Our tissues are made out of cells that attach tightly to each other to produce tissues with specialized function. In order to generate tissues with defined architecture and function, cells divide, move, change their shape and differentiate to functionally specialized cells. In the case of epithelia such as the skin, the key function of this tissue is to provide a tight bi-directional barrier that protects our body from harmful external influences such as bacteria, toxins and ultraviolet light, while keeping us from dehydrating through evaporation. We study how cells communicate with each other to produce this specific barrier through coordinated cell divisions, movements and differentiation events.
Our skin is constantly renewed by removing damaged cells to preserve the intact barrier. 500 million cells and 100 hairs (1,5 g of material) are shed every day in this renewal. This material is produced by stem cells, which are long-lived self-renewing cells that reside within the tissue and possesses a high capacity for self-renewal. Due to their potency, tight control of stem cell behavior to match the needs of the tissue is required.
We aim to understand these mechanisms by studying stem cells both in the intact tissue as well as in various cell culture systems. By studying how stem cell regulation differs in cancer and in healthy tissue, we aim to both understand the fundamental principles that underlie life and, in the process, identify therapeutic opportunities against cancer.
Adult somatic stem cells fuel tissue renewal, repair, and remodeling to maintain organ structure and function. Given their potency, even incremental alterations in stem cell behavior could lead to substantial changes in tissue size and architecture. Yet, these types of effects are strikingly rare, strongly implying that stem cells are under tight homeostatic regulation, allowing the system to react rapidly to disturbances and to efficiently restore proper functions. However, mechanisms of such population-level regulation are poorly understood.
Stem cells reside in distinct niches that mediate the balanced response of stem cells to the needs of the tissue, prevent stem cell depletion, and restrict excessive stem cell expansion. Although the importance of niches in stem cell regulation has been established, the complexity of mammalian stem cell niches has prevented identification of the precise nature of the niche-derived signals and hindered mechanistic studies of adult stem cell regulation.
Our aims to uncover how complex but stereotyped tissues are formed, maintained, and regenerated through mechanisms of stem cell and niche self-organization. We further aim to understand how cancer escapes established cell state barriers and tissue microenvironmental control, and how cancerous states could be forced into trajectories of normal morphogenesis as means to limit disease progression. To decipher these fundamental questions, my research group focuses on how single cell states are regulated by mechanochemical signals and epigenetic barriers, how single cell behavior is coordinated on the population level, and how population-level dynamics is coupled to tissue-scale dynamics and architecture. Uncovering these regulatory principles will facilitate development of stem cell (SC) therapies and effective treatments against cancers.
As self-renewing organs maintained by distinct SC populations and with clinically challenging cancers, stratified epithelia of the skin and oral cavities, as well as the simple epithelium of the intestine, represent outstanding, clinically relevant paradigms to address these questions. Our research program focuses on three main research areas that bridge scales from tissue- to molecule-level processes:
(1) Mechanisms of epithelial morphogenesis and maintenance
(2) Universal and cell state-specific principles of mechanochemical regulation of cell fate and reprogramming
(3) Mechanical regulation of genome architecture, transcription, and genome integrity.
These areas are pursued by a highly interdisciplinary research strategy that builds on mouse genetics and human patient material, combining scale-bridging tools of bioengineering and biophysics, machine learning-based quantitative imaging, genome-wide analyses, and computational modeling.
Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Nava M.M., Miroshnikova Y.A., Biggs L.C., Whitefield D.B., Metge F., Boucas J., Vihinen H., Jokitalo E., Li X., García Arcos J.M., Hoffmann B., Merkel R., Niessen C.M., Dahl K.N. & Wickström SA. May 14 2020, Cell, 181, 4, p. 800-817
Glutamine metabolism controls stem cell fate reversibility and long-term maintenance in the hair follicle. Kim C.S., Ding X., Allmeroth K., Biggs, L.C., Kolenc O.I., L’Hoest N., Chacón-Martínez C.A., Edlich-Muth C., Giavalisco P., Quinn K.P., Denzel M., Eming S.A. & Wickström S.A., 6 Oct 2020, Cell Metabolism. 32, 4, p. 629-642
Defining the design principles of skin epidermis postnatal growth. Dekoninck C., Hannezo E., Sifrim A., Malfait. M, Miroshnikova Y.A., Aragona M., Gargouri, S., de Neunheuser C., Dubois C., Voet T., Wickström S.A., Simons B. & Blanpain C., Apr 30 2020, Cell 181, 3, p. 604-620
How cancer invasion takes shape. Punovuori K. & Wickström S.A. Sep 2020 Nature. 585, 7825, p. 355-356
Epigenetic gene regulation, chromatin structure and force-induced chromatin remodelling in epidermal development and homeostasis. Miroshnikova Y.A., Cohen I., Ezhkova E. & Wickström S.A. Apr 2019 Curr Opin Genet Dev. 55, p. 46-51
Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. Miroshnikova Y.A., Le, H.Q., Schneider D., Thalheim T., Rübsam M., Bremicker N., Polleux J., Höppner N., Tarantola M., Wang I., Balland M., Niessen C.M., Galle J. & Wickström S.A. Jan 2018, 20, 1, p. 69-80
Signaling in the stem cell niche: regulating cell fate, function and plasticity. Chacon-Martinez C.A., Koester J. & Wickström S.A. Aug 1, 2018, Development. 145, 15, dev165399
Hair follicle stem cell cultures reveal self-organizing plasticity of stem cells and their progeny. Chacon-Martinez C.A., Klose M., Niemann C., Glauche I. & Wickström S.A. Jan 17, 2016, EMBOJ. 36, 2, p. 151-164.
Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment . Le H.Q., Ghatak S., Yeung C.Y., Tellkamp F., Günschmann C., Dieterich C., Yeroslaviz A., Habermann B., Pombo A., Niessen C.M. & Wickström S.A. Aug 2016, Nat Cell Biol. 18, 8, p. 864-875.
Integrin-linked kinase regulates the niche of quiescent epidermal stem cells. Morgner J., Ghatak S., Jakobi T., Dieterich C., Aumailley M., Wickström S.A. Sep 2015. Nat Commun. 6:8198.
Mirjam Binner, Masters student
Ahsan Javed, Doctoral student
Karlo Skube, Doctoral student
Ali Hashmi, Postdoctoral researcher
Michele Nava, Postdoctoral researcher
Yekaterina Miroshnikova, Postdoctoral researcher
Franziska Peters, Postdoctoral researcher
Karolina Punovuori, Postdoctoral researcher
Matthias Rübsam, Postdoctoral researcher
Aki Stubb, Postdoctoral researcher
Clementine Villeneuve, Postdoctoral researcher
Irene Ylivinkka, Postdoctoral researcher
Anu Luoto, Lab manager
Fabien Bertillot, Research engineer
Bhagwan Yadav, Bioinformatician
Sagarika Dawka, Masters student
Maribel Schönewulff, Bachelor student
Samyukta Mallick, Bachelor student
Christian Pichlo, Master student
Nadja Breidenbach, Master student
Stavroulla Artemiou, Master student
Nina L’Hoest, Master student
Tim Hammersfahr, Medical student