Measuring stem cell dynamics in the human colon--where there's a wiggle, there's a way.
The last decade has seen huge improvements in our understanding of intestinal stem cell biology, with major advances arising from the ability to transgenically label, and thus identify, murine stem cells and their progeny. In the human, transgenic labelling is not an available option and stem cell dynamic observations have been based on rare hereditary mutations and polymorphisms. Somatic mitochondrial DNA mutations cause a histochemically detectable, but neutrally selected, change in cytochrome c oxidase (CCO) enzyme activity and when this occurs in an intestinal stem cell, it can be used as an effective clonal marker in both health and disease. The intestinal crypt is the functional unit of the gut. Daughter cells are 'born' in the stem cell niche at the crypt base and proliferate, differentiate, and then apoptose as they migrate along the vertical crypt axis over 5-7 days. This stereotypical architecture provides a historical record of cell dynamics, as the distance travelled along the crypt axis is proportional to the time since the daughter cell was born. By staining, identifying, and carefully reconstructing crypt maps from serial en face sections of partially mutated mtDNA crypts, clonal ribbon images can be generated. 'Wiggles' in the width of the clonal ribbon reflect mtDNA mutated stem cell expansion or contraction events and these biological observations are applied in mathematical models. This clever approach is able to infer temporal evolutionary dynamics from a static, single time point measurement, in both normal and familial adenomatous polyposis tissue. As we have seen in the mouse, the simple ability to identify stem cell progeny can lead to a vast expansion in our understanding of stem cell evolution. The use of these techniques to trace recent stem cell dynamics in the human colon makes some headway into the knowledge gap in our understanding of murine and human intestinal stem cell biology. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.