Function of Jam-B/Jam-C interaction in homing and mobilization of human and mouse hematopoietic stem and progenitor cells.

The junctional adhesion molecules Jam-b and Jam-c interact together at interendothelial junctions and have been involved in the regulation of immune response, inflammation, and leukocyte migration. More recently, Jam-c has been found to be expressed by hematopoietic stem and progenitor cells (HSPC) in mouse. Conversely, we have reported that Jam-b is present on bone marrow stromal cells and that Jam-b-deficient mice have defects in the regulation of hematopoietic stem cell pool. In this study, we have addressed whether interaction between Jam-b and Jam-c participates to HSPC mobilization or hematopoietic reconstitution after irradiation. We show that a blocking monoclonal antibody directed against Jam-c inhibits hematopoietic reconstitution, progenitor homing to the bone marrow, and induces HSPC mobilization in a Jam-b dependent manner. In the latter setting, antibody treatment over a period of 3 days does not alter hematopoietic differentiation nor induce leukocytosis. Results are translated to human hematopoietic system in which a functional adhesive interaction between JAM-B and JAM-C is found between human HSPC and mesenchymal stem cells. Such an interaction does not occur between HSPC and human endothelial cells or osteoblasts. It is further shown that anti-JAM-C blocking antibody interferes with CD34(+) hematopoietic progenitor homing in mouse bone marrow suggesting that monoclonal antibodies inhibiting JAM-B/JAM-C interaction may represent valuable therapeutic tools to improve stem cell mobilization protocols.

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

In adult mammals, hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and are maintained in a quiescent and undifferentiated state through adhesive interactions with specialized microenvironmental niches. Although junctional adhesion molecule-C (JAM-C) is expressed by HSCs, its function in adult hematopoiesis remains elusive. Here, we show that HSCs adhere to JAM-B expressed by BM stromal cells in a JAM-C dependent manner. The interaction regulates the interplay between HSCs and BM stromal cells as illustrated by the decreased pool of quiescent HSCs observed in jam-b deficient mice. We further show that this is probably because of alterations of BM stromal compartments and changes in SDF-1α BM content in jam-b(-/-) mice, suggesting that JAM-B is an active player in the maintenance of the BM stromal microenvironment.

Cutting edge: JAM-C controls homeostatic chemokine secretion in lymph node fibroblastic reticular cells expressing thrombomodulin.

The development and maintenance of secondary lymphoid organs, such as lymph nodes, occur in a highly coordinated manner involving lymphoid chemokine production by stromal cells. Although developmental pathways inducing lymphoid chemokine production during organogenesis are known, signals maintaining cytokine production in adults are still elusive. In this study, we show that thrombomodulin and platelet-derived growth factor receptor α identify a population of fibroblastic reticular cells in which chemokine secretion is controlled by JAM-C. We demonstrate that Jam-C-deficient mice and mice treated with Ab against JAM-C present significant decreases in stromal cell-derived factor 1α (CXCL12), CCL21, and CCL19 intranodal content. This effect is correlated with reduced naive T cell egress from lymph nodes of anti-JAM-C-treated mice.