Sara Wickström

Sara Wickström
Max Planck Institute for Biology of Ageing | AGE · Research Group Wickström

MD, PhD

About

84
Publications
10,094
Reads
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4,433
Citations
Additional affiliations
September 2010 - present
Max Planck Institute for Biology of Ageing
Position
  • Max Planck Research Group Leader
April 2005 - August 2010
Max Planck Institute of Biochemistry
Position
  • PostDoc Position

Publications

Publications (84)
Article
Cells are continuously exposed to tissue-specific extrinsic forces that are counteracted by cell-intrinsic force generation through the actomyosin cytoskeleton and alterations in the material properties of various cellular components, including the nucleus. Forces impact nuclei both directly through inducing deformation, which is sensed by various...
Article
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Mechanical inputs give rise to p38 and JNK activation, which mediate adaptive physiological responses in various tissues. In skeletal muscle, contraction-induced p38 and JNK signaling ensure adaptation to exercise, muscle repair, and hypertrophy. However, the mechanisms by which muscle fibers sense mechanical load to activate this signaling have re...
Article
Cells and tissues generate and are exposed to various mechanical forces that act across a range of scales, from tissues to cells to organelles. Forces provide crucial signals to inform cell behaviour during development and adult tissue homeostasis, and alterations in forces and in their downstream mechanotransduction pathways can influence disease...
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Significance The pseudokinase integrin-linked kinase (ILK) is a central component of focal adhesions, cytoplasmic multiprotein complexes that integrate and transduce biochemical and mechanical signals from the extracellular environment into the cell and vice versa. However, the precise molecular functions, particularly the mechanosensory properties...
Article
Tissues need strategies to cope with genomic insults to maintain their integrity. In this issue of Developmental Cell, Kato et al. use in vivo fate tracing to observe selective elimination of epidermal stem cells (EpiSCs) harboring severe genomic lesions through their differentiation and compensatory expansion of surrounding intact cells.
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The mammary gland develops from the surface ectoderm during embryogenesis and proceeds through morphological phases defined as placode, hillock, bud, and bulb stages followed by branching morphogenesis. During this early morphogenesis, the mammary bud undergoes an invagination process where the thickened bud initially protrudes above the surface ep...
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Tissue turnover requires activation and lineage commitment of tissue-resident stem cells (SCs). These processes are impacted by ageing, but the mechanisms remain unclear. Here, we addressed the mechanisms of ageing in murine hair follicle SCs (HFSCs) and observed a widespread reduction in chromatin accessibility in aged HFSCs, particularly at key s...
Article
The vascular system is precisely regulated to adjust blood flow to organismal demand, thereby guaranteeing adequate perfusion under varying physiological conditions. Mechanical forces, such as cyclic circumferential stretch, are among the critical stimuli that dynamically adjust vessel distribution and diameter, but the precise mechanisms of adapta...
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The skin epidermis is attached to the underlying dermis by a laminin 332-rich basement membrane. Consequently, loss of laminin 332 leads to the severe blistering disorder epidermolysis bullosa junctionalis in human and animals. Due to the indispensable role of laminin 332 in keratinocyte adhesion in vivo, the severity of the disease has limited res...
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Stem cell differentiation is accompanied by increased mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine and spermine, which are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through translatio...
Preprint
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The epidermis consists of different compartments such as the hair follicle (HF), sebaceous gland (SG) and interfollicular epidermis (IFE), each containing distinct stem cell (SC) populations. However, with the exception of the SCs residing within the HF bulge, other epidermal SC populations remain less well understood. Here we used an epigenomic st...
Preprint
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Focal adhesions link the actomyosin cytoskeleton to the extracellular matrix regulating cell adhesion, shape, and migration. Adhesions are dynamically assembled and disassembled in response to extrinsic and intrinsic forces, but how the essential adhesion component intergrin-linked kinase (ILK) dynamically responds to mechanical force and what role...
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The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we...
Article
Stem cells reside in specialized niches that are critical for their function. Upon activation, hair follicle stem cells (HFSCs) exit their niche to generate the outer root sheath (ORS), but a subset of ORS progeny returns to the niche to resume an SC state. Mechanisms of this fate reversibility are unclear. We show that the ability of ORS cells to...
Preprint
Full-text available
Stem cell differentiation is accompanied by an increase in mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine, and spermine that are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through transl...
Article
Full-text available
Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-depend...
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Miroshnikova, Hammesfahr, and Wickström illustrate the complex cell biological changes observed in cells of patients with Lamin A/C cardiomyopathies.
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Stem cells have the ability to self-renew and differentiate along multiple lineages, driving tissue homeostasis and regeneration. Paradigms of unidirectional, hierarchical differentiation trajectories observed in embryonic and hematopoietic stem cells have traditionally been applied to tissue-resident stem cells. However, accumulating evidence impl...
Article
Biological patterns emerge through specialization of genetically identical cells to take up distinct fates according to their position within the organism. How initial symmetry is broken to give rise to these patterns remains an intriguing open question. Several theories of patterning have been proposed, most prominently Turing's reaction-diffusion...
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TGFB1 (transforming growth factor beta 1) is a potent cytokine playing a driving role in development, fibrosis and cancer. It is synthesized as prodomain-growth factor complex that requires tethering to LTBP (latent transforming growth factor beta binding protein) for efficient secretion into the extracellular space. Upon release, this large latent...
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To establish and maintain organ structure and function, tissues need to balance stem cell proliferation and differentiation rates and coordinate cell fate with position. By quantifying and modelling tissue stress and deformation in the mammalian epidermis, we find that this balance is coordinated through local mechanical forces generated by cell di...
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Generation of a barrier in multi-layered epithelia like the epidermis requires restricted positioning of functional tight junctions (TJ) to the most suprabasal viable layer. This positioning necessitates tissue-level polarization of junctions and the cytoskeleton through unknown mechanisms. Using quantitative whole-mount imaging, genetic ablation,...
Article
Cadherin-based adherens junctions (AJs) and desmosomes are crucial to couple intercellular adhesion to the actin or intermediate filament cytoskeletons, respectively. As such, these intercellular junctions are essential to provide not only integrity to epithelia and other tissues but also the mechanical machinery necessary to execute complex morpho...
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The familial partial Dunnigan lipodystrophy, characterized by subcutaneous fat loss, is frequently caused by an R482W mutation in lamin A. In this issue, Oldenburg et al. (2017. J. Cell Biol.https://doi.org/10.1083/jcb.201701043 ) demonstrate that this mutation impairs the ability of lamin A to repress the anti-adipogenic miR-335, providing a poten...
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Cells are constantly subjected to a spectrum of mechanical cues, such as shear stress, compression, differential tissue rigidity and strain, to which they adapt by engaging mechanisms of mechanotransduction. While the central role of cell adhesion receptors in this process is established, it has only recently been appreciated that mechanical cues r...
Article
Podocytes are terminally differentiated cells of the kidney filtration barrier. They are subjected to physiological filtration pressure and considerable mechanical strain, which can be further increased in various kidney diseases. When injury causes cytoskeletal reorganization and morphological alterations of these cells, the filtration barrier may...
Article
Understanding how complex tissues are formed, maintained, and regenerated through local growth, differentiation, and remodeling requires knowledge on how single-cell behaviors are coordinated on the population level. The self-renewing hair follicle, maintained by a distinct stem cell population, represents an excellent paradigm to address this ques...
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Tissue mechanics drive morphogenesis, but how forces are sensed and transmitted to control stem cell fate and self-organization remains unclear. We show that a mechanosensory complex of emerin (Emd), non-muscle myosin IIA (NMIIA) and actin controls gene silencing and chromatin compaction, thereby regulating lineage commitment. Force-driven enrichme...
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The proliferation of chronic lymphocytic leukemia (CLL) cells requires communication with the lymphoid organ microenvironment. Integrin-linked kinase (ILK) is a multifunctional intracellular adaptor protein that transmits extracellular signals to regulate malignant cell motility, metastasis, and cell cycle progression, but is poorly characterized i...
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Stem cells reside in specialized niches that are critical for their function. Quiescent hair follicle stem cells (HFSCs) are confined within the bulge niche, but how the molecular composition of the niche regulates stem cell behaviour is poorly understood. Here we show that integrin-linked kinase (ILK) is a key regulator of the bulge extracellular...
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Herpes simplex virus type 1 (HSV-1) invades its human host via skin or mucosa. We aim to understand how HSV-1 overcomes the barrier function of the host epithelia, and for this reason established an ex vivo infection assay initially with murine skin samples. Here, we report how tissue has to be prepared to be susceptible to HSV-1 infection. Most ef...
Article
Wound healing is a complex multistep process that involves a number of different cell types and requires tight regulation of biochemical and biomechanical signaling (1). Fibroblasts are required to deposit and remodel extracellular matrix (ECM) within the wound to provide mechanical stability and a protein scaffold for other cells and growth factor...
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Cell migration is mediated by the dynamic remodeling of focal adhesions (FAs). Recently, an important role of endosomal signaling in regulation of cell migration was recognized. Here, we show an essential function for late endosomes carrying the p14-MP1 (LAMTOR2/3) complex in FA dynamics. p14-MP1-positive endosomes move to the cell periphery along...
Article
Cell-matrix adhesions provide structural stability to the tissue and regulate intracellular signaling pathways that are important for cell fate decisions within the different cell populations within the skin. As a consequence of these central functions, genetic or functional impairment of various key protein components of matrix adhesions plays a c...
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ILK (integrin-linked kinase) is a central component of cell-matrix adhesions and an important regulator of integrin function. It forms a ternary complex with two other adaptor proteins, PINCH (particularly interesting cysteine- and histidine-rich protein) and parvin, forming the IPP (ILK-PINCH-parvin) complex that regulates the integrin-actin linka...
Article
Synergy in the downstream signaling pathways of the vascular endothelial growth factor receptor-2 (VEGFR-2) and the integrin αvβ3 is critical for blood vessel formation. Thus, agents that activate both receptors could possess efficient pro-angiogenic potential. Here, we created a fibrin-binding bi-functional protein (FNIII10-VEGF) consisting of the...
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Integrin-linked kinase (ILK) is an adaptor protein required to establish and maintain the connection between integrins and the actin cytoskeleton. This linkage is essential for generating force between the extracellular matrix (ECM) and the cell during migration and matrix remodelling. The mechanisms by which ILK stability and turnover are regulate...
Article
Integrin linked kinase (ILK) connects the ILK-Pinch-Parvin complex with integrin adhesion sites. Because of the functional relevance of integrin-linked signaling for endothelial cell (EC) biology, we have explored this pathway in Ilk(-/-) embryonic stem (ES) cells differentiated into ECs and vessel-like structures. We have focused in particular on...
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Cancer progresses through distinct stages, and mouse models recapitulating traits of this progression are frequently used to explore genetic, morphological, and pharmacological aspects of tumor development. To complement genomic investigations of this process, we here quantify phosphoproteomic changes in skin cancer development using the SILAC mous...
Article
Membrane trafficking pathways function to sort and transport cargoes to various intracellular compartments and to the plasma membrane. This allows precise spatiotemporal control of processes such as signal transduction, which in turn is crucial for complex cell functions such as cell division, migration and polarity. Recent studies identified cell-...
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The development of multicellular organisms, as well as maintenance of organ architecture and function, requires robust regulation of cell fates. This is in part achieved by conserved signaling pathways through which cells process extracellular information and translate this information into changes in proliferation, differentiation, migration, and...
Data
Dynamics of cell surface caveolin was analyzed by TIRF video microscopy in control (left) and ILK-K5 (right) keratinocytes expressing EGFP-caveolin-1. The movies were acquired using stream acquisition at an approximate rate of 200 ms/frame for 30 s. Related to Figure 3
Data
Dynamics of peripheral caveolin and MTs was analyzed by spinning disc confocal video microscopy in control (left) and ILK-K5 (right) keratinocytes expressing EGFP-caveolin-1 (green) and Cherry-Tubulin (red). The movies were acquired at a rate of 2 s/frame for 150 s. Related to Figure 3.
Data
Dynamics of peripheral caveolin and MTs was analyzed by spinning disc confocal video microscopy in ILK-K5 keratinocytes expressing EGFP-caveolin-1 (green) and Cherry-Tubulin (red) treated with 50 nM nocodazole and 1 μM taxol (left panel) or with 3nM taxol (right panel). The movies were acquired at a rate of 2 s/frame for 120 s. Related to Figure 3
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Caveolae are specialized compartments of the plasma membrane that are involved in signaling, endocytosis, and cholesterol transport. Their formation requires the transport of caveolin-1 to the plasma membrane, but the molecular mechanisms regulating the transport are largely unknown. Here, we identify a critical role for adhesion-mediated signaling...
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Dynamic interactions of cells with their environment regulate multiple aspects of tissue morphogenesis and function. Integrins are the major class of cell surface receptors that recognize and bind extracellular matrix proteins, resulting in the engagement and organization of the cytoskeleton as well as activation of signalling pathways to regulate...
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CYLD is a tumour-suppressor gene that is mutated in a benign skin tumour syndrome called cylindromatosis. The CYLD gene product is a deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling. Here we show that CYLD controls cell growth and division...
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During blood vessel development, vascular smooth muscle cells (vSMCs) and pericytes (PCs) are recruited to nascent vessels to stabilize them and to guide further vessel remodelling. Here, we show that loss of the focal adhesion (FA) protein alpha-parvin (alpha-pv) in mice leads to embryonic lethality due to severe cardiovascular defects. The vascul...
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The development of multicellular organisms requires integrin-mediated interactions between cells and their extracellular environment. Integrin binding to extracellular matrix catalyses assembly of multiprotein complexes, which transduce mechanical and chemical signals that regulate many aspects of cell physiology. Integrin-linked kinase (Ilk) is a...
Article
Basement membranes (BM) are dense sheets of extracellular matrix (ECM) that function as structural support for epithelial, endothelial, and mesenchymal tissues. They serve as barriers to separate tissues into compartments and provide signaling cues that regulate the behavior of these cells (Yurchenco et al., 2004). Crossing such tissue barriers is...
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Integrins are cell surface transmembrane receptors that recognize and bind to extracellular matrix proteins and counter receptors. Binding of activated integrins to their ligands induces a vast number of structural and signaling changes within the cell. Large, multimolecular complexes assemble onto the cytoplasmic tails of activated integrins to en...
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Kinases play a prominent role in tumor development, pointing to the presence of specific phosphorylation patterns in tumor tissues. Here, we investigate whether recently developed high resolution mass spectrometric (MS) methods for proteome and phosphoproteome analysis can also be applied to solid tumors. As tumor model, we used TG3 mutant mice car...