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Article ; Online: Fell Muir Lecture: Collagen fibril formation in vitro and in vivo.

Kadler, Karl E

International journal of experimental pathology

2017 Volume 98, Issue 1, Page(s) 4–16

Abstract: It is a great honour to be awarded the Fell Muir Prize for 2016 by the British Society of Matrix Biology. As recipient of the prize, I am taking the opportunity to write a minireview on collagen fibrillogenesis, which has been the focus of my research ... ...

Abstract	It is a great honour to be awarded the Fell Muir Prize for 2016 by the British Society of Matrix Biology. As recipient of the prize, I am taking the opportunity to write a minireview on collagen fibrillogenesis, which has been the focus of my research for 33 years. This is the process by which triple helical collagen molecules assemble into centimetre-long fibrils in the extracellular matrix of animals. The fibrils appeared a billion years ago at the dawn of multicellular animal life as the primary scaffold for tissue morphogenesis. The fibrils occur in exquisite three-dimensional architectures that match the physical demands of tissues, for example orthogonal lattices in cornea, basket weaves in skin and blood vessels, and parallel bundles in tendon, ligament and nerves. The question of how collagen fibrils are formed was posed at the end of the nineteenth century. Since then, we have learned about the structure of DNA and the peptide bond, understood how plants capture the sun's energy, cloned animals, discovered antibiotics and found ways of editing our genome in the pursuit of new cures for diseases. However, how cells generate tissues from collagen fibrils remains one of the big unsolved mysteries in biology. In this review, I will give a personal account of the topic and highlight some of the approaches that my research group are taking to find new insights.
MeSH term(s)	Animals ; Chick Embryo ; Extracellular Matrix/metabolism ; Extracellular Matrix/ultrastructure ; Fibrillar Collagens/metabolism ; Fibrillar Collagens/ultrastructure ; Fibroblasts/metabolism ; Fibroblasts/ultrastructure ; Humans ; Microscopy, Electron ; Procollagen/metabolism ; Skin/metabolism ; Skin/ultrastructure ; Tendons/metabolism ; Tendons/ultrastructure
Chemical Substances	Fibrillar Collagens ; Procollagen
Language	English
Publishing date	2017-05-16
Publishing country	England
Document type	Journal Article ; Lecture ; Review
ZDB-ID	1016006-1
ISSN	1365-2613 ; 0958-4625 ; 0007-1021 ; 0959-9673
ISSN (online)	1365-2613
ISSN	0958-4625 ; 0007-1021 ; 0959-9673
DOI	10.1111/iep.12224
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Article ; Online: The needle in the ECM haystack.

Kadler, Karl E

Nature reviews. Molecular cell biology

2014 Volume 15, Issue 12, Page(s) 769

MeSH term(s)	Actin Cytoskeleton ; Animals ; Cell Biology/history ; Collagen/chemistry ; Collagen/metabolism ; Embryo, Mammalian/cytology ; History, 20th Century ; Rabbits
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2014-10-22
Publishing country	England
Document type	Historical Article ; Journal Article
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/nrm3899
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Zs.A 5446: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Dynamic High-Sensitivity Quantitation of Procollagen-I by Endogenous CRISPR-Cas9 NanoLuciferase Tagging.

Calverley, Ben C / Kadler, Karl E / Pickard, Adam

Cells

2020 Volume 9, Issue 9

Abstract: The ability to quantitate a protein of interest temporally and spatially at subcellular resolution in living cells would generate new opportunities for research and drug discovery, but remains a major technical challenge. Here, we describe dynamic, high- ... ...

Abstract	The ability to quantitate a protein of interest temporally and spatially at subcellular resolution in living cells would generate new opportunities for research and drug discovery, but remains a major technical challenge. Here, we describe dynamic, high-sensitivity protein quantitation technique using NanoLuciferase (NLuc) tagging, which is effective across microscopy and multiwell platforms. Using collagen as a test protein, the CRISPR-Cas9-mediated introduction of nluc (encoding NLuc) into the Col1a2 locus enabled the simplification and miniaturisation of procollagen-I (PC-I) quantitation. Collagen was chosen because of the clinical interest in its dysregulation in cardiovascular and musculoskeletal disorders, and in fibrosis, which is a confounding factor in 45% of deaths, including those brought about by cancer. Collagen is also the cargo protein of choice for studying protein secretion because of its unusual shape and size. However, the use of overexpression promoters (which drowns out endogenous regulatory mechanisms) is often needed to achieve good signal/noise ratios in fluorescence microscopy of tagged collagen. We show that endogenous knock-in of NLuc, combined with its high brightness, negates the need to use exogenous promoters, preserves the circadian regulation of collagen synthesis and the responsiveness to TGF-β, and enables time-lapse microscopy of intracellular transport compartments containing procollagen cargo. In conclusion, we demonstrate the utility of CRISPR-Cas9-mediated endogenous NLuc tagging to robustly quantitate extracellular, intracellular, and subcellular protein levels and localisation.
MeSH term(s)	Animals ; CRISPR-Cas Systems ; Collagen Type I/analysis ; Collagen Type I/metabolism ; Luminescence ; Mice ; NIH 3T3 Cells
Chemical Substances	Col1a2 protein, mouse ; Collagen Type I
Language	English
Publishing date	2020-09-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9092070
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Article ; Online: Modeling collagen fibril self-assembly from extracellular medium in embryonic tendon.

Revell, Christopher K / Herrera, Jeremy A / Lawless, Craig / Lu, Yinhui / Kadler, Karl E / Chang, Joan / Jensen, Oliver E

Biophysical journal

2023 Volume 122, Issue 16, Page(s) 3219–3237

Abstract: Collagen is a key structural component of multicellular organisms and is arranged in a highly organized manner. In structural tissues such as tendons, collagen forms bundles of parallel fibers between cells, which appear within a 24-h window between ... ...

Abstract	Collagen is a key structural component of multicellular organisms and is arranged in a highly organized manner. In structural tissues such as tendons, collagen forms bundles of parallel fibers between cells, which appear within a 24-h window between embryonic day 13.5 (E13.5) and E14.5 during mouse embryonic development. Current models assume that the organized structure of collagen requires direct cellular control, whereby cells actively lay down collagen fibrils from cell surfaces. However, such models appear incompatible with the time and length scales of fibril formation. We propose a phase-transition model to account for the rapid development of ordered fibrils in embryonic tendon, reducing reliance on active cellular processes. We develop phase-field crystal simulations of collagen fibrillogenesis in domains derived from electron micrographs of inter-cellular spaces in embryonic tendon and compare results qualitatively and quantitatively to observed patterns of fibril formation. To test the prediction of this phase-transition model that free protomeric collagen should exist in the inter-cellular spaces before the formation of observable fibrils, we use laser-capture microdissection, coupled with mass spectrometry, which demonstrates steadily increasing free collagen in inter-cellular spaces up to E13.5, followed by a rapid reduction of free collagen that coincides with the appearance of less-soluble collagen fibrils. The model and measurements together provide evidence for extracellular self-assembly of collagen fibrils in embryonic mouse tendon, supporting an additional mechanism for rapid collagen fibril formation during embryonic development.
MeSH term(s)	Animals ; Mice ; Embryonic Development ; Extracellular Matrix/metabolism ; Collagen/metabolism ; Cell Membrane ; Tendons/chemistry ; Tendons/metabolism
Chemical Substances	Collagen (9007-34-5)
Language	English
Publishing date	2023-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2023.07.001
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The clock transcription factor BMAL1 is a key regulator of extracellular matrix homeostasis and cell fate in the intervertebral disc.

Dudek, Michal / Morris, Honor / Rogers, Natalie / Pathiranage, Dharshika Rj / Raj, Sujitha Saba / Chan, Danny / Kadler, Karl E / Hoyland, Judith / Meng, Qing-Jun

Matrix biology : journal of the International Society for Matrix Biology

2023 Volume 122, Page(s) 1–9

Abstract: ... to anticipate daily rhythmic changes in their environment. Chronic disruption to circadian rhythms (e.g ...

Abstract	The circadian clock in mammals temporally coordinates physiological and behavioural processes to anticipate daily rhythmic changes in their environment. Chronic disruption to circadian rhythms (e.g., through ageing or shift work) is thought to contribute to a multitude of diseases, including degeneration of the musculoskeletal system. The intervertebral disc (IVD) in the spine contains circadian clocks which control ∼6% of the transcriptome in a rhythmic manner, including key genes involved in extracellular matrix (ECM) homeostasis. However, it remains largely unknown to what extent the local IVD molecular clock is required to drive rhythmic gene transcription and IVD physiology. In this work, we identified profound age-related changes of ECM microarchitecture and an endochondral ossification-like phenotype in the annulus fibrosus (AF) region of the IVD in the Col2a1-Bmal1 knockout mice. Circadian time series RNA-Seq of the whole IVD in Bmal1 knockout revealed loss of circadian patterns in gene expression, with an unexpected emergence of 12 h ultradian rhythms, including FOXO transcription factors. Further RNA sequencing of the AF tissue identified region-specific changes in gene expression, evidencing a loss of AF phenotype markers and a dysregulation of ECM and FOXO pathways in Bmal1 knockout mice. Consistent with an up-regulation of FOXO1 mRNA and protein levels in Bmal1 knockout IVDs, inhibition of FOXO1 in AF cells suppressed their osteogenic differentiation. Collectively, these data highlight the importance of the local molecular clock mechanism in the maintenance of the cell fate and ECM homeostasis of the IVD. Further studies may identify potential new molecular targets for alleviating IVD degeneration.
MeSH term(s)	Animals ; Mice ; ARNTL Transcription Factors/genetics ; ARNTL Transcription Factors/metabolism ; Cell Differentiation ; Extracellular Matrix/genetics ; Extracellular Matrix/metabolism ; Homeostasis ; Intervertebral Disc/metabolism ; Intervertebral Disc Degeneration/genetics ; Mammals/metabolism ; Mice, Knockout ; Osteogenesis/genetics
Chemical Substances	ARNTL Transcription Factors ; Bmal1 protein, mouse
Language	English
Publishing date	2023-07-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1183793-7
ISSN	1569-1802 ; 0945-053X
ISSN (online)	1569-1802
ISSN	0945-053X
DOI	10.1016/j.matbio.2023.07.002
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Article ; Online: Circulating Biomarkers Specific to Myocardial Extracellular Matrix Are Required to Embrace the Heterogeneity of HFpEF.

Lewis, Gavin A / Schelbert, Erik B / Kadler, Karl E / Miller, Christopher A

Journal of the American College of Cardiology

2020 Volume 76, Issue 20, Page(s) 2416–2417

MeSH term(s)	Aminobutyrates ; Biomarkers ; Biphenyl Compounds ; Drug Combinations ; Extracellular Matrix ; Heart Failure/diagnosis ; Humans ; Stroke Volume ; Tetrazoles ; Valsartan
Chemical Substances	Aminobutyrates ; Biomarkers ; Biphenyl Compounds ; Drug Combinations ; Tetrazoles ; Valsartan (80M03YXJ7I) ; sacubitril and valsartan sodium hydrate drug combination (WB8FT61183)
Language	English
Publishing date	2020-10-27
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	605507-2
ISSN	1558-3597 ; 0735-1097
ISSN (online)	1558-3597
ISSN	0735-1097
DOI	10.1016/j.jacc.2020.08.084
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Zs.A 1846: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Collagen fibril assembly: New approaches to unanswered questions.

Revell, Christopher K / Jensen, Oliver E / Shearer, Tom / Lu, Yinhui / Holmes, David F / Kadler, Karl E

Matrix biology plus

2021 Volume 12, Page(s) 100079

Abstract: Collagen fibrils are essential for metazoan life. They are the largest, most abundant, and most versatile protein polymers in animals, where they occur in the extracellular matrix to form the structural basis of tissues and organs. Collagen fibrils were ... ...

Abstract	Collagen fibrils are essential for metazoan life. They are the largest, most abundant, and most versatile protein polymers in animals, where they occur in the extracellular matrix to form the structural basis of tissues and organs. Collagen fibrils were first observed at the turn of the 20th century. During the last 40 years, the genes that encode the family of collagens have been identified, the structure of the collagen triple helix has been solved, the many enzymes involved in the post-translational modifications of collagens have been identified, mutations in the genes encoding collagen and collagen-associated proteins have been linked to heritable disorders, and changes in collagen levels have been associated with a wide range of diseases, including cancer. Yet despite extensive research, a full understanding of how cells assemble collagen fibrils remains elusive. Here, we review current models of collagen fibril self-assembly, and how cells might exert control over the self-assembly process to define the number, length and organisation of fibrils in tissues.
Language	English
Publishing date	2021-07-13
Publishing country	Netherlands
Document type	Journal Article
ISSN	2590-0285
ISSN (online)	2590-0285
DOI	10.1016/j.mbplus.2021.100079
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Article ; Online: Dynamic High-Sensitivity Quantitation of Procollagen-I by Endogenous CRISPR-Cas9 NanoLuciferase Tagging

Ben C. Calverley / Karl E. Kadler / Adam Pickard

Cells, Vol 9, Iss 2070, p

2020 Volume 2070

Abstract	The ability to quantitate a protein of interest temporally and spatially at subcellular resolution in living cells would generate new opportunities for research and drug discovery, but remains a major technical challenge. Here, we describe dynamic, high-sensitivity protein quantitation technique using NanoLuciferase (NLuc) tagging, which is effective across microscopy and multiwell platforms. Using collagen as a test protein, the CRISPR-Cas9-mediated introduction of nluc (encoding NLuc) into the Col1a2 locus enabled the simplification and miniaturisation of procollagen-I (PC-I) quantitation. Collagen was chosen because of the clinical interest in its dysregulation in cardiovascular and musculoskeletal disorders, and in fibrosis, which is a confounding factor in 45% of deaths, including those brought about by cancer. Collagen is also the cargo protein of choice for studying protein secretion because of its unusual shape and size. However, the use of overexpression promoters (which drowns out endogenous regulatory mechanisms) is often needed to achieve good signal/noise ratios in fluorescence microscopy of tagged collagen. We show that endogenous knock-in of NLuc, combined with its high brightness, negates the need to use exogenous promoters, preserves the circadian regulation of collagen synthesis and the responsiveness to TGF-β, and enables time-lapse microscopy of intracellular transport compartments containing procollagen cargo. In conclusion, we demonstrate the utility of CRISPR-Cas9-mediated endogenous NLuc tagging to robustly quantitate extracellular, intracellular, and subcellular protein levels and localisation.
Keywords	hedging ; transaction costs ; dynamic programming ; risk management ; postdecision state variable ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells.

Pickard, Adam / Calverley, Ben C / Chang, Joan / Garva, Richa / Lu, Yinhui / Kadler, Karl E

bioRxiv : the preprint server for biology

2021

Abstract: COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, vaccine escape variants might arise leading to a re-emergence of COVID. In anticipation of such a scenario, ...

Abstract	COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, vaccine escape variants might arise leading to a re-emergence of COVID. In anticipation of such a scenario, the identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2- DOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in- line with reported proteinuria and liver damage in patients with COVID-19. We identified 35 drugs that reduced viral replication in Vero and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.
Language	English
Publishing date	2021-03-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.01.31.428851
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Article ; Online: Collagen Assembly at the Cell Surface: Dogmas Revisited.

Musiime, Moses / Chang, Joan / Hansen, Uwe / Kadler, Karl E / Zeltz, Cédric / Gullberg, Donald

Cells

2021 Volume 10, Issue 3

Abstract: With the increased awareness about the importance of the composition, organization, and stiffness of the extracellular matrix (ECM) for tissue homeostasis, there is a renewed need to understand the details of how cells recognize, assemble and remodel the ...

Abstract	With the increased awareness about the importance of the composition, organization, and stiffness of the extracellular matrix (ECM) for tissue homeostasis, there is a renewed need to understand the details of how cells recognize, assemble and remodel the ECM during dynamic tissue reorganization events. Fibronectin (FN) and fibrillar collagens are major proteins in the ECM of interstitial matrices. Whereas FN is abundant in cell culture studies, it is often only transiently expressed in the acute phase of wound healing and tissue regeneration, by contrast fibrillar collagens form a persistent robust scaffold in healing and regenerating tissues. Historically fibrillar collagens in interstitial matrices were seen merely as structural building blocks. Cell anchorage to the collagen matrix was thought to be indirect and occurring via proteins like FN and cell surface-mediated collagen fibrillogenesis was believed to require a FN matrix. The isolation of four collagen-binding integrins have challenged this dogma, and we now know that cells anchor directly to monomeric forms of fibrillar collagens via the α1β1, α2β1, α10β1 and α11β1 integrins. The binding of these integrins to the mature fibrous collagen matrices is more controversial and depends on availability of integrin-binding sites. With increased awareness about the importance of characterizing the total integrin repertoire on cells, including the integrin collagen receptors, the idea of an absolute dependence on FN for cell-mediated collagen fibrillogenesis needs to be re-evaluated. We will summarize data suggesting that collagen-binding integrins in vitro and in vivo are perfectly well suited for nucleating and supporting collagen fibrillogenesis, independent of FN.
MeSH term(s)	Animals ; Binding Sites ; Cell Adhesion ; Cell Membrane/metabolism ; Cell-Matrix Junctions/metabolism ; Extracellular Matrix/metabolism ; Fibrillar Collagens/metabolism ; Fibronectins/metabolism ; Humans ; Integrin alpha Chains/metabolism ; Integrin beta Chains/metabolism ; Protein Binding ; Protein Multimerization
Chemical Substances	Fibrillar Collagens ; Fibronectins ; Integrin alpha Chains ; Integrin beta Chains
Language	English
Publishing date	2021-03-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10030662
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