Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway

The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5+) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5+ progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.

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Transcription factor Tlx1 marks a subset of lymphoid tissue organizer-like mesenchymal progenitor cells in the neonatal spleen

Scientific Reports ◽

10.1038/s41598-019-56984-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Yuta Ueno ◽

Keiko Fujisaki ◽

Shoko Hosoda ◽

Yusuke Amemiya ◽

Shogo Okazaki ◽

...

Keyword(s):

Transcription Factor ◽

Progenitor Cells ◽

Stromal Cells ◽

Lymphoid Tissue ◽

Stromal Cell ◽

Lineage Tracing ◽

Mesenchymal Progenitor Cells ◽

Reticular Cells

AbstractThe spleen is comprised of spatially distinct compartments whose functions, such as immune responses and removal of aged red blood cells, are tightly controlled by the non-hematopoietic stromal cells that provide regionally-restricted signals to properly activate hematopoietic cells residing in each area. However, information regarding the ontogeny and relationships of the different stromal cell types remains limited. Here we have used in vivo lineage tracing analysis and in vitro mesenchymal stromal cell assays and found that Tlx1, a transcription factor essential for embryonic spleen organogenesis, marks neonatal stromal cells that are selectively localized in the spleen and retain mesenchymal progenitor potential to differentiate into mature follicular dendritic cells, fibroblastic reticular cells and marginal reticular cells. Furthermore, by establishing a novel three-dimensional cell culture system that enables maintenance of Tlx1-expressing cells in vitro, we discovered that signals from the lymphotoxin β receptor and TNF receptor promote differentiation of these cells to express MAdCAM-1, CCL19 and CXCL13, representative functional molecules expressed by different subsets of mature stromal cells in the spleen. Taken together, these findings indicate that mesenchymal progenitor cells expressing Tlx1 are a subset of lymphoid tissue organizer-like cells selectively found in the neonatal spleen.

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Abstract 16189: Lineage Tracing of Postnatal Cardiomyogenic Progenitor Cells

Circulation ◽

10.1161/circ.130.suppl_2.16189 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yuan-Hung Liu ◽

Shih-Yun Huang ◽

Yi-Shuan Lin ◽

Hsing-Yu Huang

Keyword(s):

Progenitor Cells ◽

Heart Development ◽

Lineage Tracing ◽

Mouse Heart ◽

Differentiation Potential ◽

Genetic Ablation ◽

Epicardial Cells ◽

Cardiomyogenic Differentiation

Recent studies report that postnatal mammalian hearts undergo cardiomyocyte refreshment. While the exact origin of the cells involved in postnatal cardiomyogenesis remains unclear. Here, we identified a pool of Nkx2.5 enhancer expressing cells in the postnatal mouse heart with cardiomyogenic differentiation potential in vitro. We tracked the expression of a cardiac-specific enhancer of Nkx2.5 using inducible Nkx2.5 enhancer-Cre mice from embryonic development to adulthood and post-myocardial infarction (MI) and documented the Nkx2.5 enhancer expressing cells directly contribute to postnatal cardiomyogenesis in vivo. Upon genetic ablation of these activated progenitors after myocardial injury, the cardiac function deteriorated. Transcriptomic analysis of Nkx2.5 enhancer expressing cells showed high expression of heart development genes. To trace the developmental origin of the activated Nkx2.5 cardiomyogenic progenitor cells, we created different lineage-Cre/Nkx2.5 enh-eGFP/ROSA26 reporter triple transgenic mice. Post-MI Nkx2.5 cardiomyogenic progenitor cells originated from the embryonic epicardial cells, not from the pre-existing cardiomyocytes, endothelial cells, cardiac neural crest cells, or perinatal/postnatal epicardial cells. Together, this study confirmed that cardiac lineage-specific progenitor cells, which originate from embryonic epicardium-derived cells, contribute to postnatal mammalian cardiomyogenesis.

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The Elusive Endometrial Epithelial Stem/Progenitor Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.640319 ◽

2021 ◽

Vol 9 ◽

Author(s):

Fiona L. Cousins ◽

Ronald Pandoy ◽

Shiying Jin ◽

Caroline E. Gargett

Keyword(s):

Stem Cells ◽

Progenitor Cells ◽

Potential Role ◽

Lineage Tracing ◽

Regenerative Capacity ◽

Proliferative Phase ◽

Functional Assays ◽

Human And Mouse

The human endometrium undergoes approximately 450 cycles of proliferation, differentiation, shedding and regeneration over a woman’s reproductive lifetime. The regenerative capacity of the endometrium is attributed to stem/progenitor cells residing in the basalis layer of the tissue. Mesenchymal stem cells have been extensively studied in the endometrium, whereas endometrial epithelial stem/progenitor cells have remained more elusive. This review details the discovery of human and mouse endometrial epithelial stem/progenitor cells. It highlights recent significant developments identifying putative markers of these epithelial stem/progenitor cells that reveal their in vivo identity, location in both human and mouse endometrium, raising common but also different viewpoints. The review also outlines the techniques used to identify epithelial stem/progenitor cells, specifically in vitro functional assays and in vivo lineage tracing. We will also discuss their known interactions and hierarchy and known roles in endometrial dynamics across the menstrual or estrous cycle including re-epithelialization at menses and regeneration of the tissue during the proliferative phase. We also detail their potential role in endometrial proliferative disorders such as endometriosis.

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GPR4 signaling is essential for the promotion of acid-mediated angiogenic capacity of endothelial progenitor cells by activating STAT3/VEGFA pathway in patients with coronary artery disease

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02221-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shun Ouyang ◽

Yan Li ◽

Xing Wu ◽

Yan Wang ◽

Fanmao Liu ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Progenitor Cells ◽

G Protein ◽

Endothelial Progenitor Cells ◽

Acidic Environment ◽

Artery Disease ◽

G Protein Coupled

Abstract Background Patients with coronary artery disease (CAD) are characterized by a decline in vascular regeneration, which is related to the dysfunction of endothelial progenitor cells (EPCs). G-protein-coupled receptor 4 (GPR4) is a proton-sensing G-protein-coupled receptor (GPCR) that contributes to neovascularization in acidic microenvironments. However, the role of GPR4 in regulating the angiogenic capacity of EPCs from CAD patients in response to acidity generated in ischemic tissue remains completely unclear. Methods The angiogenic capacity of EPCs collected from CAD patients and healthy subjects was evaluated in different pH environments. The GPR4 function of regulating EPC-mediated angiogenesis was analyzed both in vitro and in vivo. The downstream mechanisms were further investigated by genetic overexpression and inhibition. Results Acidic environment prestimulation significantly enhanced the angiogenic capacity of EPCs from the non-CAD group both in vivo and in vitro, while the same treatment yielded the opposite result in the CAD group. Among the four canonical proton-sensing GPCRs, GPR4 displays the highest expression in EPCs. The expression of GRP4 was markedly lower in EPCs from CAD patients than in EPCs from non-CAD individuals independent of acid stimulation. The siRNA-mediated knockdown of GPR4 with subsequent decreased phosphorylation of STAT3 mimicked the impaired function of EPCs from CAD patients at pH 6.4 but not at pH 7.4. Elevating GPR4 expression restored the neovessel formation mediated by EPCs from CAD patients in an acidic environment by activating STAT3/VEGFA signaling. Moreover, the beneficial impact of GPR4 upregulation on EPC-mediated angiogenic capacity was abrogated by blockade of the STAT3/VEGFA signaling pathway. Conclusions Our present study demonstrated for the first time that loss of GPR4 is responsible for the decline in proton sensing and angiogenic capacity of EPCs from CAD patients. Augmentation of GPR4 expression promotes the neovessel formation of EPCs by activating STAT3/VEGF signaling. This finding implicates GPR4 as a potential therapeutic target for CAD characterized by impaired neovascularization in ischemic tissues.

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WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-208577 ◽

2016 ◽

Vol 76 (1) ◽

pp. 218-226 ◽

Cited By ~ 51

Author(s):

Giovanna Nalesso ◽

Bethan Lynne Thomas ◽

Joanna Claire Sherwood ◽

Jing Yu ◽

Olga Addimanda ◽

...

Keyword(s):

Progenitor Cells ◽

Molecular Mechanisms ◽

Wnt Signalling ◽

Chondrocyte Apoptosis ◽

Primary Chondrocytes ◽

Canonical Wnt ◽

Excessive Activation ◽

Deficient Mice

ObjectiveBoth excessive and insufficient activation of WNT signalling results in cartilage breakdown and osteoarthritis. WNT16 is upregulated in the articular cartilage following injury and in osteoarthritis. Here, we investigate the function of WNT16 in osteoarthritis and the downstream molecular mechanisms.MethodsOsteoarthritis was induced by destabilisation of the medial meniscus in wild-type and WNT16-deficient mice. Molecular mechanisms and downstream effects were studied in vitro and in vivo in primary cartilage progenitor cells and primary chondrocytes. The pathway downstream of WNT16 was studied in primary chondrocytes and using the axis duplication assay in Xenopus.ResultsWNT16-deficient mice developed more severe osteoarthritis with reduced expression of lubricin and increased chondrocyte apoptosis. WNT16 supported the phenotype of cartilage superficial-zone progenitor cells and lubricin expression. Increased osteoarthritis in WNT16-deficient mice was associated with excessive activation of canonical WNT signalling. In vitro, high doses of WNT16 weakly activated canonical WNT signalling, but, in co-stimulation experiments, WNT16 reduced the capacity of WNT3a to activate the canonical WNT pathway. In vivo, WNT16 rescued the WNT8-induced primary axis duplication in Xenopus embryos.ConclusionsIn osteoarthritis, WNT16 maintains a balanced canonical WNT signalling and prevents detrimental excessive activation, thereby supporting the homeostasis of progenitor cells.

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Levelling out differences in aerobic glycolysis neutralizes the competitive advantage of oncogenic PIK3CA mutant progenitors in the esophagus

10.1101/2021.05.28.446104 ◽

2021 ◽

Author(s):

Albert Herms ◽

Bartomeu Colom ◽

Gabriel Piedrafita ◽

Kasumi Murai ◽

Swee Hoe Ong ◽

...

Keyword(s):

Competitive Advantage ◽

Progenitor Cells ◽

Cell Fate ◽

Aerobic Glycolysis ◽

Lineage Tracing ◽

Wild Type ◽

Cellular Mechanisms ◽

Mutant Cells

Normal human tissues progressively accumulate cells carrying mutations. Activating mutations in PIK3CA generate large clones in the aging human esophagus, but the underlying cellular mechanisms are unclear. Here, we tracked mutant PIK3CA esophageal progenitor cells in transgenic mice by lineage tracing. Expression of an activating heterozygous Pik3caH1047R mutation in single progenitor cells tilts cell fate towards proliferation, generating mutant clones that outcompete their wild type neighbors. The mutation leads to increased aerobic glycolysis through the activation of Hif1α transcriptional targets compared with wild type cells. We found that interventions that level out the difference in activation of the PI3K/HIF1α/aerobic glycolysis axis between wild type and mutant cells attenuate the competitive advantage of Pik3caH1047R mutant cells in vitro and in vivo. Our results suggest that clinically feasible interventions that even out signaling imbalances between wild type and mutant cells may limit the expansion of oncogenic mutants in normal epithelia.

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Bone Marrow Niches for Skeletal Progenitor Cells and their Inhabitants in Health and Disease

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190123161447 ◽

2019 ◽

Vol 14 (4) ◽

pp. 305-319 ◽

Cited By ~ 4

Author(s):

Marietta Herrmann ◽

Franz Jakob

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Progenitor Cell ◽

Adult Stem Cells ◽

Current Knowledge ◽

Cell Populations ◽

Surface Markers ◽

Bone Marrow Niches

The bone marrow hosts skeletal progenitor cells which have most widely been referred to as Mesenchymal Stem or Stromal Cells (MSCs), a heterogeneous population of adult stem cells possessing the potential for self-renewal and multilineage differentiation. A consensus agreement on minimal criteria has been suggested to define MSCs in vitro, including adhesion to plastic, expression of typical surface markers and the ability to differentiate towards the adipogenic, osteogenic and chondrogenic lineages but they are critically discussed since the differentiation capability of cells could not always be confirmed by stringent assays in vivo. However, these in vitro characteristics have led to the notion that progenitor cell populations, similar to MSCs in bone marrow, reside in various tissues. MSCs are in the focus of numerous (pre)clinical studies on tissue regeneration and repair.Recent advances in terms of genetic animal models enabled a couple of studies targeting skeletal progenitor cells in vivo. Accordingly, different skeletal progenitor cell populations could be identified by the expression of surface markers including nestin and leptin receptor. While there are still issues with the identity of, and the overlap between different cell populations, these studies suggested that specific microenvironments, referred to as niches, host and maintain skeletal progenitor cells in the bone marrow. Dynamic mutual interactions through biological and physical cues between niche constituting cells and niche inhabitants control dormancy, symmetric and asymmetric cell division and lineage commitment. Niche constituting cells, inhabitant cells and their extracellular matrix are subject to influences of aging and disease e.g. via cellular modulators. Protective niches can be hijacked and abused by metastasizing tumor cells, and may even be adapted via mutual education. Here, we summarize the current knowledge on bone marrow skeletal progenitor cell niches in physiology and pathophysiology. We discuss the plasticity and dynamics of bone marrow niches as well as future perspectives of targeting niches for therapeutic strategies.

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A Review on Melatonin’s Effects in Cancer: Potential Mechanisms

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666171121120223 ◽

2018 ◽

Vol 18 (7) ◽

pp. 985-992 ◽

Cited By ~ 3

Author(s):

Aysegul Hanikoglu ◽

Ertan Kucuksayan ◽

Rana Cagla Akduman ◽

Tomris Ozben

Keyword(s):

Systematic Review ◽

Antioxidant Activity ◽

Membrane Receptors ◽

Cancer Development ◽

Secretory Product ◽

Prevention And Treatment ◽

G Protein Coupled

This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G Protein-Coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.

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Novel Identified Circular Transcript of RCAN2, circ-RCAN2, Shows Deviated Expression Pattern in Pig Reperfused Infarcted Myocardium and Hypoxic Porcine Cardiac Progenitor Cells In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22031390 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1390

Author(s):

Julia Mester-Tonczar ◽

Patrick Einzinger ◽

Johannes Winkler ◽

Nina Kastner ◽

Andreas Spannbauer ◽

...

Keyword(s):

Myocardial Infarction ◽

Progenitor Cells ◽

Regulatory Networks ◽

Circular Rnas ◽

Cardiac Progenitor Cells ◽

Tissue Samples ◽

Healthy Myocardium ◽

Acute Mi

Circular RNAs (circRNAs) are crucial in gene regulatory networks and disease development, yet circRNA expression in myocardial infarction (MI) is poorly understood. Here, we harvested myocardium samples from domestic pigs 3 days after closed-chest reperfused MI or sham surgery. Cardiac circRNAs were identified by RNA-sequencing of rRNA-depleted RNA from infarcted and healthy myocardium tissue samples. Bioinformatics analysis was performed using the CIRIfull and KNIFE algorithms, and circRNAs identified with both algorithms were subjected to differential expression (DE) analysis and validation by qPCR. Circ-RCAN2 and circ-C12orf29 expressions were significantly downregulated in infarcted tissue compared to healthy pig heart. Sanger sequencing was performed to identify the backsplice junctions of circular transcripts. Finally, we compared the expressions of circ-C12orf29 and circ-RCAN2 between porcine cardiac progenitor cells (pCPCs) that were incubated in a hypoxia chamber for different time periods versus normoxic pCPCs. Circ-C12orf29 did not show significant DE in vitro, whereas circ-RCAN2 exhibited significant ischemia-time-dependent upregulation in hypoxic pCPCs. Overall, our results revealed novel cardiac circRNAs with DE patterns in pCPCs, and in infarcted and healthy myocardium. Circ-RCAN2 exhibited differential regulation by myocardial infarction in vivo and by hypoxia in vitro. These results will improve our understanding of circRNA regulation during acute MI.

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The Radiation-Induced Regenerative Response of Adult Tissue-Specific Stem Cells: Models and Signaling Pathways

Cancers ◽

10.3390/cancers13040855 ◽

2021 ◽

Vol 13 (4) ◽

pp. 855

Author(s):

Paola Serrano Martinez ◽

Lorena Giuranno ◽

Marc Vooijs ◽

Robert P. Coppes

Keyword(s):

Signaling Pathways ◽

Progenitor Cells ◽

Tissue Regeneration ◽

Normal Tissue ◽

Cellular Response ◽

Adult Tissue ◽

Tissue Specific ◽

Radiation Induced

Radiotherapy is involved in the treatment of many cancers, but damage induced to the surrounding normal tissue is often inevitable. Evidence suggests that the maintenance of homeostasis and regeneration of the normal tissue is driven by specific adult tissue stem/progenitor cells. These tasks involve the input from several signaling pathways. Irradiation also targets these stem/progenitor cells, triggering a cellular response aimed at achieving tissue regeneration. Here we discuss the currently used in vitro and in vivo models and the involved specific tissue stem/progenitor cell signaling pathways to study the response to irradiation. The combination of the use of complex in vitro models that offer high in vivo resemblance and lineage tracing models, which address organ complexity constitute potential tools for the study of the stem/progenitor cellular response post-irradiation. The Notch, Wnt, Hippo, Hedgehog, and autophagy signaling pathways have been found as crucial for driving stem/progenitor radiation-induced tissue regeneration. We review how these signaling pathways drive the response of solid tissue-specific stem/progenitor cells to radiotherapy and the used models to address this.

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