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.
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:
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:
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: