Molecular mechanisms regulating adult intestinal stem cells

Throughout life, the human body undergoes repeated stress and damage due to multiple reasons: a natural wear and tear process, ageing, illnesses or injury. In order to maintain their functionality, our organs and tissues require a process of constant renewal. The tissues ability to self-repair is ensured by the presence of undifferentiated cells, termed stem cells. Whenever necessary, tissue-specific stem cells divide, producing numerous cells that acquire specialised characteristics (a process known as differentiation) and replenish the damaged areas of the tissue they belong to. The mammalian intestine is a unique system to study stem cell biology: in the mouse it is estimated that the entire intestine self-renews every 3-5 days. Intestinal stem cells actively divide to replace damaged or dead cells, so that the intestine can maintain its important absorptive functions. What are the mechanisms that regulate stem cell activity? Numerous studies have shown that the presence of certain signals will determine if stem cells can activate and divide, or remain quiescent. Importantly, cells also adopt safety mechanisms that prevent unrestricted proliferation. Serious diseases, like cancer, arise when these mechanisms fail to work. While many of the genetic mechanisms governing stem cells are known, there is still much to learn. With this project, I aim to study the biochemical language that stem cells adopt to communicate to each other, and which regulate their activity. During my study, I will use novel biochemical and proteomic methods that allow to identify an entire network of proteins involved in a specific process. Findings from this research will be tested using mini-gut organoids, which are special stem- cell derived 3D structures that mimic the actual intestinal tissue. This work would not be possible without the generous funding by the FWF Lise Meitner Program, and will benefit from the experience of a leader in the stem cell field, Dr Bon-Kyoung Koo, as well as a top research institute, such as the Institute of Molecular Biotechnology (IMBA) in Vienna.

Understanding how stem cells regenerate our tissues Throughout life, the human body undergo repeated stress and damage. The reasons of these damages are multiple: a natural "wear and tear" process, aging, illness or injury. In order to maintain their functionality, our organs and tissues require constant renewal, a process mediated by undifferentiated cells, termed stem cells. When necessary, tissue-specific stem cells divide, producing numerous cells that acquire specialized characteristics (a process known as differentiation) and replenish the damaged areas of the tissue they belong to. The mammalian intestine is a unique system to study stem cell biology: in the mouse it is estimated that the entire intestine self-renews every 3-5 days. Intestinal stem cells actively divide to replace damaged or dead cells, so that the intestine can maintain its important physiological functions. It is important to maintain a balance between cell self-renewal and differentiation: disruption of this equilibrium is at the basis of human diseases, such as cancer. What are the genetic elements required to keep this natural balance? Our study has identified some of such genes. For example, we found that Daam1 and 2, genes involved in modulating the cell cytoskeleton and shape, are required for the differentiation of a very important intestinal cell type, the Paneth cell. Paneth cells in the intestine have anti-microbial activity, but they also provide growth factors that stimulate the stem cells, that is, they form a suitable environment (called niche) that sustains intestinal stem cells. Without Paneth cells, intestinal stem cells are gradually lost. But how does Daam1/2 regulate Paneth cell differentiation? Daam1/2 are known factors of a cell signaling pathway, called Wnt/PCP (planar cell polarity). In our study we show that Wnt/PCP, through Daam1/2, is instrumental in giving the right set of instructions to some of the intestinal stem cells to become Paneth cells, which in turn will support stem cells (forming a positive feedback loop) by providing essential factors. Many tumors induce the uncontrolled growth of niche cells, such as the Paneth cells, which then help the maintenance of tumor stem cells. Our observations imply that it may be possible to attack some forms of colorectal cancers by preventing the formation of Paneth cells, via alterations of the Wnt/PCP pathway. This work would have not been possible without the generous funding by the FWF Lise Meitner Programme, the guidance of a leader in the stem cell field, Dr Bon-Kyoung Koo as well as the tremendous opportunities for scientific training and growth offered by the Institute of Molecular Biotechnology (IMBA) in Vienna. If you want to know more about Daam1/2 and Paneth cells, check our preprint at https://www.biorxiv.org/content/10.1101/2023.01.24.525366v1