The regulation of stem cell self‐renewal

Abstract

The mechanisms that regulate stem cell self‐renewal are fundamental to the formation and maintenance of normal hematopoiesis as well as hematopoietic malignancies. Fetal stem cells differ phenotypically and functionally from adult stem cells in diverse tissues. However, little is known about how these differences are regulated. To address this we compared the gene expression profiles of fetal versus adult hematopoietic stem cells (HSCs) and discovered that the Sox17 transcription factor is specifically and preferentially expressed in fetal and neonatal but not adult HSCs (Cell 130:470). Germline deletion of Sox17 led to severe fetal hematopoietic defects, including a lack of detectable definitive HSCs. Conditional deletion of Sox17 led to the loss of fetal and neonatal but not adult HSCs. Sox17 expression by HSCs was extinguished three to four weeks after birth as HSCs acquired adult properties. During this transition, loss of Sox17 expression by individual cells correlated with slower proliferation and the acquisition of an adult phenotype. Sox17 thus distinguishes the transcriptional regulation of fetal and neonatal HSCs from that of adult HSCs.As HSCs enter the postnatal period, they become dependent upon the polycomb family transcriptional repressor, Bmi‐1. Bmi‐1 is required for the postnatal maintenance of every type of stem cell yet examined including HSCs (Nature 423:302, 2003) and neural stem cells (Nature 425:962, 2003). Bmi‐1‐deficient mice die by early adulthood with stem cell depletion, growth retardation, ataxia, and seizures. These phenotypes correlate with increased expression of the cyclin‐dependent kinase inhibitor p16Ink4a and the p53 agonist p19Arf, which promote cellular senescence. Deletion of Ink4a and/or Arf from Bmi‐1−/− mice partially rescues stem cell self‐renewal and stem cell frequency (G&D 19:1432, 2005). Despite ongoing Bmi‐1 expression, Ink4a expression increases with age, reducing stem cell frequency and function (Nature 443:448). The regulation of stem cell self‐renewal throughout life by networks of proto‐oncogenes and tumor suppressors emphasizes the mechanistic links between stem cell self‐renewal and cancer cell proliferation.