The stem cells of small intestinal crypts: where are they?

Abstract

Recently, there has been resurgence of interest in the question of small intestinal stem cells, their precise location and numbers in the crypts. In this article, we attempt to re-assess the data, including historical information often omitted in recent studies on the subject. The conclusion we draw is that the evidence supports the concept that active murine small intestinal stem cells in steady state are few in number and are proliferative. There are two evolving, but divergent views on their location (which may be more related to scope of capability and reversibility than to location) several lineage labelling and stem cell self-renewing studies (based on Lgr5 expression) suggest a location intercalated between the Paneth cells (crypt base columnar cells (CBCCs)), or classical cell kinetic, label-retention and radiobiological evidence plus other recent studies, pointing to a location four cell positions luminally from the base of the crypt The latter is supported by recent lineage labelling of Bmi-1-expressing cells and by studies on expression of Wip-1 phosphatase. The situation in the human small intestine remains unclear, but recent mtDNA mutation studies suggest that the stem cells in humans are also located above the Paneth cell zone. There could be a distinct and as yet undiscovered relationship between these observed traits, with stem cell properties both in cells of the crypt base and those at cell position 4.

Figure 1

 Label retaining cells in small intestinal crypts. (a) BrdU pulse labelling showing the distribution of S‐phase cells. (b) [³H]dT label retaining cell at about cell position 5. Paneth cells are clearly visible and centripetally located mitotic figures can be seen. Mice were irradiated with 12 Gy and then received 12‐hourly injections of [³H]dT over days 1–6. The mice were killed and the intestines fixed and prepared for histology on day 21 (15 days and 15 divisions after the last thymidine injection). (c) BrdU label retaining cell at about cell position 4. Mice were irradiated as above and were given bromodeoxyuridine ad libitum in the drinking water for 6 days before being killed and treated as above on day 13 (7 days post‐BrdU. (d) A further example of [³H]dT label retaining cells at cell position 4–5. I am grateful to Dr Kee Woei Ng for this photomicrograph.

Figure 2

 Apoptotic cells at cell position 4–6 after exposure to 1 Gy of radiation. (a) Haematoxylin and eosin. (b) TUNEL staining. (c and d) Caspase‐3 staining.

Figure 3

 Schematic diagram of the lower region of small intestinal crypt in longitudinal section and a transverse section at about cell position 4. The position of the actual (ASC) and potential (PSc) stem cells is shown together with the possible relationship to the early transit generation (T₁–T₃). Some of the features and characteristics (based on various publications cited in the text) associated with ASCs are shown. The Paneth cell precursors (PCPs) may alternatively be regarded as ASCs, or part of the ASC population, and in the lower regions of the crypt (crypt base or cp 1–4) have been termed crypt base columnar cells (CBCCs). The pericryptal fibroblasts (PCF), which may undergo endoreduplication (160), could be important elements for the intestinal niche.