Lhx6 regulates canonical Wnt signaling to control the fate of mesenchymal progenitor cells during mouse molar root patterning

Mammalian tooth crown formation has long served as a model for investigating how patterning and morphogenesis are orchestrated during development. However, the mechanism underlying root patterning and morphogenesis remains poorly understood. In this study, we find that Lhx6 labels a subpopulation of root progenitor cells in the apical dental mesenchyme, which is closely associated with furcation development. Loss of Lhx6 leads to furcation and root number defects, indicating that Lhx6 is a key root patterning regulator. Among the multiple cellular events regulated by Lhx6 is the odontoblast fate commitment of progenitor cells, which it controls in a cell-autonomous manner. Specifically, Lhx6 loss leads to elevated expression of the Wnt antagonist Sfrp2 and down-regulation of Wnt signaling in the furcation region, while overactivation of Wnt signaling in Lhx6+ progenitor cells partially restore the furcation defects in Lhx6-/- mice. Collectively, our findings have important implications for understanding organ morphogenesis and future strategies for tooth root regeneration.

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Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons

10.1101/2020.01.14.905919 ◽

2020 ◽

Author(s):

Jana Heppt ◽

Marie-Theres Wittmann ◽

Jingzhong Zhang ◽

Daniela Vogt-Weisenhorn ◽

Nilima Prakash ◽

...

Keyword(s):

Young Adult ◽

Wnt Signaling ◽

Progenitor Cells ◽

Dendritic Growth ◽

Functional Integration ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Canonical Wnt Signaling ◽

Adult Born Neurons ◽

Canonical Wnt

AbstractIn adult hippocampal neurogenesis neural stem/progenitor cells generate new dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult-born neurons. Here, we investigated the role of canonical Wnt/β-catenin-signaling in dendritogenesis of adult-born neurons. We show that canonical Wnt-signaling follows a biphasic pattern, with high activity in stem/progenitor cells, attenuation in early immature neurons, and re-activation during maturation, and demonstrate that the biphasic activity pattern is required for proper dendrite development. Increasing β-catenin-signaling in maturing neurons of young adult mice transiently accelerated dendritic growth, but eventually resulted in dendritic defects and excessive spine numbers. In middle-aged mice, in which protracted dendrite and spine development was paralleled by lower canonical Wnt-signaling activity, enhancement of β-catenin-signaling restored dendritic growth and spine formation to levels observed in young adult animals. Our data indicate that precise timing and strength of β-catenin-signaling is essential for the correct functional integration of adult-born neurons and suggest Wnt/β-catenin-signaling as a pathway to ameliorate deficits in adult neurogenesis during aging.

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Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells

International Journal of Molecular Medicine ◽

10.3892/ijmm.17.4.681 ◽

2006 ◽

Cited By ~ 5

Author(s):

Masuko Katoh ◽

Masaru Katoh

Keyword(s):

Wnt Signaling ◽

Progenitor Cells ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Canonical Wnt Signaling ◽

Notch Ligand ◽

Evolutionarily Conserved ◽

Canonical Wnt

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326 Dysregulated Canonical Wnt Signaling in Lrig1+ Colonic Progenitor Cells Leads to Genetically Heterogeneous, Hypermutated Adenomas

Gastroenterology ◽

10.1016/s0016-5085(16)30372-9 ◽

2016 ◽

Vol 150 (4) ◽

pp. S77

Author(s):

Anne E. Powell ◽

Jumpei Kondo ◽

Jessica Preston ◽

Phillip J. Dexheimer ◽

Jeff Franklin ◽

...

Keyword(s):

Wnt Signaling ◽

Progenitor Cells ◽

Canonical Wnt Signaling ◽

Canonical Wnt

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Mesenchymal stem cell perspective: cell biology to clinical progress

npj Regenerative Medicine ◽

10.1038/s41536-019-0083-6 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 125

Author(s):

Mark F. Pittenger ◽

Dennis E. Discher ◽

Bruno M. Péault ◽

Donald G. Phinney ◽

Joshua M. Hare ◽

...

Keyword(s):

Progenitor Cells ◽

Stromal Cells ◽

Cell Biology ◽

Cellular Therapy ◽

Human Mscs ◽

Intercellular Signaling ◽

Mesenchymal Progenitor Cells ◽

A Cell

AbstractThe terms MSC and MSCs have become the preferred acronym to describe a cell and a cell population of multipotential stem/progenitor cells commonly referred to as mesenchymal stem cells, multipotential stromal cells, mesenchymal stromal cells, and mesenchymal progenitor cells. The MSCs can differentiate to important lineages under defined conditions in vitro and in limited situations after implantation in vivo. MSCs were isolated and described about 30 years ago and now there are over 55,000 publications on MSCs readily available. Here, we have focused on human MSCs whenever possible. The MSCs have broad anti-inflammatory and immune-modulatory properties. At present, these provide the greatest focus of human MSCs in clinical testing; however, the properties of cultured MSCs in vitro suggest they can have broader applications. The medical utility of MSCs continues to be investigated in over 950 clinical trials. There has been much progress in understanding MSCs over the years, and there is a strong foundation for future scientific research and clinical applications, but also some important questions remain to be answered. Developing further methods to understand and unlock MSC potential through intracellular and intercellular signaling, biomedical engineering, delivery methods and patient selection should all provide substantial advancements in the coming years and greater clinical opportunities. The expansive and growing field of MSC research is teaching us basic human cell biology as well as how to use this type of cell for cellular therapy in a variety of clinical settings, and while much promise is evident, careful new work is still needed.

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Abstract 14: The Cytoskeletal Architecture of Myocytes Derived from Human Cardiac Progenitor Cells

Circulation Research ◽

10.1161/res.115.suppl_1.14 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Francesco Pasqualini ◽

Moises Di Sante ◽

João D Pereira ◽

Piero Anversa ◽

Marcello Rota ◽

...

Keyword(s):

Wnt Signaling ◽

Progenitor Cells ◽

Wnt Pathway ◽

Cardiac Cells ◽

Cardiac Progenitor Cells ◽

Homogeneous Population ◽

Cardiomyogenic Differentiation ◽

Induced Pluripotent ◽

Canonical Wnt

The stem cell antigen c-kit characterizes a heterogeneous pool of human cardiac progenitor cells (hCPCs) that exhibit a remarkable degree of regenerative potential and are currently employed in clinical trials. While this hCPC pool contains distinct subpopulations of c-kit+ cells that preferentially differentiate into muscular or vascular cardiac cells, we hypothesize that hCPCs may be coerced to specify only along the cardiomyogenic lineage by manipulating the Wnt/β-catenin pathway. We report that pharmacological inhibition of the non-canonical Wnt pathway facilitated the commitment of more than >95% c-kit+ hCPCs to the cardiomyocyte lineage after 4 days in-vitro: this constitutes a substantially more homogeneous population than previously reported with dexamethasone treatment. The hCPC-derived myocytes stained positive for Nkx2.5, a transcription factor that orchestrates cardiomyogenic differentiation, and for the contractile protein sarcomeric α-actin. To test if we could push the cells towards a more mature phenotype, we mimicked the cyclic modulation of the Wnt pathway observed during development. While activation of Wnt signaling resulted in widespread cell death and reduction in cell size, subsequent Wnt inhibition prompted the spared cells to proliferate. With this protocol, hCPC-derived myocytes increased in size and displayed more mature cytoskeletal architectures. In contrast with dexamethasone treated cells, where the localization of α-sarcomeric actinin is mostly diffuse in the cytoplasm, here we observed both Z-bodies and Z-disks like structures. The latter exhibited a periodicity of ~1.6 um and were clustered in larger, more aligned actin bundles. This finding suggests that the tension developed along these cytoskeletal components may play a role in the recruitment of sarcomeric proteins. In conclusion, Wnt signaling inhibition in hCPCs may be sufficient to obtain a homogeneous population of cells with features of myocytes, characterized by improved cytoskeletal organization than dexamethasone treated cells and similar to that observed in myocytes derived from human induced pluripotent stem cells.

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The Importance of the Canonical Wnt Signaling Pathway in the Porcine Endometrial Stromal Stem/Progenitor Cells: Implications for Regeneration

Stem Cells and Development ◽

10.1089/scd.2015.0078 ◽

2015 ◽

Vol 24 (24) ◽

pp. 2873-2885 ◽

Cited By ~ 13

Author(s):

Joanna Bukowska ◽

Adam Janusz Ziecik ◽

Joanna Laguna ◽

Barbara Gawronska-Kozak ◽

Gabriel Bodek

Keyword(s):

Wnt Signaling ◽

Progenitor Cells ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Canonical Wnt Signaling ◽

Canonical Wnt

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Non-canonical Wnt Signaling Enhances Differentiation of Human Circulating Progenitor Cells to Cardiomyogenic Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m500323200 ◽

2005 ◽

Vol 280 (17) ◽

pp. 16838-16842 ◽

Cited By ~ 96

Author(s):

Masamichi Koyanagi ◽

Judith Haendeler ◽

Cornel Badorff ◽

Ralf P. Brandes ◽

Jörg Hoffmann ◽

...

Keyword(s):

Wnt Signaling ◽

Progenitor Cells ◽

Canonical Wnt Signaling ◽

Canonical Wnt

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The Wnt Signaling Antagonist Kremen1 is Required for Development of Thymic Architecture

Clinical and Developmental Immunology ◽

10.1080/17402520600935097 ◽

2006 ◽

Vol 13 (2-4) ◽

pp. 299-319 ◽

Cited By ~ 44

Author(s):

Masako Osada ◽

Emi Ito ◽

Hector A. Fermin ◽

Edwin Vazquez-Cintron ◽

Tadmiri Venkatesh ◽

...

Keyword(s):

Wnt Signaling ◽

Wnt Signaling Pathway ◽

Fold Increase ◽

Negative Regulator ◽

Thymic Epithelial Cells ◽

Canonical Wnt Signaling ◽

Thymocyte Proliferation ◽

Elevated Expression ◽

Wnt Inhibitor ◽

Canonical Wnt

Wnt signaling has been reported to regulate thymocyte proliferation and selection at several stages during T cell ontogeny, as well as the expression ofFoxN1in thymic epithelial cells (TECs). Kremen1 (Krm1) is a negative regulator of the canonical Wnt signaling pathway, and functions together with the secreted Wnt inhibitor Dickkopf (Dkk) by competing for the lipoprotein receptor-related protein (LRP)-6 co-receptor for Wnts. Herekrm1knockout mice were used to examinekrm1expression in the thymus and its function in thymocyte and TEC development.krm1expression was detected in both cortical and medullary TEC subsets, as well as in immature thymocyte subsets, beginning at the CD25+CD44+ (DN2) stage and continuing until the CD4+CD8+(DP) stage. Neonatal mice show elevated expression ofkrm1in all TEC subsets.krm1− / −mice exhibit a severe defect in thymic cortical architecture, including large epithelial free regions. Much of the epithelial component remains at an immature Keratin 5+(K5) Keratin 8+(K8) stage, with a loss of defined cortical and medullary regions. A TOPFlash assay revealed a 2-fold increase in canonical Wnt signaling in TEC lines derived fromkrm1− / −mice, when compared withkrm1+ / +derived TEC lines. Fluorescence activated cell sorting (FACS) analysis of dissociated thymus revealed a reduced frequency of both cortical (BP1+EpCAM+) and medullary (UEA-1+EpCAMhi) epithelial subsets, within thekrm1− / −thymus. Surprisingly, no change in thymus size, total thymocyte number or the frequency of thymocyte subsets was detected inkrm1− / −mice. However, our data suggest that a loss of Krm1 leads to a severe defect in thymic architecture. Taken together, this study revealed a new role for Krm1 in proper development of thymic epithelium.

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