Selective expression of the human class Ib HLA molecule HLA-G in immunologically protected sites and its function in the inhibition of NK and T-cell effector functions support an important role of this molecule in immunoregulation. Here, we demonstrate that HLA-G is constitutively expressed in the endocrine compartment of the human pancreas. Surface expression of this HLA determinant in endocrine cells is regulated in response to growth and inflammatory stimuli. Furthermore, we provide evidence that HLA-G expressed in this tissue may associate with a subset of insulin-containing granules and may be shuttled to the cell surface in response to secretory stimuli. Thus, HLA-G presentation by endocrine cells may be regulated in concert with their secretory activity. These results identify the expression of a major histocompatibility complex locus with putative regulatory functions in human pancreatic islets, a finding with potentially important implications for the progression of autoimmunity as well as for the establishment of transplant tolerance to this tissue. Diabetes

Circulating endothelial progenitors contribute to neovascularization at sites of injury and tumorigenesis in postnatal life. Yet, the molecular mechanisms initiating the endothelial developmental program of these precursors remain elusive. Here we provide evidence that endothelial development from progenitors circulating in human cord blood requires angiopoietins, a set of growth factors also involved in vascular branching during embryogenesis. We show that cord blood cells with the potential for endothelial development reside in a CD34 ؉ CD11b ؉ subset capable of autonomously producing and binding angiopoietins. Functionally, endogenous angiopoietin-1 regulates initial endothelial cell commitment, whereas angiopoietin-2 enhances expansion of the endothelial cell progeny. These IntroductionNeovascularization is a multistep process, requiring the timely expression of various growth factors and receptors on endothelial cell progenitors. Thus, vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (or KDR) regulate the migration, proliferation, and commitment of pluripotent hemangioblasts, 1,2 leading to the formation of the primitive vascular network. Subsequently, remodeling of the primary vascular plexus by sprouting and branching of blood vessels requires Tie-1 and Tie-2 expression on endothelial cells and their progenitors. [3][4][5][6] Tie-2 binds 2 mutually antagonistic peptides, angiopoietin-1 and angiopoietin-2. 7,8 Angiopoietin-1 signals Tie-2 phosphorylation, whereas angiopoietin-2 inhibits this effect. 8 Consistent with a role of Tie-2/ angiopoietins in the remodeling of the primary vascular network, knock-out of the Tie-2 gene or transgenic overexpression of its antagonistic ligand angiopoietin-2 leads to the formation of an immature vascular tree, lacking branching from large to small vessels. 8,9 Conversely, overexpression of the agonistic ligand for Tie-2, angiopoietin-1, increases the number, size, and branching of blood vessels. 10,11 Interestingly, angiopoietin-1 also regulates the endothelial developmental program of fetal Tie-2 ϩ hematopoietic cells. 12,13 Accordingly, fetal hematopoietic progenitors can rescue endothelial development in murine models of defective angiogenesis, and this effect requires angiopoietin-1. 14 Thus, following the formation of the primitive vascular network, the Tie-2/angiopoietin pathway is critical for expansion, rearrangement, and differentiation of blood vessels arising from endothelial and hematopoietic precursors.Postnatally, vascular remodeling occurs at sites of physiologic and pathologic angiogenesis (eg, ovulating follicle, wounds, and tumors). [15][16][17][18] Recently, circulating endothelial progenitors of hematopoietic origin were shown to contribute to neovascularization at those sites. [19][20][21][22][23][24][25] Cells with this developmental potential express CD34, reside in the bone marrow, and may circulate to the periphery in response to injury, [20][21][22][23][24] cytokines, or tumor inoculation. 23,25 Interestingly, CD34 ϩ cells gi...