Development, Vol 110, Issue 4 1001-1020, Copyright © 1990 by Company of Biologists

JOURNAL ARTICLES

Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt

CS Potten and M Loeffler
CRC Department of Epithelial Cell Biology, Christie Hospital & Holt Radium Institute, Manchester, UK.

We consider some of the problems involved in current discussions on stem cells in adult mammalian tissues. The present concepts involve a number of pitfalls, weaknesses and logical, semantic and classification problems. This indicates the necessity for new and well-defined concepts that are amenable to experimental analysis. One of the major difficulties in considering stem cells is that they are defined in terms of their functional capabilities which can only be assessed by testing the abilities of the cells, which itself may alter their characteristics during the assay procedure: a situation similar to the uncertainty principle in physics. The terms that describe stem cell functions are often not well defined and are used loosely, which can lead to confusion. If such context-dependent interactions exist between the manipulation and measurement process and the challenged stem cells, the question of, for example, the number of stem cells, in a tissue has to be posed in a new way. Rather than obtaining a single number one might end up with various different numbers under different circumstances, all being complementary. This might suggest that stemness is not a property but a spectrum of capabilities from which to choose. This concept might facilitate a reconciliation between the different and sometimes opposing experimental results. Given certain experimental evidence, we have attempted to provide a novel concept to describe structured cell populations in tissues involving stem cells, transit cells and mature cells. It is based on the primary assumption that the proliferation and differentiation/maturation processes are in principle independent entities in the sense that each may proceed without necessarily affecting the other. Stem cells may divide without maturation while cells approaching functional competence may mature but do not divide. In contrast, transit cells divide and mature showing intermediate properties between stem cells and mature functional cells. The need to describe this transition process and the variable coupling between proliferation and maturation leads us to formulate a spiral model of cell and tissue organisation. This concept is illustrated for the intestinal epithelium. It is concluded that the small intestinal crypts contain 4-16 actual stem cells in steady state but up to 30-40 potential stem cells (clonogenic cells) which may take over stem cell properties following perturbations. This implies that transit cells can under certain circumstances behave like actual stem cells while they undergo maturation under other conditions. There is also evidence that the proliferation and differentiation/maturation processes are subject to controls that ultimately lead to a change in the spiral trajectories.(ABSTRACT TRUNCATED AT 400 WORDS)
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				R. M. Seaberg and D. van der Kooy Adult Rodent Neurogenic Regions: The Ventricular Subependyma Contains Neural Stem Cells, But the Dentate Gyrus Contains Restricted Progenitors J. Neurosci., March 1, 2002; 22(5): 1784 - 1793. [Abstract] [Full Text] [PDF]

				T.-L. Wang, C. Rago, N. Silliman, J. Ptak, S. Markowitz, J. K. V. Willson, G. Parmigiani, K. W. Kinzler, B. Vogelstein, and V. E. Velculescu Prevalence of somatic alterations in the colorectal cancer cell genome PNAS, February 20, 2002; (2002) 261714699. [Abstract] [Full Text] [PDF]

				R. Galli, R. Fiocco, L. De Filippis, L. Muzio, A. Gritti, S. Mercurio, V. Broccoli, M. Pellegrini, A. Mallamaci, and A. L. Vescovi Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system Development, January 4, 2002; 129(7): 1633 - 1644. [Abstract] [Full Text] [PDF]

				F. Zhang, R. L. White, and K. L. Neufeld Cell Density and Phosphorylation Control the Subcellular Localization of Adenomatous Polyposis Coli Protein Mol. Cell. Biol., December 1, 2001; 21(23): 8143 - 8156. [Abstract] [Full Text] [PDF]

				B. M. Boman, J. Z. Fields, O. Bonham-Carter, and O. A. Runquist Computer Modeling Implicates Stem Cell Overproduction in Colon Cancer Initiation Cancer Res., December 1, 2001; 61(23): 8408 - 8411. [Abstract] [Full Text] [PDF]

				A. M. Carothers, K. A. Melstrom Jr., J. D. Mueller, M. J. Weyant, and M. M. Bertagnolli Progressive Changes in Adherens Junction Structure during Intestinal Adenoma Formation in Apc Mutant Mice J. Biol. Chem., October 12, 2001; 276(42): 39094 - 39102. [Abstract] [Full Text] [PDF]

				B. Seri, J. M. Garcia-Verdugo, B. S. McEwen, and A. Alvarez-Buylla Astrocytes Give Rise to New Neurons in the Adult Mammalian Hippocampus J. Neurosci., September 15, 2001; 21(18): 7153 - 7160. [Abstract] [Full Text] [PDF]

				L. Li, J. N. Rao, X. Guo, L. Liu, R. Santora, B. L. Bass, and J.-Y. Wang Polyamine depletion stabilizes p53 resulting in inhibition of normal intestinal epithelial cell proliferation Am J Physiol Cell Physiol, September 1, 2001; 281(3): C941 - C953. [Abstract] [Full Text] [PDF]

				Y. Yatabe, S. Tavare, and D. Shibata Investigating stem cells in human colon by using methylation patterns PNAS, August 21, 2001; (2001) 191225998. [Abstract] [Full Text] [PDF]

				K. U. Hong, S. D. Reynolds, A. Giangreco, C. M. Hurley, and B. R. Stripp Clara Cell Secretory Protein-Expressing Cells of the Airway Neuroepithelial Body Microenvironment Include a Label-Retaining Subset and Are Critical for Epithelial Renewal after Progenitor Cell Depletion Am. J. Respir. Cell Mol. Biol., June 1, 2001; 24(6): 671 - 681. [Abstract] [Full Text] [PDF]

				J. J. Minguell, A. Erices, and P. Conget Mesenchymal Stem Cells Experimental Biology and Medicine, June 1, 2001; 226(6): 507 - 520. [Abstract] [Full Text] [PDF]

				C. S. Potten, J. A. O'Shea, C. L. Farrell, K. Rex, and C. Booth The Effects of Repeated Doses of Keratinocyte Growth Factor on Cell Proliferation in the Cellular Hierarchy of the Crypts of the Murine Small Intestine Cell Growth Differ., May 1, 2001; 12(5): 265 - 275. [Abstract] [Full Text] [PDF]

				S. Paku, J. Schnur, P. Nagy, and S. S. Thorgeirsson Origin and Structural Evolution of the Early Proliferating Oval Cells in Rat Liver Am. J. Pathol., April 1, 2001; 158(4): 1313 - 1323. [Abstract] [Full Text] [PDF]