The Wickström lab combines state-of-the-art scale-bridging technologies from nanoscale atomic force microscopy and next-generation sequencing to novel ex vivo tissue culture methods, the whole organism live imaging and in silico modeling all the way up to analysis of the clinical patient material.

The research is highly interdisciplinary and involves collaborations with mathematicians, physicists, and clinical oncologists. Recent work from the Wickström group has uncovered how a generation of cellular forces is important for controlling stem cell fate and coordinating cell fate with cell position within the tissue. Furthermore, the laboratory has discovered how extrinsic forces generated by the tissue impact chromatin structure and epigenetic gene silencing, thereby controlling the transcriptional state and lineage commitment of stem cells. Read more about the ongoing projects below.

Recent Research Highlights

  • Discovery of how force induces calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin proximal to the nuclear lamina. The resulting changes in chromatin mobility, viscoelasticity, and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage (Nava, Miroshnikova et al. Cell 2020)
  • Identifying the mechanistic principles that allow maintenance of a stratified epithelium through biomechanical coupling of cell division, differentiation and delamination (Miroshnikova et al., Nat Cell Biol 2018)
  • Discovery of a novel mechanism by which mechanical force regulates nuclear architecture and chromatin structure, thereby affecting epigenetic silencing of epidermal stem cell lineage commitment genes (Le et al. Nat Cell Biol 2016)
  • Establishing a ex vivo niche that allows enrichment and dynamic, bidirectional reprogramming of hair follicle stem cells (HFSCs) (Chacon-Martinez et al. EMBOJ 2016) as well as cancer stem cells (tumor initiating cells) from squamous cell carcinomas, and which can now be used as a high throughput discovery tool for adult stem cell and cancer biology (patent EP15188393.1 pending)


Stem cell-niche interactions in fate decisions and phenotypic plasticity

Niches are critical for stem cell (SC) function, but it is not clear how they are established and how the niche architecture impacts the organization and fate of resident SCs and their progeny. Murine hair follicle stem cells (HFSCs) represent one of the most successful genetic model systems used to uncover fundamental biology of adult tissue-resident SCs. However, the lack of a system that recapitulates their native niche, enabling maintenance of HFSCs in the absence of other heterologous cell types, and allowing precise manipulation and monitoring of HFSC fate decisions has been one of the major obstacles in understanding HFSC regulation and function. We have now broken through this barrier by deconstructing the essential components of the niche, enabling us to develop an ex vivo culture system that, for the first time, allows to enrich and maintain HFSCs without loss of their multipotency (Chacón-Martínez et al., EMBOJ 2016).

Intriguingly, studies using this system have shown that epidermal cell mixtures self-evolve into a population equilibrium state of HFSCs and differentiated progeny. Strikingly, we further observe that dynamic, bidirectional interconversion of HFSCs and differentiated cells drives this self-organizing process. Moreover, HFSCs can be derived completely de novo even from purified populations of non-HFSCs. The unique tunable, defined nature of the culture system allows us to:

  1. Delineate how niche composition, mechanics, and topology regulate SC fate and reprogramming
  2. Dissect the genetic and epigenetic requirements of the observed phenotypic plasticity
  3. Identify druggable pathways that regulate the plasticity of SC fate on the population level

Biomechanics of epidermal stratification, homeostasis, and aging

How precise, dynamic coordination of cell position and fate are achieved and maintained in mammalian organs is a fundamental open question. We address this in the mammalian epidermis, a highly stereotypically organized stratified epithelium where self-renewal is maintained by SCs that pass through defined stages of differentiation while transiting upwards through the cell layers (Miroshnikova et al, Nat Cell Biol 2018). We hypothesize that biomechanical signaling integrates single cell behavior to couple proliferation, cell fate and positioning to generate and maintain global patterns of a multicellular tissue. Our current work aims to:

  1. Establish quantitative principles of the stratification process by combining biomechanical analyses, in vivo imaging, and mathematical modeling
  2. Delineate the in vivo role of cortical tension and actomyosin contractility in stratification and skin barrier function
  3. Discover the epigenetic mechanisms by which age-related changes in tissue mechanics contribute to the decline of stemness during aging

Mechanotransduction in the regulation of nuclear architecture, gene expression, and stem cell fate

Tissue mechanics and cellular interactions are a driving force of morphogenesis, but little is known about the mechanisms that sense physical forces and how they control organ growth and patterning through SC fate and self-organization. To decipher how mechanical forces regulate SC identity, we have sought to identify pathways that respond to force and establish their functional significance in SC fate determination. We show that a mechanosensory complex of emerin (Emd), non-muscle myosin IIA (NMIIA) and actin relays extrinsic mechanical forces by controlling gene silencing and chromatin compaction, thereby regulating the kinetics of lineage commitment. Force leads to defective switch from H3K9me2,3 to H3K27me3 occupancy at constitutive heterochromatin as well as transcriptional repression and subsequent accumulation of H3K27me3 at facultative heterochromatin (Le et al., Nat Cell Biol 2016). Taken together, our results reveal how mechanical signals integrate transcriptional regulation, chromatin organization, and nuclear architecture to control lineage commitment and tissue morphogenesis. Our ongoing projects aim to:

  1. Characterize the effect of extrinsic force on 3D chromatin organization at a high spatiotemporal resolution
  2. Identify the molecular mechanisms by which actin dynamics and nuclear actin regulate gene expression and SC fate
  3. Uncover the molecular mechanisms by which nuclear envelope transmits mechanical signals to chromatin and characterize the functional relevance of this signaling during mechanical stress and aging
  4. Decipher how different forms of heterochromatin act as rheological elements of the nucleus and function in the mechanical response of the nucleus