Stem Cells in Organ Regeneration

Every day our body makes and loses billions of cells. This continuous regeneration is sustained by the presence of stem cells, which act as a lifelong reservoir by their ability to self-renew and differentiate into all the different lineages of a tissue. Despite the highly dynamic nature of this process, the field has been limited by the inability to track the same cells over time and interrogate their behaviors in a live mammal. To overcome this challenge, my lab has developed novel tools that integrate imaging of stem cells in their niche in live mice with genetics and cell biological approaches, allowing us to understand the complex orchestration of tissue regeneration using the skin as model system (Figure 1 & Movie).

We image the skin of live anesthetized transgenic mice in which cells are fluorescently labelled. By these means, we can visualize, with high resolution, different populations of cells within the skin and follow their behaviors over time.

Using this approach, our work has so far demonstrated that location dictates stem cell fate (Rompolas, 2013); stem cells are dispensable for tissue growth while the niche is required (Rompolas, 2012; Rompolas, 2013); a β-catenin-mediated non cell-autonomous mechanism regulates stem cell activation (Deschene*, Myung*, 2014); retinoic acid-driven differentiation leads to skin tumor regression (Zito, 2014); extrinsic mechanisms involving TGF-β signaling and the phagocytic activity of neighboring cells regulate stem cell elimination (Mesa, 2015); stem cells do not appear to be intrinsically biased towards either self-renewal or differentiation but instead appear to be influenced by the fate of their sister cells (Rompolas*, Mesa*, 2016). Thus, our novel approaches have allowed us to get a fresh look at processes that have been investigated for decades, leading to the capture of novel principles of stem cell biology and tissue regeneration.

Despite these insights, many questions about the cellular processes underlying regeneration remain. To build on our previous work, we aim to understand what processes tissues use in response to different challenges such as 1) demand for constant regeneration during homeostasis, 2) wound repair, and 3) presence of mutated cancerous cells.