Prof. Dr. Carien M. Niessen

Research Area: Cell fate regulation in epithelial tissue function and ageing


1. Research Background:

How epithelia coordinate cell and tissue structure with growth and metabolic activity to control morphogenesis and homeostasis of tissues is a fundamental question in biology. Altered regulation of epithelial cell/tissue architecture disturbs tissue homeostasis and promotes ageing and ageing-associated diseases, such as cancer and a range of inflammatory diseases. Using the self-renewing epidermis as a paradigm the Niessen laboratory asks how key regulators of the cyto-architecture control the formation and maintenance of epithelial tissues. More specifically, we ask how cell adhesion and polarity integrate with growth and inflammatory pathways to control stem cells, differentiation, tissue integrity and homeostasis in a stratifying epithelium, the epidermis of skin. Furthermore we ask if and how age-associated alterations in molecular regulators of cell architecture alter stem cell behavior and result in skin cancer and skin barrier related diseases.  

2. Research questions addresses by the group:

  1. How do cadherins and polarity signaling pathways regulate the establishment and maintenance of the epidermal skin barrier and how does improper skin barrier function contributes to (age-associated) disease?
  2. How do core polarity complexes regulate epidermal progenitor cell behavior and cell fate decisions in the mammalian stratifying epithelia?
  3. How does the insulin/IGF pathway control epidermal morphogenesis, homeostasis and barrier function?
  4. How do aging and external age accelerators such as UV light affect cell fate decisions and tissue architecture to alter epidermal barrier function?

3. Possible projects:

  1. How does aging affect epidermal stem cell behavior?
    Using different Cre drivers to fluorescently label different epidermal stem cell populations, we will use intravital microscopy to dynamically follow different epidermal stem cell populations in vivo and ask how aging impacts onactivation, localization, division speed and orientation, migration and death of stem cells. These functional data will be linked to proteomic data sets to identify potential molecular candidates that mediate the age-dependent changes in epidermal stem cells.
  2. Role of polarity and metabolic signals in stem cell aging
    We previously found that loss of polarity signaling and its upstream regulator Insulin/IGF-1 results in reduced stem cell numbers and altered stem cell behavior and regenerative responses.  We would therefore like to use these two mouse models to examine how these pathways alter stem cell behavior and responses to injury and whether this mimics the behavior of naturally aged stem cells.
  3. Role of EGFR receptor signaling in regulation epidermal barrier function
    We recently identified an E-cadherin-mediated mechanical circuit that integrates adhesion, contractile forces and EGFR signaling to drive the polarized organization of junctional tension necessary to build an in vivo epithelial barrier. These results suggest that EGFR integrates regulation of the structural barrier with innate immune barrier function. To address this hypothesis we therefore will inactivate EGFR in different epidermal populations and assess structural barrier functions as well as innate immune responses. We will also develop optogenetic tools to spatiotempraolly control EGFR activation in vivo and in vitro.

4. Applied Methods and model organisms:

All three projects depend on transgenic mouse models, most of which already exist in the lab or are in the process of being generated. Basic analysis of these lines includes histochemistry, immuno histochemistry and high resolution whole mount imaging. In close collaboration with the laboratory of Valentina Greco (Yale University), we have established non-invasive intravital microscopy (see e.g. Rompolas, Nature, 2012, 2013), which using different fluorescent mouse reporter lines enables revisiting the same stem cell populations within the epidermis. This technique will be used in all 3 projects. In the 3rd project we will also use in vivo imaging on embryos.

Another great advantage of using the epidermis as a paradigm for epithelial renewal and barrier function is not only the obvious ability to easily assess phenotypes but also the ability to isolate and culture epidermal keratinocytes. Projects will use these cultured cells from the different transgenic lines to assess biophysical (traction force and atomic force microscopy, cell stretching) and biochemical parameters and perform life cell imaging  in 2d and 3d culture systems. All projects will also make use and /or take advantage of the fact that we have established SILAC  and have and will perform proteomics and phospho- proteomics of cells and isolated epidermis of the different mouse models. Finally, when necessary we will perform  RNA sequencing and ATAC sequencing to assess overall transcriptional changes and identify potential transcriptional regulators and motifs.