JAM-B regulates maintenance of hematopoietic stem cells in the bone marrow

Abstract

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...

Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination

“…Dorsal root ganglion neuron and spinal cord neuron dissections were done on embryonic day 15. Junction Adhesion Molecule 2 (JAM2) knockout mice are as previously described (Arcangeli et al, 2011, MGI:5779544). The jam2:beta-galactosidase knock-in mice were purchased from Jackson Laboratory (B6N(Cg)-Jam2 tm1.1(KOMP)Mbp /J, Stock No: 024055, MGI:5522546).…”

Homing of Human B Cells to Lymphoid Organs and B-Cell Lymphoma Engraftment Are Controlled by Cell Adhesion Molecule JAM-C

“…In addition, the presence of JAM-B in murine bone marrow endothelial cells has been confirmed by flow cytometry and immunofluorescence (23). To ensure that JAM-B is also expressed by endothelial cells in NOD/SCID mice, lymph nodes and spleen sections were stained for JAM-B, and bone marrow was analyzed by flow cytometry for the presence of JAM-Bpositive endothelial cells.…”

Ptk7-Deficient Mice Have Decreased Hematopoietic Stem Cell Pools as a Result of Deregulated Proliferation and Migration

“…Indeed, CD150 + CD48 2 LSK cells contain ∼40% of HSCs with long-term reconstitution potential in BM, as well as in FL (3). Hematopoiesis is a highly controlled multi-step process that relies on complex interaction networks involving cell surface receptors, growth factors, and adhesion molecules expressed by HSCs and their environment (4)(5)(6)(7)(8). Because HSCs generate 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.…”

“…HSCs are retained in these BM niches by cell surface molecules endowed with adhesive and/or signaling functions expressed by HSCs. These receptors belong to different protein families, including integrins (VLA-4) (10), Ig superfamily adhesion molecules (6,11), G protein-coupled receptors (CXCR4) (12), and tyrosine kinase receptors (TIE2, c-Kit) (13)(14)(15), which interact with ligands present within the BM microenvironment (16). The discovery of novel molecules implicated in this multi-step program is of particular importance to grasping its complexity, to developing new strategies aimed at the regeneration of damaged hematopoietic tissues, and to understanding hematopoietic diseases.…”