Wnt signaling in hematopoiesis: Crucial factors for self-renewal, proliferation, and cell fate decisions

2010 ◽  
pp. n/a-n/a ◽  
Author(s):  
Frank J.T. Staal ◽  
Tiago C. Luis
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Self Renewal ◽  
Cell Fate Decisions

scholarly journals Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels

2008 ◽  
Vol 28 (21) ◽  
pp. 6668-6680 ◽  
Author(s):  
Albertus T. J. Wierenga ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Expression Patterns ◽  
Activity Levels ◽  
Dependent Manner ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

ABSTRACT The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34+ cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34+ cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.

scholarly journals Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2420-2429 ◽  
Author(s):  
Christoph Schaniel ◽  
Dario Sirabella ◽  
Jiajing Qiu ◽  
Xiaohong Niu ◽  
Ihor R. Lemischka ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Cell Fate ◽  
Sonic Hedgehog ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Cell Niche ◽  
Wnt Inhibitory Factor 1 ◽  
Stem Cell Pool

Abstract The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potential. Primitive stem and progenitor populations were more proliferative and elevated in bone marrow and spleen, manifesting an impaired ability to maintain a self-renewing stem cell pool. Exhaustion of the stem cell pool was apparent only in the context of systemic stress by chemotherapy or transplantation of wild-type stem cells into irradiated Wif1 hosts. Paradoxically this is mediated, at least in part, by an autocrine induction of canonical Wnt signaling in stem cells on sequestration of Wnts in the environment. Additional signaling pathways are dysregulated in this model, primarily activated Sonic Hedgehog signaling in stem cells as a result of Wif1-induced osteoblastic expression of Sonic Hedgehog. We find that dysregulation of the stem cell niche by overexpression of an individual component impacts other unanticipated regulatory pathways in a combinatorial manner, ultimately disrupting niche mediated stem cell fate decisions.

scholarly journals Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

2015 ◽  
Vol 309 (8) ◽  
pp. C511-C521 ◽  
Author(s):  
Laura Novellasdemunt ◽  
Pedro Antas ◽  
Vivian S. W. Li
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Wnt Pathway ◽  
High Throughput Sequencing ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Evolutionarily Conserved

The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.

scholarly journals Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling

2016 ◽  
Vol 113 (51) ◽  
pp. E8267-E8276 ◽  
Author(s):  
Xiang Li ◽  
Xiaojing Yue ◽  
William A. Pastor ◽  
Lizhu Lin ◽  
Romain Georges ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Ectopic Expression ◽  
Embryonic Stem ◽  
Mesodermal Cell ◽  
Cell Fate Decisions ◽  
Tet Proteins ◽  
Mesoderm Specification ◽  
Wnt Inhibitor

TET-family dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and oxidized methylcytosines in DNA. Here, we show that mouse embryonic stem cells (mESCs), either lacking Tet3 alone or with triple deficiency of Tet1/2/3, displayed impaired adoption of neural cell fate and concomitantly skewed toward cardiac mesodermal fate. Conversely, ectopic expression of Tet3 enhanced neural differentiation and limited cardiac mesoderm specification. Genome-wide analyses showed that Tet3 mediates cell-fate decisions by inhibiting Wnt signaling, partly through promoter demethylation and transcriptional activation of the Wnt inhibitor secreted frizzled-related protein 4 (Sfrp4). Tet1/2/3-deficient embryos (embryonic day 8.0–8.5) showed hyperactivated Wnt signaling, as well as aberrant differentiation of bipotent neuromesodermal progenitors (NMPs) into mesoderm at the expense of neuroectoderm. Our data demonstrate a key role for TET proteins in modulating Wnt signaling and establishing the proper balance between neural and mesodermal cell fate determination in mouse embryos and ESCs.

scholarly journals β-catenin Signaling Regulates Cell Fate Decisions at the Transition Zone of the Chondro-Osseous Junction During Fracture Healing

2020 ◽  
Author(s):  
Sarah Anne Wong ◽  
Diane Hu ◽  
Tiffany Shao ◽  
Erene Niemi ◽  
Emilie Barruet ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Fracture Healing ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Lineage Tracing ◽  
Fracture Callus ◽  
Knock Out ◽  
Marrow Cavity ◽  
Cell Fate Decisions ◽  
Wnt Ligands

AbstractChondrocytes within the fracture callus transform into osteoblasts during bone regeneration, but the molecular mechanisms regulating this process are unknown. Wnt ligands are expressed within the fracture callus, and hypertrophic chondrocytes undergoing transformation to osteoblasts exhibit nuclear localization of β-catenin, indicating active Wnt signaling in these cells. Here, we show that conditional knock out (cKO) of β-catenin in chondrocytes inhibits the transformation of chondrocytes to osteoblasts, while stabilization of β-catenin in chondrocytes accelerates this process. After cKO, chondrocyte-derived cells were located in the bone marrow cavity and upon re-fracture formed cartilage. Lineage tracing in wild type mice revealed that in addition to osteoblasts, chondrocytes give rise to stem cells that contribute to repair of subsequent fractures. These data indicate that Wnt signaling directs cell fate choices of chondrocytes during fracture healing by stimulating transformation of chondrocytes to osteoblasts, and provide a framework for developing Wnt-therapies to stimulate repair.

scholarly journals SOX2-phosphorylation toggles a bistable differentiation-switch in squamous cell carcinoma

2021 ◽  
Author(s):  
Steven Hoang-Phou ◽  
Ana Sastre-Perona ◽  
Matteo Abbruzzese ◽  
Zhe Ying ◽  
Jasmin Siegle ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Squamous Cell ◽  
Tumor Formation ◽  
Transcriptional Networks ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Cell Fate Decisions ◽  
Cell Type Specific ◽  
Network Switch

SummaryThe fate choice between stem cell self-renewal and differentiation is regulated by bistable transcriptional networks, which are balanced in homeostasis and imbalanced in tumors. Yet, how stem cells switch from self-renewal to differentiation remains a conundrum. Here, we discover a molecular mechanism that allows stem cell-like tumor propagating cells (TPCs) in squamous cell carcinomas (SCCs) to switch from a mutually exclusive SOX2-PITX1-TP63 self-renewal circuit to a KLF4 driven differentiation program, dependent on the relative occupancy of a novel Klf4-regulatory enhancer cluster (Klf4EC944) by SOX2 or KLF4, respectively. We find SOX2 occupies this site in TPCs to inhibit Klf4 transcription, but upon phosphorylation SOX2 becomes evicted from Klf4EC944, allowing residual KLF4 to occupy this site instead, boost the expression of KLF4 and its downstream targets, and differentiate self-renewing TPCs into post-mitotic SCC cells. This mechanism allows SOX2 to promote self-renewal and tumor formation, while preserving the differentiation potential in SCC cells. Our data suggest that stochastic cell fate decisions depend on the effective concentration of enzymatically regulated transcription factors. The surprising specificity by which SOX2-phosphorylation governs the bistable Klf4EC944 network-switch in SCCs reveals a conceptual framework for the identification of similar switches in other stem cell and cancer types and their potential development into cell type specific differentiation therapies for diseases in which tissue homeostasis has gone awry.

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