No abstract

Adult stem cells are critical for maintaining cellular homeostasis throughout life, yet the effects of age on their regenerative capacity are poorly understood. All lymphoid and myeloid blood cell lineages are continuously generated from hematopoietic stem cells present in human bone marrow. With age, significant changes in the function and composition of mature blood cells are observed. In this study, we report that age-related changes also occur in the human hematopoietic stem cell compartment. We find that the proportion of multipotent CD34(+) CD38(-) cells increases in the bone marrow of elderly (>70 years) individuals. CD34(+) CD38(+) CD90(-) CD45RA(+/-) CD10(-) and CD34(+) CD33(+) myeloid progenitors persist at the same level in the bone marrow, while the frequency of early CD34(+) CD38(+) CD90(-) CD45RA(+) CD10(+) and committed CD34(+) CD19(+) B-lymphoid progenitors decreases with age. In contrast to mice models of aging, transplantation experiments with immunodeficient NOD/SCID/IL-2Rγ null (NSG) mice showed that the frequency of NSG repopulating cells does not change significantly with age, and there is a decrease in myeloid lineage reconstitution. An age-related decrease in the capacity of CD34(+) cells to generate myeloid cells was also seen in colony-forming assays in vitro. Thus, with increasing age, human hematopoietic stem/progenitor cells undergo quantitative changes as well as functional modifications.

IntroductionThe junctional adhesion molecules (JAMs) are a subset of the immunoglobulin (Ig) protein superfamily and are characterized by the presence of both a type V and a type C2 extracellular Ig domain. JAMs and related molecules have been involved in the control of interendothelial junctions and leukocyte transendothelial migration through homotypic and heterotypic interactions. 1-5 JAM-B has been previously shown to interact with JAM-C and contributes to leukoendothelial and interendothelial cell-cell adhesion. 6,7 In mice, JAM-B expression is restricted to endothelial cells whereas JAM-C is expressed by various cell types including endothelial, 1,2 fibroblastic, 8 and smooth muscle cells. 9 Moreover, we have recently shown that JAM-C expression in lymph node fibroblastic cells is required for constitutive secretion of several chemokines such as SDF-1␣. 10 Recently, expression of several JAM family members, such as JAM-A, JAM-C, JAM4, or ESAM, has been reported in hematopoietic stem cells (HSCs), although a function for these proteins in hematopoiesis remains unknown. [11][12][13][14][15][16] In adult mammals, HSCs are rare cells mainly located in the bone marrow (BM) and able to generate all mature blood cells. In mice, HSCs are comprised within the LSK compartment as defined by the Lineage Neg c-kit Hi Sca-1 Hi (LSK) phenotype; the LSK compartment can be further subdivided using additional markers such as CD34, CD150, or CD48. Indeed, CD34 Neg CD135 Neg LSK, or Thy-1 Lo LSK 17,18 and CD150 Pos CD48 Neg LSK cells 19 have been shown to contain, respectively, around 20% and 50% of HSCs with long-term hematopoietic reconstitution potential (LT-HSCs). Because HSCs give rise to mature hematopoietic cells, including immune cells, their replacement must be adjusted to homeostatic or stress conditions such as infections, inflammation, or blood loss, and their expansion must be controlled to avoid exhaustion through inappropriate proliferation and differentiation. This is possible by the coordinated regulation of quiescence, self-renewal, and differentiation of HSCs through appropriate signals delivered by functional microenvironments called niches. [20][21][22] HSCs are restrained in these specialized microenvironments by interactions mediated by adhesion molecules and chemokine receptors expressed by HSCs, such as VLA-4 or CXCR4, with their ligands present within the BM microenvironment. Other signaling pathways controlled by growth factors and their receptors expressed on HSCs, such as angiopoietin-1 and TIE2, SCF and KIT, Thrombopoietin and MPL, have also been involved in HSC maintenance and retention in BM niches. 23,24 Whether the JAM family members expressed on HSCs also contribute to this signaling network has not been addressed so far.When necessary, HSCs enter the cell cycle to maintain BM cellularity and replenish peripheral blood in a process called mobilization, which can be induced using various hematopoietic growth factors, cyclophosphamide in combination with G-CSF (Cy/G-CSF), or intravenous inject...