevent ageing. Nevertheless, the creation of Wnt-based therapies has been hampered by challenges in developing potent and selective Wnt activators without off-target effects, such as oncogenesis. On the other hand, to avoid these risks, their use to promote ex vivo expansion during tissue engineering is a promising application.
Citations
More filters
01 Jan 2006
TL;DR: Advances in graft preparation, combining better preservation of stem cells with ease of application of the graft, are described, and improvements have been applied to cultures of ocular limbal cells, which contain the keratinocyte stem cells of the corneal epithelium.
Abstract: The only cultured cell types extensively used for tissue regeneration are the keratinocyte and the chondrocyte. Cultured autologous keratinocytes derived from the epidermis have been used for many years to produce grafts that regenerate an epidermis over a full-thickness wound, such as a third-degree burn. But there have been many failures of engraftment, and in the absence of criteria for the quality of the cultures, the causes of failure cannot be analyzed. It has become clear that the essential feature of the graft is the presence of an adequate number of stem cells. This article describes the criteria for estimating that number. Advances in graft preparation, combining better preservation of stem cells with ease of application of the graft, are also described. These improvements have been applied to cultures of ocular limbal cells, which contain the keratinocyte stem cells of the corneal epithelium. Cultures meeting the criteria of stem cell number have been grafted to 116 patients suffering from chemical destruction of the limbus. The procedure has been highly successful in the alleviation of suffering and the restoration of vision.
132 citations
DOI•
29 Oct 2021
TL;DR: In this paper, the relationship between plasma membrane components and extracellular or membrane-associated modulators to activate Wnt signaling pathways in several brain and metabolic diseases is discussed, and the Wnt-receptor complex can be targeted based on the composition and organization of the plasma membrane.
Abstract: Wnt signaling pathways constitute a group of signal transduction pathways that direct many physiological processes, such as development, growth, and differentiation. Dysregulation of these pathways is thus associated with many pathological processes, including neurodegenerative diseases, metabolic disorders, and cancer. At the same time, alterations are observed in plasma membrane compositions, lipid organizations, and ordered membrane domains in brain and metabolic diseases that are associated with Wnt signaling pathway activation. Here, we discuss the relationships between plasma membrane components-specifically ligands, (co) receptors, and extracellular or membrane-associated modulators-to activate Wnt pathways in several brain and metabolic diseases. Thus, the Wnt-receptor complex can be targeted based on the composition and organization of the plasma membrane, in order to develop effective targeted therapy drugs.
9 citations
TL;DR:
Abstract: The subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) is a neurogenic niche of the adult brain that contains neural stem cells (NSCs) able to generate excitatory glutamatergic granule neurons, which integrate into the DG circuit and contribute to hippocampal plasticity, learning, and memory. Thus, endogenous NSCs could be harnessed for therapeutic purposes. In this context, it is critical to characterize the molecular mechanisms controlling the generation and functional integration of adult-born neurons. Adult hippocampal neurogenesis is tightly controlled by both cell-autonomous mechanisms and the interaction with the complex niche microenvironment, which harbors the NSCs and provides the signals to support their maintenance, activation, and differentiation. Among niche-derived factors, Wnt ligands play diverse roles. Wnts are secreted glycoproteins that bind to Frizzled receptors and co-receptors to trigger the Wnt signaling pathway. Here, we summarize the current knowledge about the roles of Wnts in the regulation of adult hippocampal neurogenesis. We discuss the possible contribution of the different niche cells to the regulation of local Wnt signaling activity, and how Wnts derived from different cell types could induce differential effects. Finally, we discuss how the effects of Wnt signaling on hippocampal network activity might contribute to neurogenesis regulation. Although the evidence supports relevant roles for Wnt signaling in adult hippocampal neurogenesis, defining the cellular source and the mechanisms controlling secretion and diffusion of Wnts will be crucial to further understand Wnt signaling regulation of adult NSCs, and eventually, to propose this pathway as a therapeutic target to promote neurogenesis.
7 citations
TL;DR: Clear insights are given into the implications of telocytes in the WNT signaling pathway, but also TGFB and PI3K/AKT pathways that, inter alia, conduct cardiomyocytes differentiation, maturation and final integration into heart adult architecture, which strengthens evidence for telocytes as promising candidates for cellular therapies in various heart pathologies.
Abstract: Cardiac interstitium is a complex and dynamic environment, vital for normal cardiac structure and function. Telocytes are active cellular players in regulating main events that feature myocardial homeostasis and orchestrating its involvement in heart pathology. Despite the great amount of data suggesting (microscopically, proteomically, genetically, etc.) the implications of telocytes in the different physiological and reparatory/regenerative processes of the heart, understanding their involvement in realizing the heart’s mature cytoarchitecture is still at its dawn. Our scrutiny of the recent literature gave clearer insights into the implications of telocytes in the WNT signaling pathway, but also TGFB and PI3K/AKT pathways that, inter alia, conduct cardiomyocytes differentiation, maturation and final integration into heart adult architecture. These data also strengthen evidence for telocytes as promising candidates for cellular therapies in various heart pathologies.
4 citations
TL;DR: Wang et al. as mentioned in this paper showed that Wnt/β-catenin signaling plays a critical role in melanocyte regeneration by driving the differentiation of melanocyte stem cells (McSCs) into melanocytes.
Abstract: Vitiligo is a common chronic skin disease which has an adverse impact on the patients' life. Its pathogenesis is complex, involving autoimmunity and oxidative stress (OS). Autoimmunity leads to the loss of epidermal melanocytes and the formation of the depigmented patches of the disease. Treatment of vitiligo should control the exaggerated immune response to arrest the progress of active disease, and then promote the melanocytes to re-pigmentation. Wnt/β-catenin signaling pathway has been of recent interest in vitiligo. Wnt/β-catenin signaling pathway is downregulated in vitiligo. Upregulation of Wnt/β-catenin signaling possibly control vitiligo autoimmune response by protecting melanocyte from OS damage, inhibiting CD8+ T cell effector cell differentiation and enhancing Treg. Wnt/β-catenin signaling plays a critical role in the melanocyte regeneration by driving the differentiation of melanocyte stem cells (McSCs) into melanocytes. Promoting Wnt/β-catenin signaling can not only arrest the progress of active disease of vitiligo, but also promote the re-pigmentation. Some of the main effective therapies for vitiligo are likely to work by activating Wnt/β-catenin signaling. Agents that can enhance the effect of Wnt/β-catenin signaling may become potential candidates for the development of new drugs for vitiligo treatment.
2 citations
References
More filters
TL;DR: It is concluded that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
Abstract: The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
5,193 citations
TL;DR: The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels, and that receptor-ligand specificity and feedback loops help to determine WNT signaling outputs.
Abstract: Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.
5,129 citations
TL;DR: An update of the core Wnt/β-catenin signaling pathway is provided, how its various components contribute to disease, and outstanding questions to be addressed in the future are discussed.
4,561 citations
TL;DR: Human diploid epidermis epidermal cells have been successfully grown in serial culture and it is possible to isolate keratinocyte clones free of viable fibroblasts, and human diploids keratinocytes appear to have a finite culture lifetime.
4,114 citations
TL;DR: The core Wnt/β-catenin signaling pathway is described, how it controls stem cells, and contributes to disease, and strategies for Wnt-based therapies are discussed.
2,663 citations