[Exploring new molecules that regulate hematopoietic stem cells and early stages of lymphoid hematopoiesis: the functional significance of ESAM and SATB1].

Hematopoietic stem cells (HSCs) possess multilineage differentiation capability, which sustains the production of blood and immune cells throughout life. However, the precise mechanisms by which HSCs initiate differentiation toward a particular lineage and the factors that attenuate their lymphopoietic potential with aging are yet to be elucidated. Our group has investigated this issue for over two decades. We initially developed a method for segregating early lymphoid progenitors from HSCs and identified two molecules: endothelial cell-selective adhesion molecule (ESAM), highly expressed in HSCs, and special AT-rich sequence binding protein 1 (SATB1), expressed in early lymphoid progenitors. ESAM marks HSCs across species, including humans. In addition to its significance in stress-induced hematopoiesis, ESAM is also useful in identifying features of human acute myeloid leukemia stem cells. Further, we determined the role of SATB1 in the early HSC differentiation processes toward the lymphoid lineage. Remarkably, SATB1 expression in HSCs significantly decreased with aging, whereas its exogenous induction in aged HSCs rejuvenated their lymphopoietic potential. Furthermore, SATB1-expressing HSCs demonstrated robust lymphopoietic and long-term reconstituting capability, whereas HSCs without SATB1 skewed toward the myeloid lineage. Thus, our continuing research has revealed the significance of ESAM and SATB1 in the fundamental biology of HSCs.