title: 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 CD150(hi) 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.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Jeannet
authors.forename: Qi
authors.initials: Q
authors.lastname: Cai
authors.forename: Hongjun
authors.initials: H
authors.lastname: Liu
authors.forename: Hieu
authors.initials: H
authors.lastname: Vu
authors.forename: Ya-Huei
authors.initials: YH
authors.lastname: Kuo
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule