Publications by authors named "Emanuel Rognoni"

21 Publications

  • Page 1 of 1

Dissecting Fibroblast Heterogeneity in Health and Fibrotic Disease.

Curr Rheumatol Rep 2020 06 19;22(8):33. Epub 2020 Jun 19.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.

Purpose Of Review: Fibroblasts, the major cell population in all connective tissues, are best known for their role in depositing and maintaining the extracellular matrix. Recently, numerous specialised functions have been discovered revealing unpredicted fibroblast heterogeneity. We will discuss this heterogeneity, from its origins in development to alterations in fibrotic disease conditions.

Recent Findings: Advances in lineage tracing and single-cell transcriptional profiling techniques have revealed impressive diversity amongst fibroblasts in a range of organ systems including the skin, lung, kidney and heart. However, there are major challenges in assimilating the findings and understanding their functional significance. Certain fibroblast subsets can make specific contributions to healthy tissue functioning and to fibrotic disease processes; thus, therapeutic manipulation of particular subsets could be clinically beneficial. Here we propose that four key variables determine a fibroblast's phenotype underpinning their enormous heterogeneity: tissue status, regional features, microenvironment and cell state. We review these in different organ systems, highlighting the importance of understanding the divergent fibroblast properties and underlying mechanisms in tissue fibrosis.
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http://dx.doi.org/10.1007/s11926-020-00903-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305072PMC
June 2020

The Roles of YAP/TAZ and the Hippo Pathway in Healthy and Diseased Skin.

Cells 2019 05 3;8(5). Epub 2019 May 3.

Department of Biology and Biochemistry & Centre for Therapeutic Innovation, University of Bath, Claverton Down, Bath BA2 7AY, UK.

Skin is the largest organ of the human body. Its architecture and physiological functions depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, homeostasis and repair. While several stem cell populations have been identified in the epidermis with distinct locations and functions, there is additional heterogeneity within the mesenchymal cells of the dermis. Here, we discuss the current knowledge of how the Hippo pathway and its downstream effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) contribute to the maintenance, activation and coordination of the epidermal and dermal cell populations during development, homeostasis, wound healing and cancer.
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http://dx.doi.org/10.3390/cells8050411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562585PMC
May 2019

Mutant Lef1 controls Gata6 in sebaceous gland development and cancer.

EMBO J 2019 05 18;38(9). Epub 2019 Mar 18.

Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK

Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.
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http://dx.doi.org/10.15252/embj.2018100526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484415PMC
May 2019

Fibroblast state switching orchestrates dermal maturation and wound healing.

Mol Syst Biol 2018 08 29;14(8):e8174. Epub 2018 Aug 29.

Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK

Murine dermis contains functionally and spatially distinct fibroblast lineages that cease to proliferate in early postnatal life. Here, we propose a model in which a negative feedback loop between extracellular matrix (ECM) deposition and fibroblast proliferation determines dermal architecture. Virtual-tissue simulations of our model faithfully recapitulate dermal maturation, predicting a loss of spatial segregation of fibroblast lineages and dictating that fibroblast migration is only required for wound healing. To test this, we performed live imaging of dermal fibroblasts, which revealed that homeostatic tissue architecture is achieved without active cell migration. In contrast, both fibroblast proliferation and migration are key determinants of tissue repair following wounding. The results show that tissue-scale coordination is driven by the interdependence of cell proliferation and ECM deposition, paving the way for identifying new therapeutic strategies to enhance skin regeneration.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113774PMC
http://dx.doi.org/10.15252/msb.20178174DOI Listing
August 2018

Loxl2 is dispensable for dermal development, homeostasis and tumour stroma formation.

PLoS One 2018 28;13(6):e0199679. Epub 2018 Jun 28.

Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, London, United Kingdom.

Lysyl oxidase-like 2 (LOXL2) is a copper-dependent monoamine oxidase that contributes to the remodelling of the extracellular matrix (ECM) by cross linkage of collagen and elastin fibres and has emerged as a potential therapeutic target in cancer and fibrosis. In the skin, LOXL2 is essential for epidermal cell polarity and differentiation. However, its role in the dermis has not been evaluated. We found that Loxl2 is dispensable for mouse dermal development, maturation and homeostasis, yet affects dermal stiffness. Neither loss of Loxl2 nor increased Loxl2 expression affected dermal architecture following treatment with the phorbol ester TPA. Furthermore, Loxl2 expression did not alter the stroma of DMBA-TPA-induced tumours. We conclude that, although Loxl2 is expressed in both dermis and epidermis, its function appears largely confined to the epidermis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199679PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023175PMC
December 2018

Skin Cell Heterogeneity in Development, Wound Healing, and Cancer.

Trends Cell Biol 2018 09 25;28(9):709-722. Epub 2018 May 25.

King's College London, Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK. Electronic address:

Skin architecture and function depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, homeostasis and repair. While several stem cell populations have been identified in the epidermis with distinct locations and functions, it is now recognised that there is additional heterogeneity within the mesenchymal cells of the dermis. Here, we discuss recent insights into how these distinct cell populations are maintained and coordinated during development, homeostasis, and wound healing. We highlight the importance of the local environment, or niche, in cellular plasticity. We also discuss new mechanisms that have been identified as influencing wound repair and cancer progression.
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http://dx.doi.org/10.1016/j.tcb.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098245PMC
September 2018

Dermal Blimp1 Acts Downstream of Epidermal TGFβ and Wnt/β-Catenin to Regulate Hair Follicle Formation and Growth.

J Invest Dermatol 2017 11 28;137(11):2270-2281. Epub 2017 Jun 28.

King's College London Centre for Stem Cells and Regenerative Medicine, Great Maze Pond, London, UK. Electronic address:

B-lymphocyte-induced maturation protein 1 (Blimp1) is a transcriptional repressor that regulates cell growth and differentiation in multiple tissues, including skin. Although in the epidermis Blimp1 is important for keratinocyte and sebocyte differentiation, its role in dermal fibroblasts is unclear. Here we show that Blimp1 is dynamically regulated in dermal papilla cells during hair follicle (HF) morphogenesis and the postnatal hair cycle, preceding dermal Wnt/β-catenin activation. Blimp1 ablation in E12.5 mouse dermal fibroblasts delayed HF morphogenesis and growth and prevented new HF formation after wounding. By combining targeted quantitative PCR screens with bioinformatic analysis and experimental validation we demonstrated that Blimp1 is both a target and a mediator of key dermal papilla inductive signaling pathways including transforming growth factor-β and Wnt/β-catenin. Epidermal overexpression of stabilized β-catenin was able to override the HF defects in Blimp1 mutant mice, underlining the close reciprocal relationship between the dermal papilla and adjacent HF epithelial cells. Overall, our study reveals the functional role of Blimp1 in promoting the dermal papilla inductive signaling cascade that initiates HF growth.
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http://dx.doi.org/10.1016/j.jid.2017.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646946PMC
November 2017

Wounding induces dedifferentiation of epidermal Gata6 cells and acquisition of stem cell properties.

Nat Cell Biol 2017 Jun 15;19(6):603-613. Epub 2017 May 15.

King's College London Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Campus, Great Maze Pond, London SE1 9RT, UK.

The epidermis is maintained by multiple stem cell populations whose progeny differentiate along diverse, and spatially distinct, lineages. Here we show that the transcription factor Gata6 controls the identity of the previously uncharacterized sebaceous duct (SD) lineage and identify the Gata6 downstream transcription factor network that specifies a lineage switch between sebocytes and SD cells. During wound healing differentiated Gata6 cells migrate from the SD into the interfollicular epidermis and dedifferentiate, acquiring the ability to undergo long-term self-renewal and differentiate into a much wider range of epidermal lineages than in undamaged tissue. Our data not only demonstrate that the structural and functional complexity of the junctional zone is regulated by Gata6, but also reveal that dedifferentiation is a previously unrecognized property of post-mitotic, terminally differentiated cells that have lost contact with the basement membrane. This resolves the long-standing debate about the contribution of terminally differentiated cells to epidermal wound repair.
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http://dx.doi.org/10.1038/ncb3532DOI Listing
June 2017

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells.

Nat Commun 2017 03 23;8:14744. Epub 2017 Mar 23.

Centre for Stem Cells and Regenerative Medicine, Faculty of Life Sciences &Medicine, King's College London, 28th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, UK.

Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal and neoplastic (cutaneous squamous cell carcinoma, cSCC) human epidermal cells. The Hippo effector YAP was amongst the top positive growth regulators in both screens. By integrating the Hippo network interactome with our data sets, we identify WW-binding protein 2 (WBP2) as an important co-factor of YAP that enhances YAP/TEAD-mediated gene transcription. YAP and WPB2 are upregulated in actively proliferating cells of mouse and human epidermis and cSCC, and downregulated during terminal differentiation. WBP2 deletion in mouse skin results in reduced proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signalling. We propose that defective intercellular adhesion contributes to uncontrolled cSCC growth by preventing inhibition of YAP/WBP2.
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http://dx.doi.org/10.1038/ncomms14744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376649PMC
March 2017

Reply to Chi et al.

J Invest Dermatol 2017 01 13;137(1):247-248. Epub 2016 Sep 13.

Centre for Stem Cells and Regenerative Medicine at King's College London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2016.08.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641501PMC
January 2017

Inhibition of β-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing.

Development 2016 07 10;143(14):2522-35. Epub 2016 Jun 10.

King's College London Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital Campus, Great Maze Pond, London SE1 9RT, UK

New hair follicles (HFs) do not form in adult mammalian skin unless epidermal Wnt signalling is activated genetically or within large wounds. To understand the postnatal loss of hair forming ability we monitored HF formation at small circular (2 mm) wound sites. At P2, new HFs formed in back skin, but HF formation was markedly decreased by P21. Neonatal tail also formed wound-associated HFs, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with a reduction in Lrig1-positive papillary fibroblasts in wounds. Comparative gene expression profiling of back and tail dermis at P1 and dorsal fibroblasts at P2 and P50 showed a correlation between loss of HF formation and decreased expression of genes associated with proliferation and Wnt/β-catenin activity. Between P2 and P50, fibroblast density declined throughout the dermis and clones of fibroblasts became more dispersed. This correlated with a decline in fibroblasts expressing a TOPGFP reporter of Wnt activation. Surprisingly, between P2 and P50 there was no difference in fibroblast proliferation at the wound site but Wnt signalling was highly upregulated in healing dermis of P21 compared with P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds, whereas β-catenin activation reduced HF regeneration in neonatal wounds. Our data support a model whereby postnatal loss of hair forming ability in wounds reflects elevated dermal Wnt/β-catenin activation in the wound bed, increasing the abundance of fibroblasts that are unable to induce HF formation.
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http://dx.doi.org/10.1242/dev.131797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958333PMC
July 2016

Integrins synergise to induce expression of the MRTF-A-SRF target gene ISG15 for promoting cancer cell invasion.

J Cell Sci 2016 Apr 12;129(7):1391-403. Epub 2016 Feb 12.

Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried 82152, Germany

Integrin-mediated activation of small GTPases induces the polymerisation of G-actin into various actin structures and the release of the transcriptional co-activator MRTF from G-actin. Here we report that pan-integrin-null fibroblasts seeded on fibronectin and expressing β1- and/or αV-class integrin contained different G-actin pools, nuclear MRTF-A (also known as MKL1 or MAL) levels and MRTF-A-SRF activities. The nuclear MRTF-A levels and activities were highest in cells expressing both integrin classes, lower in cells expressing β1 integrins and lowest in cells expressing the αV integrins. Quantitative proteomics and transcriptomics analyses linked the differential MRTF-A activities to the expression of the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), which is known to modify focal adhesion and cytoskeletal proteins. The malignant breast cancer cell line MDA-MB-231 expressed high levels of β1 integrins, ISG15 and ISGylated proteins, which promoted invasive properties, whereas non-invasive MDA-MB-468 and MCF-7 cell lines expressed low levels of β1 integrins, ISG15 and ISGylated proteins. Our findings suggest that integrin-adhesion-induced MRTF-A-SRF activation and ISG15 expression constitute a newly discovered signalling circuit that promotes cell migration and invasion.
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http://dx.doi.org/10.1242/jcs.177592DOI Listing
April 2016

Kindlin-2 cooperates with talin to activate integrins and induces cell spreading by directly binding paxillin.

Elife 2016 Jan 27;5:e10130. Epub 2016 Jan 27.

Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.

Integrins require an activation step prior to ligand binding and signaling. How talin and kindlin contribute to these events in non-hematopoietic cells is poorly understood. Here we report that fibroblasts lacking either talin or kindlin failed to activate β1 integrins, adhere to fibronectin (FN) or maintain their integrins in a high affinity conformation induced by Mn(2+). Despite compromised integrin activation and adhesion, Mn(2+) enabled talin- but not kindlin-deficient cells to initiate spreading on FN. This isotropic spreading was induced by the ability of kindlin to directly bind paxillin, which in turn bound focal adhesion kinase (FAK) resulting in FAK activation and the formation of lamellipodia. Our findings show that talin and kindlin cooperatively activate integrins leading to FN binding and adhesion, and that kindlin subsequently assembles an essential signaling node at newly formed adhesion sites in a talin-independent manner.
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http://dx.doi.org/10.7554/eLife.10130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749545PMC
January 2016

The kindlin family: functions, signaling properties and implications for human disease.

J Cell Sci 2016 Jan;129(1):17-27

Max Planck Institute of Biochemistry, Martinsried 82152, Germany

The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation. Another hallmark of kindlins is their involvement in disease. Mutations in the KINDLIN-1 (also known as FERMT1) gene cause Kindler syndrome (KS)--in which mainly skin and intestine are affected, whereas mutations in the KINDLIN-3 (also known as FERMT3) gene cause leukocyte adhesion deficiency type III (LAD III), which is characterized by impaired extravasation of blood effector cells and severe, spontaneous bleedings. Also, aberrant expression of kindlins in various forms of cancer and in tissue fibrosis has been reported. Although the malfunctioning of integrins represent a major cause leading to kindlin-associated diseases, increasing evidence also point to integrin-independent functions of kindlins that play an important role in the pathogenesis of certain disease aspects. Furthermore, isoform-specific kindlin functions have been discovered, explaining, for example, why loss of kindlins differentially affects tissue stem cell homeostasis or tumor development. This Commentary focuses on new and isoform-specific kindlin functions in different tissues and discusses their potential role in disease development and progression.
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http://dx.doi.org/10.1242/jcs.161190DOI Listing
January 2016

Fate of Prominin-1 Expressing Dermal Papilla Cells during Homeostasis, Wound Healing and Wnt Activation.

J Invest Dermatol 2015 Dec 19;135(12):2926-2934. Epub 2015 Aug 19.

King's College London, Centre for Stem Cells and Regenerative Medicine, Guy's Hospital Campus, London, UK. Electronic address:

Prominin-1/CD133 (Prom1) is expressed by fibroblasts in the dermal papilla (DP) of the hair follicle (HF). By examining endogenous Prom1 expression and expression of LacZ in the skin of Prom1CreERLacZ (Prom1C-L) mice, in which a CreERT2-IRES-nuclear LacZ cassette is knocked into the first ATG codon of Prom1, we confirmed that Prom1 is expressed in the DP of all developing HFs and also by postnatal anagen follicles. To analyze the fate of Prom1+ DP cells, we crossed Prom1C-L mice with Rosa26-CAG flox/stop/flox tdTomato reporter mice and applied 4-hydroxytamoxifen (4OHT) to back skin at postnatal day (P) 1 and P2. We detected tdTomato+ cells in ~50% of DPs. The proportion of labeled cells per DP increased between P5 and P63, while the total number of cells per DP declined. Following full thickness wounding, there was no migration of tdTomato-labeled cells out of the DP. When β-catenin was activated in Prom1+ DP cells there was an increase in the size of anagen and telogen DP, but the proportion of tdTomato-labeled cells did not increase. We conclude that Prom1+ DP cells do not contribute to dermal repair but are nevertheless capable of regulating DP size via β-catenin-mediated intercellular communication.
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http://dx.doi.org/10.1038/jid.2015.319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650270PMC
December 2015

Kindlin-3-mediated integrin adhesion is dispensable for quiescent but essential for activated hematopoietic stem cells.

J Exp Med 2015 Aug 17;212(9):1415-32. Epub 2015 Aug 17.

Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany

Hematopoietic stem cells (HSCs) generate highly dividing hematopoietic progenitor cells (HPCs), which produce all blood cell lineages. HSCs are usually quiescent, retained by integrins in specific niches, and become activated when the pools of HPCs decrease. We report that Kindlin-3-mediated integrin activation controls homing of HSCs to the bone marrow (BM) and the retention of activated HSCs and HPCs but not of quiescent HSCs in their BM niches. Consequently, Kindlin-3-deficient HSCs enter quiescence and remain in the BM when cotransplanted with wild-type hematopoietic stem and progenitor cells (HSPCs), whereas they are hyperactivated and lost in the circulation when wild-type HSPCs are absent, leading to their exhaustion and reduced survival of recipients. The accumulation of HSPCs in the circulation of leukocyte adhesion deficiency type III patients, who lack Kindlin-3, underlines the conserved functions of Kindlin-3 in man and the importance of our findings for human disease.
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http://dx.doi.org/10.1084/jem.20150269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548061PMC
August 2015

Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation.

Nat Med 2014 Apr 30;20(4):350-9. Epub 2014 Mar 30.

Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany.

Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)β(6) integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β-mediated growth-inhibitory signals and Wnt-β-catenin-mediated growth-promoting signals.
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http://dx.doi.org/10.1038/nm.3490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982140PMC
April 2014

Visualization of endothelial actin cytoskeleton in the mouse retina.

PLoS One 2012 24;7(10):e47488. Epub 2012 Oct 24.

Walter Brendel Centre of Experimental Medicine and Munich Heart Alliance, Ludwig-Maximilians University Munich, Munich, Germany.

Angiogenesis requires coordinated changes in cell shape of endothelial cells (ECs), orchestrated by the actin cytoskeleton. The mechanisms that regulate this rearrangement in vivo are poorly understood - largely because of the difficulty to visualize filamentous actin (F-actin) structures with sufficient resolution. Here, we use transgenic mice expressing Lifeact-EGFP to visualize F-actin in ECs. We show that in the retina, Lifeact-EGFP expression is largely restricted to ECs allowing detailed visualization of F-actin in ECs in situ. Lifeact-EGFP labels actin associated with cell-cell junctions, apical and basal membranes and highlights actin-based structures such as filopodia and stress fiber-like cytoplasmic bundles. We also show that in the skin and the skeletal muscle, Lifeact-EGFP is highly expressed in vascular mural cells (vMCs), enabling vMC imaging. In summary, our results indicate that the Lifeact-EGFP transgenic mouse in combination with the postnatal retinal angiogenic model constitutes an excellent system for vascular cell biology research. Our approach is ideally suited to address structural and mechanistic details of angiogenic processes, such as endothelial tip cell migration and fusion, EC polarization or lumen formation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047488PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480364PMC
April 2013

Integrin-linked kinase at a glance.

J Cell Sci 2012 Apr;125(Pt 8):1839-43

Max Planck Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany.

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http://dx.doi.org/10.1242/jcs.093864DOI Listing
April 2012

YB-1 dependent virotherapy in combination with temozolomide as a multimodal therapy approach to eradicate malignant glioma.

Int J Cancer 2011 Sep 6;129(5):1265-76. Epub 2011 Jan 6.

Institut für Experimentelle Onkologie und Therapieforschung, Klinikum Rechts der Isar, Munich, Germany.

The human Y-box binding protein 1 (YB-1) is known to be a promising target for cancer therapy. We have demonstrated that YB-1 plays an important role in the adenoviral life cycle by regulating the adenoviral E2-gene expression. Thus, we studied the oncolytic effect of the recombinant adenovirus Ad-Delo3-RGD, in which the transactivation domain CR3 of the E1A protein is ablated to enable viral replication only in YB-1 positive cancer cells. In vitro Southern Blot analysis and cytopathic effect assays demonstrate high anti-glioma potency, which was significantly increased in combination with temozolomide (TMZ), daunorubicin and cisplatin. Since vascular endothelial growth factor (VEGF) is thought to promote the hypervascular phenotype of primary, malignant brain tumors, we also tested Ad-Delo3-RGD in regard to the inhibition of VEGF expression. Indeed, we found that Ad-Delo3-RGD induced VEGF down regulation, which was even amplified under hypoxic conditions. Tumor-bearing nudemice treated with the YB-1 dependent oncolytic adenovirus showed significantly smaller tumors than untreated controls. Furthermore, combination therapy with TMZ led to a regression in all treated animals with complete tumor regression in 33 % of analyzed mice, which was verified by bioluminescence imaging and histological studies. In addition, histopathological evaluation revealed enhanced apoptosis and a reduction in tumor vessel formation, indicating that Ad-Delo3-RGD has an anti-angiogenic effect in addition to its oncolytic capacity in vivo. Hence, our results demonstrate that the combination therapy of YB-1 dependent virotherapy and TMZ is effective in a xenograft glioma mouse model and might be useful in a YB-1 based clinical setting.
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http://dx.doi.org/10.1002/ijc.25783DOI Listing
September 2011

Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction.

PLoS Genet 2008 Dec 5;4(12):e1000289. Epub 2008 Dec 5.

Department of Molecular Medicine, Max-Planck Institute of Biochemistry, Martinsried, Germany.

Kindler Syndrome (KS), characterized by transient skin blistering followed by abnormal pigmentation, skin atrophy, and skin cancer, is caused by mutations in the FERMT1 gene. Although a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown. The FERMT1 gene product belongs to a family of focal adhesion proteins (Kindlin-1, -2, -3) that bind several beta integrin cytoplasmic domains. Here, we show that deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC. This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation, leading to detachment of this barrier followed by a destructive inflammatory response.
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http://dx.doi.org/10.1371/journal.pgen.1000289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585060PMC
December 2008