SUMMARY Stem cells persist throughout life in diverse tissues by undergoing self-renewing divisions. Self-renewal capacity declines with age, partly due to increasing p16Ink4a expression, but little is known about the mechanisms responsible for these changes. We discovered the Hmga2 transcriptional regulator was highly expressed in fetal neural stem cells but expression declined with age, partly due to increasing let-7b microRNA expression. Hmga2 deficiency reduced stem cell frequency and self-renewal throughout the central and peripheral nervous systems of fetal and young adult mice, but not old adult mice where it was no longer expressed. Hmga2 deficiency did not affect restricted neural progenitor proliferation. Hmga2 deficient fetal and young adult stem cells exhibited increased p16Ink4a and p19Arf expression, and deletion of p16Ink4a and/or p19Arf partially rescued their self-renewal. let-7b over-expression reduced Hmga2 expression and increased p16Ink4a/p19Arf expression. Changes in let-7b and Hmga2 expression during stem cell aging increase p16Ink4a/p19Arf expression and reduce self-renewal.

The adhesive properties of the endothelium, the single-cell lining of the cardiovascular system, are central to its physiology and pathophysiology (1, 2). In health, the luminal endothelial cell surface is a relatively nonadhesive and nonthrombo-

Angiopoietin-1 (Ang1) is a strong apoptosis survival factor for endothelial cells. In this study, the receptor/second messenger signal transduction pathway for the antiapoptotic effect of Ang1 on human umbilical vein endothelial cells was examined. Pretreatment with soluble Tie2 receptor, but not Tie1 receptor, blocked the Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of Tie2 and the p85 subunit of phosphatidylinositol 3'-kinase (PI 3'-kinase) and increased PI 3'-kinase activity in a dose-dependent manner. The PI 3'-kinase-specific inhibitors wortmannin and LY294002 blocked the Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of the serine-threonine kinase Akt at Ser473 in a PI 3'-kinase-dependent manner. Expression of a dominant-negative form of Akt reversed the Ang1-induced antiapoptotic effect. Ang1 mRNA and protein were present in vascular smooth muscle cells but not in endothelial cells. Cultured vascular smooth muscle cells, but not human umbilical vein endothelial cells, secreted Ang1. These findings indicate that the Tie2 receptor, PI 3'-kinase, and Akt are crucial elements in the signal transduction pathway leading to endothelial cell survival induced by the paracrine activity of Ang1.

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 transcriptional regulator is specifically expressed in fetal and neonatal but not adult HSCs. Germline deletion of Sox17 led to severe fetal hematopoietic defects, including a lack of detectable definitive HSCs. Conditional deletion of Sox17 from hematopoietic cells led to the loss of fetal and neonatal but not adult HSCs. HSCs stopped expressing Sox17 approximately 4 weeks after birth. During this transition, loss of Sox17 expression correlated with slower proliferation and the acquisition of an adult phenotype by individual HSCs. Sox17 is thus required for the maintenance of fetal and neonatal HSCs and distinguishes their transcriptional regulation from adult HSCs.