Regulation of progenitor properties and tissue dysfunction by cellular senescence

Due to both internal and external factors, our bodies are constantly exposed to tissue damage. Effective tissue regeneration is relatively rare in nature, and we are no different. While some degree of self-repair occurs, the damaged tissue is usually replaced with fibrotic material, which does not restore the original function of what was lost. The limited regenerative potential of our body also progressively declines as we age, and is accompanied by the wide-spread accumulation of irreparable, non-proliferating cells: senescent cells. Over the last few years, an association has been observed between senescent cells and stem cells. It has been hypothesized that these two cell types may influence each other in the context of tissue damage and repair, and that this interaction might play an important role in how well, or how poorly, the tissue regenerates. To be able to develop better methods to improve tissue repair, it is therefore desirable to understand how senescence and stemness are causally connected. When it comes to regeneration after damage, the liver is perhaps one of the most relevant organs in the body, since it is capable of remarkable recovery after insult. However, when this recovery is dysfunctional, chronic liver damage usually leads to the development of serious pathologies, such as liver fibrosis, cirrhosis, and cancer. Both the liver and kidney are known to present an accumulation of senescent and stem cells after damaging insults. Models for these two tissues are therefore particularly relevant to causally assess how cellular senescence may drive features of stemness and decline in tissue function. In this thesis we studied the manner through which senescent cells are able to influence the differentiation of neighboring cells, both in a liver and kidney context, and how this influence might affect how the organ responds to damage. We explored these aspects through the use of both in vitro and in vivo models. In Chapter 2 we showcase how iPSC-derived multicellular liver structures can be used to model various types of liver damage, thus offering a valuable intermediate model to bridge in vitro and in vivo studies. We also showcase how these models can be used to test the efficacy of anti-fibrotic drugs. In Chapter 3 we show that senescent cells are able to induce de-differentiation of human hepatocytes, and that this process is mediated by IL-1β and IL-6, through the activation of NF-κB in the hepatocytes, with CD44 potentially playing a key causative role. We also show that senescent cells prolong the liver’s normal damage response, by locking liver cells into a poorly differentiated state. Finally, we show that hepatocyte de-differentiation can be reversed, leading to better hepatocyte differentiation, and improved in vivo homeostasis recovery, through the selective removal of senescent cells. In Chapter 4 we showcase iPSC-derived multicellular kidney structures as a valuable model for studying the influence of senescent cells on kidney differentiation. In Chapter 5 we offer a general discussion of the results, and the implications of our findings for the development of future therapeutic strategies.