Special Issue "Wnt Signaling in Stem Cells"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics".

Deadline for manuscript submissions: closed (30 November 2017)

Special Issue Editors

Guest Editor
Prof. Dr. Ethan Lee

Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37240, USA
Website | E-Mail
Interests: Wnt signaling; Xenopus laevis; biochemistry; ubiquitination; chemical biology; systems biology
Guest Editor
Prof. Dr. Yashi Ahmed

Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA
Website | E-Mail
Interests: Wingless; Drosophila genetics; APC, ADP-ribosylation; intestinal stem cells Introduction
Guest Editor
Prof. Dr. Robert J. Coffey

Department of Cell and Developmental Biology and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Website | E-Mail
Interests: EGFR; Epithelial Polarity; Vesicle Trafficking; Wnt signaling; Naked2; GI Cancer

Special Issue Information

Dear Colleagues,

We write to invite you to contribute to a Special Issue in Genes that will be focused on Wnt signalling in stem cells. Originally identified as an evolutionarily conserved key determinant of embryonic patterning and an oncogenic pathway, Wnt signaling has been shown to play a major role in the maintenance, renewal, and differentiation of a number of stem cell lineages in the adult multicellular organism (including gastrointestinal, hematopoietic, neural, mammary, epidermal, follicular, testicular, and ovarian lineages). Thus, modulating this pathway has enormous potential in regenerative medicine and in the treatment of major human cancers. Major questions that are currently being investigated include the role of Wnt signaling in regulating stem cell self-renewal, proliferation, and differentiation as well as the characterization of cells in the niche that produce and receive the Wnt signal. In addition, the detailed mechanisms by which the Wnt pathway is controlled and maintained in the stem cell niche remain ill defined.

This Special Issue will highlight reviews, new methods, and original articles that advance our understanding of the Wnt pathway and its role in stem cell biology. We welcome contributions in the areas of Wnt/b-catenin as well as noncanonical Wnt signaling, as both have been implicated in stem cell regulation. Topics of interest include, but are not limited to, the role of Wnt signaling in maintenance, proliferation, and differentiation of stem cells of various organ lineages; the role of Wnt signaling in embryonic stem cells and cancer stem cells; and the role of Wnt signaling in controlling and regulating stem cell niches. We also welcome studies that highlight new technologies, new modes of regulation, and/or novel components of the Wnt signaling pathway that reveal underlying biochemical mechanisms that may ultimately control stem cell behavior. Finally, we welcome studies that make use of traditional as well as non-traditional model organisms that may provide insight into the evolutionarily conserved role of Wnt signaling in stem cell function across phyla. We look forward to your contributions.

Prof. Dr. Ethan Lee
Prof. Dr. Yashi Ahmed
Prof. Dr. Robert J. Coffey
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Wnt signaling
  • stem cells
  • development
  • regenerative medicine
  • cancer
  • model organisms

Published Papers (7 papers)

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Research

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Open AccessArticle WNT9A Is a Conserved Regulator of Hematopoietic Stem and Progenitor Cell Development
Genes 2018, 9(2), 66; doi:10.3390/genes9020066
Received: 30 November 2017 / Revised: 10 January 2018 / Accepted: 23 January 2018 / Published: 29 January 2018
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Abstract
Hematopoietic stem cells (HSCs) differentiate into all cell types of the blood and can be used therapeutically to treat hematopoietic cancers and disorders. Despite decades of research, it is not yet possible to derive therapy-grade HSCs from pluripotent precursors. Analysis of HSC development
[...] Read more.
Hematopoietic stem cells (HSCs) differentiate into all cell types of the blood and can be used therapeutically to treat hematopoietic cancers and disorders. Despite decades of research, it is not yet possible to derive therapy-grade HSCs from pluripotent precursors. Analysis of HSC development in model organisms has identified some of the molecular cues that are necessary to instruct hematopoiesis in vivo, including Wnt9A, which is required during an early time window in zebrafish development. Although bona fide HSCs cannot be derived in vitro, it is possible to model human hematopoietic progenitor development by differentiating human pluripotent stem cells to hematopoietic cells. Herein, we modulate WNT9A expression during the in vitro differentiation of human embryonic stem cells to hematopoietic progenitor cells and demonstrate that WNT9A also regulates human hematopoietic progenitor cell development in vitro. Overexpression of WNT9A only impacts differentiation to CD34+/CD45+ cells during early time windows and does so in a dose-dependent manner. The cells that receive the Wnt signal—not the cells that secrete WNT9A—differentiate most efficiently to hematopoietic progenitors; this mimics the paracrine action of Wnt9a during in vivo hematopoiesis. Taken together, these data indicate that WNT9A is a conserved regulator of zebrafish and human hematopoietic development. Full article
(This article belongs to the Special Issue Wnt Signaling in Stem Cells)
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Review

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Open AccessReview Wnt Signaling and Its Impact on Mitochondrial and Cell Cycle Dynamics in Pluripotent Stem Cells
Genes 2018, 9(2), 109; doi:10.3390/genes9020109
Received: 19 December 2017 / Revised: 13 February 2018 / Accepted: 14 February 2018 / Published: 19 February 2018
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Abstract
The core transcriptional network regulating stem cell self-renewal and pluripotency remains an intense area of research. Increasing evidence indicates that modified regulation of basic cellular processes such as mitochondrial dynamics, apoptosis, and cell cycle are also essential for pluripotent stem cell identity and
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The core transcriptional network regulating stem cell self-renewal and pluripotency remains an intense area of research. Increasing evidence indicates that modified regulation of basic cellular processes such as mitochondrial dynamics, apoptosis, and cell cycle are also essential for pluripotent stem cell identity and fate decisions. Here, we review evidence for Wnt regulation of pluripotency and self-renewal, and its connections to emerging features of pluripotent stem cells, including (1) increased mitochondrial fragmentation, (2) increased sensitivity to cell death, and (3) shortened cell cycle. We provide a general overview of the stem cell–specific mechanisms involved in the maintenance of these uncharacterized hallmarks of pluripotency and highlight potential links to the Wnt signaling pathway. Given the physiological importance of stem cells and their enormous potential for regenerative medicine, understanding fundamental mechanisms mediating the crosstalk between Wnt, organelle-dynamics, apoptosis, and cell cycle will be crucial to gain insight into the regulation of stemness. Full article
(This article belongs to the Special Issue Wnt Signaling in Stem Cells)
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Open AccessReview The Role of Wnt Signal in Glioblastoma Development and Progression: A Possible New Pharmacological Target for the Therapy of This Tumor
Genes 2018, 9(2), 105; doi:10.3390/genes9020105
Received: 13 December 2017 / Revised: 12 February 2018 / Accepted: 13 February 2018 / Published: 17 February 2018
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Abstract
Wnt is a complex signaling pathway involved in the regulation of crucial biological functions such as development, proliferation, differentiation and migration of cells, mainly stem cells, which are virtually present in all embryonic and adult tissues. Conversely, dysregulation of Wnt signal is implicated
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Wnt is a complex signaling pathway involved in the regulation of crucial biological functions such as development, proliferation, differentiation and migration of cells, mainly stem cells, which are virtually present in all embryonic and adult tissues. Conversely, dysregulation of Wnt signal is implicated in development/progression/invasiveness of different kinds of tumors, wherein a certain number of multipotent cells, namely “cancer stem cells”, are characterized by high self-renewal and aggressiveness. Hence, the pharmacological modulation of Wnt pathway could be of particular interest, especially in tumors for which the current standard therapy results to be unsuccessful. This might be the case of glioblastoma multiforme (GBM), one of the most lethal, aggressive and recurrent brain cancers, probably due to the presence of highly malignant GBM stem cells (GSCs) as well as to a dysregulation of Wnt system. By examining the most recent literature, here we point out several factors in the Wnt pathway that are altered in human GBM and derived GSCs, as well as new molecular strategies or experimental drugs able to modulate/inhibit aberrant Wnt signal. Altogether, these aspects serve to emphasize the existence of alternative pharmacological targets that may be useful to develop novel therapies for GBM. Full article
(This article belongs to the Special Issue Wnt Signaling in Stem Cells)
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Open AccessReview The Pleiotropic Effects of the Canonical Wnt Pathway in Early Development and Pluripotency
Genes 2018, 9(2), 93; doi:10.3390/genes9020093
Received: 13 December 2017 / Revised: 30 January 2018 / Accepted: 30 January 2018 / Published: 14 February 2018
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Abstract
The technology to derive embryonic and induced pluripotent stem cells from early embryonic stages and adult somatic cells, respectively, emerged as a powerful resource to enable the establishment of new in vitro models, which recapitulate early developmental processes and disease. Additionally, pluripotent stem
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The technology to derive embryonic and induced pluripotent stem cells from early embryonic stages and adult somatic cells, respectively, emerged as a powerful resource to enable the establishment of new in vitro models, which recapitulate early developmental processes and disease. Additionally, pluripotent stem cells (PSCs) represent an invaluable source of relevant differentiated cell types with immense potential for regenerative medicine and cell replacement therapies. Pluripotent stem cells support self-renewal, potency and proliferation for extensive periods of culture in vitro. However, the core pathways that rule each of these cellular features specific to PSCs only recently began to be clarified. The Wnt signaling pathway is pivotal during early embryogenesis and is central for the induction and maintenance of the pluripotency of PSCs. Signaling by the Wnt family of ligands is conveyed intracellularly by the stabilization of β-catenin in the cytoplasm and in the nucleus, where it elicits the transcriptional activity of T-cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors. Interestingly, in PSCs, the Wnt/β-catenin–TCF/LEF axis has several unrelated and sometimes opposite cellular functions such as self-renewal, stemness, lineage commitment and cell cycle regulation. In addition, tight control of the Wnt signaling pathway enhances reprogramming of somatic cells to induced pluripotency. Several recent research efforts emphasize the pleiotropic functions of the Wnt signaling pathway in the pluripotent state. Nonetheless, conflicting results and unanswered questions still linger. In this review, we will focus on the diverse functions of the canonical Wnt signaling pathway on the developmental processes preceding embryo implantation, as well as on its roles in pluripotent stem cell biology such as self-renewal and cell cycle regulation and somatic cell reprogramming. Full article
(This article belongs to the Special Issue Wnt Signaling in Stem Cells)
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Open AccessReview Renal Tubule Repair: Is Wnt/β-Catenin a Friend or Foe?
Genes 2018, 9(2), 58; doi:10.3390/genes9020058
Received: 11 December 2017 / Revised: 14 January 2018 / Accepted: 16 January 2018 / Published: 24 January 2018
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Abstract
Wnt/β-catenin signaling is extremely important for proper kidney development. This pathway is also upregulated in injured renal tubular epithelia, both in acute kidney injury and chronic kidney disease. The renal tubular epithelium is an important target of kidney injury, and its response (repair
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Wnt/β-catenin signaling is extremely important for proper kidney development. This pathway is also upregulated in injured renal tubular epithelia, both in acute kidney injury and chronic kidney disease. The renal tubular epithelium is an important target of kidney injury, and its response (repair versus persistent injury) is critical for determining whether tubulointerstitial fibrosis, the hallmark of chronic kidney disease, develops. This review discusses how Wnt/β-catenin signaling in the injured tubular epithelia promotes either repair or fibrosis after kidney injury. There is data suggesting that epithelial Wnt/β-catenin signaling is beneficial in acute kidney injury and important in tubular progenitors responsible for epithelial repair. The role of Wnt/β-catenin signaling in chronically injured epithelia is less clear. There is convincing data that Wnt/β-catenin signaling in interstitial fibroblasts and pericytes contributes to the extracellular matrix accumulation that defines fibrosis. However, some recent studies question whether Wnt/β-catenin signaling in chronically injured epithelia actually promotes fibrosis or repair. Full article
(This article belongs to the Special Issue Wnt Signaling in Stem Cells)
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Open AccessReview Wnt, RSPO and Hippo Signalling in the Intestine and Intestinal Stem Cells
Genes 2018, 9(1), 20; doi:10.3390/genes9010020
Received: 30 November 2017 / Revised: 22 December 2017 / Accepted: 28 December 2017 / Published: 8 January 2018
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Abstract
In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers.
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In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL pool. Wnt ligands can trigger alternative signalling that directly involves some of the Hippo pathway components such as YAP1, TAZ and TEADs. By upregulating Wnt pathway agonists, the alternative Wnt signalling can inhibit the canonical Wnt pathway activity. Full article
(This article belongs to the Special Issue Wnt Signaling in Stem Cells)
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Other

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Open AccessOpinion Modeling the Role of Wnt Signaling in Human and Drosophila Stem Cells
Genes 2018, 9(2), 101; doi:10.3390/genes9020101
Received: 28 December 2017 / Revised: 8 February 2018 / Accepted: 9 February 2018 / Published: 16 February 2018
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Abstract
The discovery of induced pluripotent stem (iPS) cells, barely more than a decade ago, dramatically transformed the study of stem cells and introduced a completely new way to approach many human health concerns. Although advances have pushed the field forward, human application remains
[...] Read more.
The discovery of induced pluripotent stem (iPS) cells, barely more than a decade ago, dramatically transformed the study of stem cells and introduced a completely new way to approach many human health concerns. Although advances have pushed the field forward, human application remains some years away, in part due to the need for an in-depth mechanistic understanding. The role of Wnts in stem cells predates the discovery of iPS cells with Wnts established as major pluripotency promoting factors. Most work to date has been done using mouse and tissue culture models and few attempts have been made in other model organisms, but the recent combination of clustered regularly interspaced short palindromic repeats (CRISPR) gene editing with iPS cell technology provides a perfect avenue for exploring iPS cells in model organisms. Drosophila is an ideal organism for such studies, but fly iPS cells have not yet been made. In this opinion article, we draw parallels between Wnt signaling in human and Drosophila stem cell systems, propose ways to obtain Drosophila iPS cells, and suggest ways to exploit the versatility of the Drosophila system for future stem cell studies. Full article
(This article belongs to the Special Issue Wnt Signaling in Stem Cells)
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