Integrin α2 and Akt in early hematopoiesis

Abstract: Hematopoiesis is a tightly regulated process in which hematopoietic stem cells reside at the apex of the hierarchy,
and produce all kinds of mature blood cells by differentiation to replenish the cell loss in homeostasis and acute
injury. In past few decades, much effort has been made to purify hematopoietic stem cells (HSCs) and lineagecommitted
progenitor cells both in mouse and human, enabling further characterization of these cell populations
not only in normal hematopoiesis, but also in various hematological malignancies. However, while the isolation of
different cell populations in mouse hematopoietic system is achieved with a very high purity, purification of
human hematopoietic stem and progenitor cells still far lags behind.

Integrins are heterodimeric transmembrane protein receptors regulating many important cellular processes
including homing of HSCs by binding to neighboring cells or extracellular matrix proteins. First, we showed that
integrin α2 is a novel marker improving the prospective isolation of human cord blood HSCs. We found integrin
α2 receptor was preferentially expressed in cord blood-derived CD34+CD38-CD90+ in vivo long-term
repopulating cells, demonstrated by 24-week limiting-dilution xenotransplantations using immunodeficient mice.
Second, we revealed that integrin α2, which is a marker for megakaryoctyes and platelets, was not expressed in the
immature CD34+CD38-CD45RA- bipotential megakaryocyte-erythrocyte progenitors in human bone marrow,
providing a means for enriching this novel bipotent progenitor population for further studies on early
megakaryocytic and erythroid lineage fate decisions. In addition, we demonstrated that hyperactivation of Akt,
which is a key intrinsic factor regulating the homeostasis of HSCs, was incompatible with the survival and growth
promoting ability of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) signaling in murine stem
and progenitor cells.

Prospective isolation of more homogenous stem and progenitor cell populations in human and understanding the
instrinsic regulation of HSC homeostasis will give important insights into the HSC maintenance and fate decisions
in normal hematopoiesis, as well as the pathogenesis of various hematological disorders.