Mucin-like molecules as regulators of haemopoiesis

Adhesive interactions are of fundamental importance to the regulation of haemopoiesis. Current evidence suggests that the localisation of hemopoiesis to the bone marrow (BM) involves developmentally regulated adhesive interactions between primitive haemopoietic progenitor cells (HPC) and elements of the marrow stroma. Cell adhesion molecules (CAM) representing several adhesion molecule superfamilies including CD44, and various members of the integrin, and immunoglobulin (Ig) superfamilies participate in these interactions. Sialomucins represent an additional class of CAM expressed by mature leukocytes and vascular endothelial cells whose role in supporting HPC-stromal cell adhesion has not been extensively studied. In addition to sialomucins such as CD34 and CD43 whose expression on HPC is well documented, previous studies from this laboratory have demonstrated expression of several additional mucin-like molecules by these cells including PSGL-1/CD162 and the recently identified CD164. PSGL-1 is a 240 kDa homodimeric sialomucin which represents the sole ligand for P-selectin/CD62P on human HPC. Significantly, adhesion of CD34' cells to CD62P in vitro results in a profound inhibition of their proliferation in stromal cell-free, cytokine supported culture. Several distinct mechanisms acting in concert on hierarchically distinct populations of HPC appear to contribute to the inhibition of haemopoiesis mediated by PSGL-1. CD34TD38' clonogenic progenitors exhibit a reduced rate of proliferation on CD62P while approximately 40% of CD34XD38' pre-CFU undergo apoptosis. CD164 is a 160-170 kDa disulphide linked homodimeric mucin-like molecule expressed on both HPC and marrow stromal cells. Antibody to CD164 partially blocks the attachment of CD34 cells to BM stromal cells in vitro suggesting a pro-adhesive role for CD164, Although the physiological ligand for CD164 is unknown, use of antiCD164 antibody as a 'surrogate' ligand markedly suppresses cytokine supported haemopoiesis in vitro an effect mediated in part by the inhibition of recruitment of quiescent CD34 CD38~ cells into division. These studies therefore imply key roles for PSGL-1 and CD164 as signalling molecules on primitive HPC and in accord with previous studies by others on CD43 suggest important functions for this class of molecules as negative regulators of haemopoiesis. The mechanisms which ultimately contribute to the inhibition of HPC growth will require identification of the signal transduction pathways and c>loplasmic effectors engaged by mucin-like moleculesinHPC.