Differentiation of primitive human multipotent hematopoietic progenitors into single lineage clonogenic progenitors is accompanied by alterations in their interaction with fibronectin.

Abstract

SummaryWe have previously demonstrated that primitive progenitors from human bone marrow termed long term bone marrow culture initiating cells (LTBMC-IC) adhere avidly to irradiated bone marrow stroma, while more mature clonogenic progenitors fail to do so. In this study we examine the interaction between these progenitors and components of the bone marrow stroma. . This study demonstrates that adhesive interactions between primitive hematopoietic progenitors and the extracellular matrix component fibronectin can occur. Specific changes in adhesion to the 33/66 kD cell-adhesion promoting fragment and the 75 kD RGDS-dependent cell-adhesion fragment of fibronectin are associated with differentiation of primitive multi-lineage progenitors into committed single-lineage progenitors . Such differences in adhesive interaction with fibronectin may allow hematopoietic progenitors at various stages of differentiation to interact with specific supportive loci of the bone marrow microenvironment . Finally, the ability to block adhesion of LTBMC-IC to intact irradiated stroma with peptides FN-C/H II, FN-C/H I and CS1 suggests that receptors responsible for this interaction may be important in the homing of primitive progenitors to the bone marrow.

MUC18, a member of the immunoglobulin superfamily, is expressed on bone marrow fibroblasts and a subset of hematological malignancies

“…The MUC18 antigen contains an amino acid sequence in the second Ig loop very similar to the glycosaminoglycan recognition sequence found at the same position in the related IgSF molecules, NCAM and PECAM-1. 17,34, 35 Verfaillie et al 36 have demonstrated binding of early hemopoietic progenitors to fibronectin via heparan sulphate on hemopoietic cells, and others have shown that stromalassociated proteoglycans are also likely to have an adhesive role. 37,38 Thus, binding to glycosaminoglycans may provide a direct mechanism for binding of hemopoietic progenitors or perhaps an indirect mechanism for co-localization of stromal and hemopoietic cells.…”

p210BCR/ABL-induced alteration of pre-mRNA splicing in primary human CD34+ hematopoietic progenitor cells

“…[20][21][22] We and others have shown that the function of b1-integrins on CML CD34 þ progenitors is abnormal, resulting in decreased adhesion, increased migration, and failure to inhibit proliferation upon integrin engagement. [23][24][25][26] How p210 BCR/ABL negatively influences b1-integrin function in CML is not known.…”

CD34+ marrow progenitors from MDS patients with high levels of intramedullary apoptosis have reduced expression of α4β1 and α5β1 integrins

“…Several studies have proven that survival, proliferation and differentiation of HPC is dependent on a4b1 (or VLA-4) and a5b1 (or VLA-5) integrin-mediated interactions between progenitors and fibronectin. [8][9][10][11] A 75 kDa proteolytic fragment in the center of the fibronectin molecule contains the peptide RGD and interacts with most cells via the a5b1 integrin receptor. Adhesion to fibronectin can also occur in an RGD-independent manner via the 33/66 kDa COOH-terminal 'heparin-binding domain' containing the minimal recognition site for the a4b1 integrin receptor.…”