JAM2 represents high lymphoid potential in hematopoietic stem cells

Phenotypically well-characterized hematopoietic stem cells (HSCs) still represent a heterogeneous pool of primitive cells regarding to their output and functionality. Although several markers have previously been reported to be able to subdivide HSCs into different subcategories, exploration of additional markers will allow profound understanding of the complex molecular mechanisms of HSC regulation, including activation and lineage choices. We show that expression of Junctional adhesion molecule 2 (Jam2) represents higher reconstitution capacity of HSCs. Flow cytometry analyses showed that around 50% of CD150+CD48-KSL cells in mouse bone marrow (BM) were positive for Jam2 (Jam2+HSC), while other Jam family member Jam1 was expressed on all HSCs and Jam3 was not detected. Jam2 positivity may reflect activity of HSCs, as most of EPCR+HSCs were also Jam2+. Functional differences of Jam2+ and Jam2-HSCs were tested by transplantation into lethally irradiated mice and blood analyses showed higher reconstitution of Jam2+HSCs. In case of transplantation using lower number of HSCs (5 cells) both frequency and chimerism level of reconstituted mice was higher with Jam2+HSCs. Further analysis showed that the expression of Jam2 on HSC is reversible and not hierarchical, as both Jam2+ and Jam2-HSCs could reconstitute opposite populations in the BM. Of note, Jam2+HSCs show higher chimerism level within lymphoid cells, particularly T cells, whereas the chimerism within myeloid cells was not significantly different from Jam2-HSCs. Higher T cell reconstitution was even more pronounced in secondary transplantation experiments, with contribution of Jam2+HSCs close to 100%. Previous reports indicate that Notch signaling may be mediated through Jam2 to Jam1 interaction, which implies that Jam2 expressing HSCs may be poised for an interaction with the specific microenvironment that triggers the production of T cells through the induction or enhancement of Notch signaling. Our findings suggest that Jam2 is a new marker for a subset of HSCs that preferentially generate T cells. Since efficient and immediate generation of T cells in transplantation therapy is important to minimize infectious risks, understanding the molecular basis of the Jam-Notch cooperation would contribute to establish safer and more efficient treatment options.