Alcam regulates long-term hematopoietic stem cell engraftment and self-renewal

Abstract

Hematopoietic stem cells (HSCs) reside in a specialized bone marrow (BM) microenvironment that supports the maintenance and functional integrity of long-term (LT)- HSCs throughout postnatal life. The objective of this work is to study the role of activated leukocyte cell adhesion molecule (Alcam) in HSC differentiation and self-renewal using an Alcam-null (Alcam-/-) mouse model. We show here that Alcam is differentially regulated in adult hematopoiesis and is highly expressed in LT-HSCs where its level progressively increases with age. Young adult Alcam-/- mice had normal homeostatic hematopoiesis and normal numbers of phenotypic HSCs. However, Alcam -/- HSCs had reduced long-term replating capacity in vitro and reduced long-term engraftment potential upon transplantation. We show that Alcam-/- BM contain a markedly lower frequency of long-term repopulating cells than wild type. Further, the long-term repopulating potential and engraftment efficiency of Alcam-/- LT-HSCs was greatly compromised despite a progressive increase in phenotypic LT-HSC numbers during long-term serial transplantation. In addition, an age-associated increase in phenotypic LT-HSC cellularity was observed in Alcam-/- mice. This increase was predominately within the CD150hi fraction and was accompanied by significantly reduced leukocyte output. Consistent with an aging-like phenotype, older Alcam-/- LT-HSCs display myeloid-biased repopulation activity upon transplantation. Finally, Alcam-/- LT-HSCs display premature elevation of age-associated gene expression, including Selp, Clu, Cdc42, and Foxo3. Together, this study indicates that Alcam regulates functional integrity and self-renewal of LT-HSCs. © AlphaMed Press.