Author
Fiona M. Watt
Other affiliations: Wellcome Trust Centre for Stem Cell Research, Cancer Research UK, University College London ...read more
Bio: Fiona M. Watt is an academic researcher from King's College London. The author has contributed to research in topics: Cellular differentiation & Stem cell. The author has an hindex of 113, co-authored 476 publications receiving 44949 citations. Previous affiliations of Fiona M. Watt include Wellcome Trust Centre for Stem Cell Research & Cancer Research UK.
Papers published on a yearly basis
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TL;DR: Both intrinsic and extrinsic signals regulate stem cell fate and some of these signals have now been identified and can be exploited in the application of stem cells to tissue replacement therapy.
Abstract: Stem cells are currently in the news for two reasons: the successful cultivation of human embryonic stem cell lines and reports that adult stem cells can differentiate into developmentally unrelated cell types, such as nerve cells into blood cells Both intrinsic and extrinsic signals regulate stem cell fate and some of these signals have now been identified Certain aspects of the stem cell microenvironment, or niche, are conserved between tissues, and this can be exploited in the application of stem cells to tissue replacement therapy
1,798 citations
Francis Crick Institute1, Fox Chase Cancer Center2, Washington University in St. Louis3, Cold Spring Harbor Laboratory4, Salk Institute for Biological Studies5, Howard Hughes Medical Institute6, Cornell University7, Goethe University Frankfurt8, Fred Hutchinson Cancer Research Center9, Massachusetts Institute of Technology10, Harvard University11, University of Manchester12, New York University13, University of Texas Health Science Center at Houston14, University of Pennsylvania15, Stony Brook University16, Hofstra University17, Weizmann Institute of Science18, Oregon Health & Science University19, University of California, San Francisco20, King's College London21, Johns Hopkins University22
TL;DR: This Consensus Statement issues a call to action for all cancer researchers to standardize assays and report metadata in studies of cancer-associated fibroblasts to advance the understanding of this important cell type in the tumour microenvironment.
Abstract: Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
1,616 citations
TL;DR: It is concluded that stem cells exert a mechanical force on collagen fibres and gauge the feedback to make cell-fate decisions, and are regulated by the elastic modulus of PAAm.
Abstract: To investigate how substrate properties influence stem-cell fate, we cultured single human epidermal stem cells on polydimethylsiloxane (PDMS) and polyacrylamide (PAAm) hydrogel surfaces, 0.1 kPa-2.3 MPa in stiffness, with a covalently attached collagen coating. Cell spreading and differentiation were unaffected by polydimethylsiloxane stiffness. However, cells on polyacrylamide of low elastic modulus (0.5 kPa) could not form stable focal adhesions and differentiated as a result of decreased activation of the extracellular-signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling pathway. The differentiation of human mesenchymal stem cells was also unaffected by PDMS stiffness but regulated by the elastic modulus of PAAm. Dextran penetration measurements indicated that polyacrylamide substrates of low elastic modulus were more porous than stiff substrates, suggesting that the collagen anchoring points would be further apart. We then changed collagen crosslink concentration and used hydrogel-nanoparticle substrates to vary anchoring distance at constant substrate stiffness. Lower collagen anchoring density resulted in increased differentiation. We conclude that stem cells exert a mechanical force on collagen fibres and gauge the feedback to make cell-fate decisions.
1,393 citations
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Howard Hughes Medical Institute1, Broad Institute2, Massachusetts Institute of Technology3, Wellcome Trust Sanger Institute4, European Bioinformatics Institute5, University of Cambridge6, Harvard University7, Weizmann Institute of Science8, University of Zurich9, Laboratory of Molecular Biology10, Utrecht University11, École Polytechnique Fédérale de Lausanne12, University of Pennsylvania13, German Cancer Research Center14, Heidelberg University15, Ludwig Maximilian University of Munich16, John Radcliffe Hospital17, Newcastle University18, Stanford University19, University of Oxford20, University of California, San Francisco21, Allen Institute for Brain Science22, Karolinska Institutet23, Royal Institute of Technology24, Icahn School of Medicine at Mount Sinai25, University of Cape Town26, University Medical Center Groningen27, Radboud University Nijmegen28, Kettering University29, University of Edinburgh30, Babraham Institute31, New York University32, Netherlands Cancer Institute33, Ragon Institute of MGH, MIT and Harvard34, University of Texas Health Science Center at Houston35, Technische Universität München36, Technical University of Denmark37, University of California, Berkeley38, King's College London39, California Institute of Technology40
TL;DR: An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease.
Abstract: The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
1,391 citations
TL;DR: Some of the evidence that ECM components regulate differentiation and development are summarized, the regulatory mechanisms involved are described and the intracellular events that may transduce signals are discussed.
Abstract: Differentiation is a continuously regulated process and interactions between the cell and its environment play a major role in maintaining stable expression of differentiation specific genes (Blau and Baltimore, 1991). An important component of the cellular environment is the extracel-lular matrix (ECM), which is composed of glycoproteins, proteoglycans and glycosaminoglycans that are secreted and assembled locally into an organised network to which cells adhere (Hay, 1981). An ECM is present within mam-malian embryos from the two-cell stage and is a component of the environment of all cell types, although the composition of the ECM and the spatial relationships between cells and ECM differ between tissues. Cells may be completely surrounded by ECM, as is the case for chondrocytes, or may contact the ECM only at one surface, as exemplified by epithelial and endothelial cells. In some tissues only a proportion of the cells are exposed to ECM: for example , in stratified epithelia. The ECM offers structural support for cells, and can also act as a physical barrier or selective filter to soluble molecules. It has been clear for many years (Grobstein, 1954; Bis-sell et al., 1982) that the ECM plays a role in regulating the differentiated phenotype of cells (reviewed by Watt, 1986), but the mechanisms involved remained largely mysterious until recently, when cell-binding sites within individual ECM glycoproteins and specific ECM receptors were identified. The cell-binding sites were mapped by using pro-teolytic fragments and synthetic peptides to define the minimal sequences responsible for adhesive activity. In the case of fibronectin, the primary determinant of cell-binding activity for many cell types resides in the sequence GRGDSP, which occurs in one of the type III repeats that form the central domain of the molecule (Ruoslahti and Pierschbacher, 1987). Subsequently, RGD-containing sequences have been found in other matrix proteins, and additional short linear adhesive sequence motifs have been defined, although it is clear that the three-dimensional structure of matrix proteins is also an important determinant of adhesive activity (reviewed by Humphries, 1990). Affinity chromatography techniques, together with adhesion-perturbing antibodies that recognise specific plasma membrane glycoproteins, allowed the identification of ECM receptors, many of which belong to the integrin family of α/β het-erodimers (Ruoslahti and Pierschbacher, 1987; Hynes, 1987). In this review, we will summarise some of the evidence that ECM components regulate differentiation and development , describe the regulatory mechanisms involved and, finally, discuss the intracellular events that may transduce signals …
1,241 citations
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TL;DR: It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration.
Abstract: Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.
12,395 citations
10,063 citations
TL;DR: Stem cell biology has come of age: Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine.
Abstract: Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis.
8,999 citations
TL;DR: A strategy to "anchor" diverse datasets together, enabling us to integrate single-cell measurements not only across scRNA-seq technologies, but also across different modalities.
7,892 citations
TL;DR: An analytical strategy for integrating scRNA-seq data sets based on common sources of variation is introduced, enabling the identification of shared populations across data sets and downstream comparative analysis.
Abstract: Computational single-cell RNA-seq (scRNA-seq) methods have been successfully applied to experiments representing a single condition, technology, or species to discover and define cellular phenotypes. However, identifying subpopulations of cells that are present across multiple data sets remains challenging. Here, we introduce an analytical strategy for integrating scRNA-seq data sets based on common sources of variation, enabling the identification of shared populations across data sets and downstream comparative analysis. We apply this approach, implemented in our R toolkit Seurat (http://satijalab.org/seurat/), to align scRNA-seq data sets of peripheral blood mononuclear cells under resting and stimulated conditions, hematopoietic progenitors sequenced using two profiling technologies, and pancreatic cell 'atlases' generated from human and mouse islets. In each case, we learn distinct or transitional cell states jointly across data sets, while boosting statistical power through integrated analysis. Our approach facilitates general comparisons of scRNA-seq data sets, potentially deepening our understanding of how distinct cell states respond to perturbation, disease, and evolution.
7,741 citations