Sara A. Wickström

Bio: Sara A. Wickström is an academic researcher from Max Planck Society. The author has contributed to research in topics: Integrin & Stem cell. The author has an hindex of 34, co-authored 70 publications receiving 4321 citations. Previous affiliations of Sara A. Wickström include University of Helsinki & University of Cologne.

Genetic and cell biological analysis of integrin outside-in signaling.

Abstract: 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 engage and organize the cytoskeleton, and activate signaling pathways that ultimately lead to changes in gene expression. Additionally, integrin-mediated signaling intersects with growth factor-mediated signaling through various levels of cross-talk. This review discusses recent work that has tremendously broadened our understanding of the complexity of integrin-mediated signaling.

Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment

Abstract: 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 enrichment of Emd at the outer nuclear membrane of epidermal stem cells leads to defective heterochromatin anchoring to the nuclear lamina and a switch from H3K9me2,3 to H3K27me3 occupancy at constitutive heterochromatin. Emd enrichment is accompanied by the recruitment of NMIIA to promote local actin polymerization that reduces nuclear actin levels, resulting in attenuation of transcription and subsequent accumulation of H3K27me3 at facultative heterochromatin. Perturbing this mechanosensory pathway by deleting NMIIA in mouse epidermis leads to attenuated H3K27me3-mediated silencing and precocious lineage commitment, abrogating morphogenesis. Our results reveal how mechanics integrate nuclear architecture and chromatin organization to control lineage commitment and tissue morphogenesis.

The ILK/PINCH/parvin complex: the kinase is dead, long live the pseudokinase!

Abstract: 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 cell behaviour and morphogenetic processes. The ternary complex of integrin‐linked kinase (ILK), PINCH, and parvin (IPP complex), which was identified more than a decade ago, interacts with the cytoplasmic tail of β integrins and couples them to the actin cytoskeleton. In addition, ILK has been shown to act as a serine/threonine kinase and to directly activate several signalling pathways downstream of integrins. However, the kinase activity of ILK and the precise functions of the IPP complex have remained elusive and controversial. This review focuses on the recent advances made towards understanding the specialized roles this complex and its individual components have acquired during evolution.

Endostatin associates with integrin alpha5beta1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells.

Abstract: Endostatin, the COOH-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis and tumor growth. To understand the mechanisms behind endostatin action, we analyzed the plasma membrane- extracellular matrix interactions of recombinant human endostatin in cultured microvascular endothelial cells. We observed that endostatin induced rapid clustering of α5β1 integrin associated with actin stress fibers and its concomitant colocalization with the membrane anchor protein caveolin-1. Furthermore, endostatin could be coimmunoprecipitated with α5β1 and caveolin-1 from endothelial cell extracts. Endostatin treatment induced phosphatase-dependent activation of caveolin-associated Src family kinases. The disassembly of actin stress fibers and focal adhesions by endostatin was found to occur via activation of Src and in a tyrosyl phosphatase-dependent manner. The endostatin-treated cells void of the focal adhesions had impaired ability to deposit fibronectin into their extracellular matrices and were unable to migrate in response to basic fibroblast growth factor in a wounding experiment. These results indicate that recombinant endostatin interacts with α5β1 integrin and caveolin-1 at the endothelial cell surface. In addition, the antimigratory effect of endostatin involves phosphatase-dependent Src activation and impaired cell-matrix interactions.

The Extracellular Matrix: Not Just Pretty Fibrils

Abstract: The extracellular matrix (ECM) and ECM proteins are important in phenomena as diverse as developmental patterning, stem cell niches, cancer, and genetic diseases. The ECM has many effects beyond providing structural support. ECM proteins typically include multiple, independently folded domains whose sequences and arrangement are highly conserved. Some of these domains bind adhesion receptors such as integrins that mediate cell-matrix adhesion and also transduce signals into cells. However, ECM proteins also bind soluble growth factors and regulate their distribution, activation, and presentation to cells. As organized, solid-phase ligands, ECM proteins can integrate complex, multivalent signals to cells in a spatially patterned and regulated fashion. These properties need to be incorporated into considerations of the functions of the ECM.

Designing hydrogels for controlled drug delivery.

Abstract: Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel-drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

Wound repair and regeneration: Mechanisms, signaling, and translation

Abstract: The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body’s natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.