Clinical Implications of Basic Research
The Paneth Cell, Caloric Restriction, and Intestinal Integrity
Hans Clevers, M.D., Ph.D.
N Engl J Med 2012; 367:1560-1561October 18,
Paneth cells reside in the stem-cell compartments of the small bowel and fuel the activity of stem cells. Yilmaz and coworkers1 have recently found that Paneth cells sense the nutritional state in the gut and control stem-cell activity accordingly. These investigators went on to report that administration of the drug rapamycin (now known as sirolimus) mimics caloric restriction in that it induces Paneth cells to expand the intestinal stem-cell pool. Their observations imply that sirolimus may find application in treatments aimed at boosting stem-cell function in the gut, such as after radiation therapy or chemotherapy.
The Paneth cell is arguably the most beautiful cell of the human body. Gustav Schwalbe and Joseph Paneth first described these small-intestinal epithelial cells, with their characteristic granules. The postmitotic Paneth cells are located at the bottoms of the crypts of Lieberkühn, little pits that surround the base of luminal protrusions called villi. Most of the epithelial cells of the crypt proliferate quickly and power the rapid turnover of the epithelium. In fact, the small-intestinal epithelium is the self-renewal champion of the mammalian body, with a life cycle of less than a week, leaving skin and bone marrow far behind. Generated from stem cells near crypt bottoms, epithelial daughter cells proliferate intensely for 2 days, after which they exit the crypts and differentiate (Figure 1Figure 1
Building Up the Bowel.). They then move onto the flanks of the villi to digest and absorb nutrients and finally die at the villus tips on day 5. The Paneth cells also derive from stem cells but do not participate in this “race of the lemmings”: they reside at the base of the crypts, where they live for up to 2 months.
It took scientists almost a century after the discoveries of Schwalbe and Paneth to begin to understand the raison d'être of the Paneth cell. It is now clear that its granules contain a bounty of secreted molecules that have vital effects on gut physiology. The first discoveries revealed a host of bactericidal products such as lysozyme and the defensin peptides, suggesting that the Paneth cells are sentries of the elusive crypt stem cells.2
Independently, studies of Lgr5, a stem-cell marker, confirmed the nearly 40-year-old notion of C.P. Leblond that a rare and diminutive cell type, intermingled with Paneth cells, represents the crypt stem cell.3 Single Lgr5-positive stem cells obtained from the guts of adult mice or men can be grown into ever-expanding “miniguts” that can even be transplanted. Paneth cells are essential to this process, since they provide crucial stem-cell growth signals.4 Thus, Paneth cells not only protect but also fuel the stem cells. They are the quintessential niche cells.
Yilmaz et al. now provide an unexpected twist to the relationship of Lgr5 stem cells and their Paneth-cell progeny.1 They report that caloric restriction — that is, a reduction of caloric intake while adequate nutrition is maintained — reshapes the small intestine. Under conditions of caloric restriction, the stem cell–Paneth cell compartment expands at the apparent expense of differentiation as the villi shorten. This phenomenon is recapitulated in culture, where the formation of miniguts is strongly enhanced by caloric restriction. Yilmaz et al. showed that calorie-restricted Paneth cells support the vigorous expansion of Lgr5-positive stem cells in culture, and that a molecule called mTORC1 (mammalian target of rapamycin complex 1) kinase in the Paneth cell acts as the sensor of the organism's nutritional state. Sirolimus is an inhibitor of mTORC1 kinase that has been approved by the Food and Drug Administration. Its application reproduces the effects of caloric restriction on crypts, suggesting that it could improve intestinal stem-cell function in patients.
In summary, the nutritional status of an organism is sensed by Paneth cells, which respond to low levels of nutrients by augmenting the intestinal stem-cell pool. Why would caloric restriction increase intestinal stem-cell numbers at the expense of more differentiated cells? The authors speculate that this may be an advantageous strategy in low-calorie conditions. Preservation of an expanded stem-cell pool may prepare the intestine for rapid regeneration once food becomes available again. This would enable a person to adapt to the effects of alternating periods of food scarcity and abundance. Meanwhile, its proposed role as a buffer between famine and cornucopia lends further splendor to the Paneth cell.
From the Hubrecht Institute and University Medical Center Utrecht, Utrecht, the Netherlands.
1 Yilmaz OH, Katajisto P, Lamming DW, et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 2012;486:490-495
.2 Ouellette AJ. Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol 2010;26:547-553
.3 Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am J Anat 1974;141:537-561
.4 Sato T, van Es JH, Snippert HJ, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 2011;469:415-418