JUNCTIONAL ADHESION MOLECULE A (JAM-A) IS CRITICAL FOR HSC HOMING AND MAINTENANCE OF STEM CELL QUIESCENCE IN THE ENDOSTEAL NICHE

Abstract

Efficient homing of hematopoietic stem cells (HSC) from blood to the bone marrow (BM) following transplant is critical for achieving optimal engraftment. Indeed, HSC mobilized using the growth factor G-CSF are known to have reduced engraftment potential compared to native BM HSC, potentially due to impaired homing ability. Thus, the characterization of novel homing mechanisms will allow identification of improved mobilization strategies that are not solely reliant on HSC number but also HSC quality. In this study, we demonstrate junctional adhesion molecule A (JAM-A) has multi-faceted roles in HSC regulation during steady state and following mobilization. Specifically, JAM-A is critical for HSC homing and engraftment post-transplant and contributes to the maintenance of HSC quiescence in the endosteal niche. Furthermore, G-CSF mobilization significantly reduces JAM-A expression on HSC as a result of JAM-A cleavage by the enzyme TACE, which is upregulated following G-CSF. In addition, the significantly impaired homing potential of HSC mobilized with G-CSF is attributed to lower levels of JAM-A, CXCR4 as well as α4β1 and α9β1 integrins. In contrast, we show that HSC mobilized using the combination of the α4β1/α9β1 integrin antagonist BOP and the CXCR4 antagonist AMD3100 had significantly greater homing and long-term multi-lineage engraftment potential; in part due to higher levels of JAM-A, CXCR4 and α4β1/α9β1 integrins on mobilized cells. In addition, compared to G-CSF, which requires multiple doses over several days, mobilization with BOP plus AMD3100 occurred 1h following a single injection. Thus, our results identify JAM-A as a critical regulator of stem and progenitor trafficking to and maintenance in the BM and suggests the use of G-CSF independent mobilization regimes that do not abrogate JAM-A expression/function should result in improved stem cell transplants.