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 allows systematic identification of factors that drive stem cell dynamics and plasticity (Kim et al., Cell Metabolism 2020; 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. Our recent work reveals how mechanical signals modulate transcriptional regulation, chromatin organization, and nuclear architecture to control lineage commitment, tissue morphogenesis, and aging (Koester et al., Nat Cell Biol 2021; Nava, Miroshnikova et al., Cell 2020, Le et al., Nat Cell Biol 2016). 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
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