Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation

Abstract

Differentiation of hematopoietic stem cells (HSCs) after birth is largely restricted to the bone marrow cavity, where HSCs are associated closely with osteoblasts (OBs). How OBs localize HSCs to the endosteal niche remains unclear. To explore adhesive interactions between HSCs and OBs, a cell blot analysis was used that revealed 2 major bands that corresponded to monomers and multimers of annexin II (Anxa2). Immunohistochemistry revealed that OBs and marrow endothelial cells express Anxa2 at high levels. Function-blocking studies confirmed that Anxa2 mediates HSC adhesion mainly via the N-terminal portion of the Anxa2 peptide. Adhesion of HSCs to OBs derived from Anxa2-deficient animals (Anxa2−/−) was significantly impaired compared with OBs obtained from wild-type animals (Anxa2+/+). Moreover, fewer HSCs were found in the marrow of Anxa2−/− versus Anxa2+/+ animals. Short-term lodging, engraftment, and survival of irradiated mice with whole marrow cells were substantially inhibited by N-terminal peptide fragments of Anxa2 or anti-Anxa2 antibodies. Similar findings were noted in long-term competitive repopulation studies. Collectively, these findings reveal that Anxa2 regulates HSC homing and binding to the bone marrow microenvironment and suggest that Anxa2 is crucial for determining the bone marrow niche of HSCs.

The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites

“…5,37,38 Yet, other cells may in fact be capable of expressing CXCL12 and presenting it to HSCs including the recently described CXCL12-abundant reticular cells. 46 Our recent data also demonstrate that annexin II plays an important role in the localization of HSCs to the endosteal niche 47 ( Figure 2). Such that blocking annexin II with antibody or competing peptide prevents engraftment and survival in lethally irradiated animals.…”

“…Such that blocking annexin II with antibody or competing peptide prevents engraftment and survival in lethally irradiated animals. 47 Another group of adhesion molecules probably provides survival signals or generates activation of a quiescent state in HSCs after they are localized to the endosteal niche. These are known to include ostepontin (OPN), 48,49 very late antigen-4 (VLA-4)/fibronectin (FN) or vascular cell adhesion molecule-1 (VCAM-1), 50 leukocyte function associated antigen-1 (LFA-1)/ intercellular adhesion molecule-1 (ICAM-1), 50 and N-cadherin.…”

Communications between bone cells and hematopoietic stem cells

“…Jung et al found that Annexin II is expressed by both osteoblasts and HSC and that the N-terminal portion of the peptides interact to adhere the cells together. Further, Anxa2 −/− mice have fewer HSC in the bone marrow and exhibited less efficient engraftment and survival of irradiated mice transplanted with whole bone marrow [75]. Thus, Anxa2 appears to play a critical role in HSC homing and may function in the maintenance of HSC in the niche.…”

Homing of Cancer Cells to the Bone

“…Anxa2 expressed by osteoblasts and marrow endothelial cells, facilitate adhesion and homing of HSCs to the bone marrow niche and also regulates engraftment of HSCs following transplantation. Fewer HSCs are found in the marrow of Anxa2 deficient mice thus indicating that Anxa2 acts as an adhesion ligand for HSC homing [89]. Anxa2 is also associated with proliferative and invasive cancers including lung, pancreatic, brain, colon and gastric carcinomas, and is associated with poor prognosis [90][91][92][93].…”