Molecular Determinants of Asymmetric Stem Cell Kinetics

In many somatic tissues of adult mammals, short-lived mature differentiated tissue cells are continuously renewed by long-lived stem cells that divide with asymmetric cell kinetics. Somatic stem cells divide into daughters that differ in cell kinetics fate. One daughter becomes a new stem cell, whereas depending on the tissue, the other daughter either differentiates immediately or divides to produce a pool of cells that differentiate into terminally arrested mature functional tissue cells. By asymmetric kinetics, stem cells preserve their number while simultaneously renewing differentiated cells. The difficulties in performing analyses of asymmetric cell kinetics by rare stem cells in vivo have resulted in limited progress in defining mechanisms that govern somatic stem cell kinetics. We have developed several cultured cell lines that recapitulate the essential features of somatic stem cell asymmetric kinetics. With these unique cell lines, we identified the first described asymmetric cell kinetics control genes. These genes turned out to be the p53 tumor suppressor gene and the gene encoding the rate-limiting enzyme for guanine-nucleotide biosynthesis, inosine monophosphate dehydrogenase (IMPDH). Along with their gene activation target (the p21wafl cyclin-dependent kinase inhibitor) and products (guanine ribonucleotides), respectively, p53 and IMPDH constitute a molecular-biochemical pathway that controls asymmetric cell kinetics. This pathway is essential to normal somatic stem cell function and defects in it lead to pathological stem cell states like cancer.