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 (WT). 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.

CD166 regulates human and murine hematopoietic stem cells and the hematopoietic niche

“…More definitive studies are required to ascertain the role of CD166 in HSCniche interactions. Our studies examined lodgment of marrowhomed CD166 2/2 cells under permutations not examined by Jeannet et al, 12 perhaps leading to different conclusions regarding homing of KO cells to the BM of recipient mice.…”

“…Although our studies do not contradict the findings of Notta et al, 21 Figure 5A). Jeannet et al 12 only examined the homing of KO cells to the BM of WT recipients, and hence no defect in homing was observed. Our data ( Figure 5A) demonstrate that overall, the homing of KO cells to the BM is inefficient, and that homing of KO cells to the microenvironment of KO recipients is significantly reduced.…”

“…Our data ( Figure 5A) demonstrate that overall, the homing of KO cells to the BM is inefficient, and that homing of KO cells to the microenvironment of KO recipients is significantly reduced. In the studies of Jeannet et al, 12 the HN of KO mice was not analyzed. Because CXCR4 expression on CD166 2/2 HSPC is normal ( Figure 5E), it suggests that CD166 may not play a critical role in homing and retention of HSPC in the marrow, but it may be critical for HSC-HN interactions that ensure survival and function of these cells.…”

“…Recently, Jeannet et al 12 reported that CD166 is differentially regulated in adult hematopoiesis and that CD166 2/2 HSC have an engraftment defect, although young CD166 2/2 mice displayed normal hematopoietic counts and numbers of phenotypically defined HSC. However, these studies 12 did not examine the potential of CD166 to identify bona fide normal murine and human HSC, nor did they investigate the functional capacity of CD166 in the niche.…”

“…However, these studies 12 did not examine the potential of CD166 to identify bona fide normal murine and human HSC, nor did they investigate the functional capacity of CD166 in the niche.…”