Paneth Cells: tales of a gutsy cell

The focus of this thesis is the study of Paneth cells and their role in the intestinal stem cell niche in homeostasis, injury and tissue repair and cancer. Paneth cells are niche cells for the rapidly dividing Lgr5+ intestinal stem cells.
In chapter 2 we describe a method designed to elucidate and dissect genetic and/or biochemical modifications in Lgr5+ intestinal stem cells or Paneth cells. We used the striking ability of these cells to attach to each other and form organoids or 3D “mini-guts” ex-vivo. The developing of this method was essential for the rest of the discoveries elucidated in this thesis.
In chapter 3 the role of the secretory phospholipase A2 group IIa (Pla2g2a ) or Mom1 in Paneth cells is studied. The study elucidated the role of phospholipases in homeostasis to downregulate canonical Wnt signalling in Paneth cells by upregulating yes associated protein 1 (Yap ). Under tissue injury conditions Pla2g2a was highly secreted and acted in opposite fashion thus by upregulating canonical Wnt signaling. In Chapter 4, the metabolism of the intestinal niche and stem cells is elucidated. Strikingly Paneth cells were found to be highly glycolytic whereas Lgr5+ stem cells used oxidative phosphorylation for their metabolic needs. The work done elucidated that lactate, the end product of glycolysis, secreted by Paneth cells was taken up by Lgr5+ stem cells and used by stem cells to fuel their metabolism. In other terms Paneth cells provide a metabolic niche for intestinal stem cells. In chapter 5 of this thesis another important role of Paneth cells is described. Under severe tissue injury conditions these cells can de-differentiate and regenerate the small intestine, giving rise to all intestinal cell lineages.
In Chapter 4, the metabolism of the intestinal niche and stem cells is elucidated.

Strikingly Paneth cells were found to be highly glycolytic whereas Lgr5+ stem cells used oxidative phosphorylation for their metabolic needs. The work done elucidated that lactate, the end product of glycolysis, secreted by Paneth cells was taken up by Lgr5+ stem cells and used by stem cells to fuel their metabolism. In other terms Paneth cells provide a metabolic niche for intestinal stem cells. In chapter 5 of this thesis another important role of Paneth cells is described. Under severe tissue injury conditions these cells can de-differentiate and regenerate the small intestine, giving rise to all intestinal cell lineages.