Expression and function of cell adhesion molecules on fetal liver, cord blood and bone marrow hematopoietic progenitors: Implications for anatomical localization and developmental stage specific regulation of hematopoiesis

The mechanism of localization, migration, and regulation of hematopoiesis a t different stages of ontogeny is not well understood, but may relate to th e specific adhesive interactions between hematopoietic stem cells and their microenvironment at different ontogenic stages. We studied the expression of cell adhesion molecules (CAM) on fetal liver (FL), umbilical cord blood (UCB) and adult bone marrow (ABM) CD34(+) cells, and the adhesion of commit ted progenitors (CFC) from all three sources to ABM stromal layers and puri fied extracellular matrix proteins. Compared to ABM CFC, significantly more UCB CFC and fewer FL CFC adhered to ABM stroma. Adhesion of FL CFC to fibr onectin (FN), the 75 kD RGD containing FN fragment and the 33-66 kD COOH-te rminal heparin binding FN fragment was also significantly less than that of ABM CFC. Like ABM CFC, the adhesion of FL CFC was mediated through alpha 4 beta 1 and alpha 5 beta 1 integrins. Of note, more FL CD34(+) cells expres sed alpha 5 integrins and the number of alpha 4, alpha 5 and beta 1 integin s per cell (mean channel frequency) was similar or higher for FL CD34(+) ce lls than ABM CD34(+) cells. Further, treatment of FL CFC with a beta 1 inte grin activating antibody (8A2), increased adhesion of FL CFC to FN to the s ame level as that of 8A2 treated ABM CFC. This suggests that the alpha 4 be ta 1 and alpha 5 beta 1 integrins on FL CD34(+) cells may be present in a l ow avidity/affinity state. We also show that unlike ABM, FL CD34(+) cells e xpressed alpha 2 and that approximately 20% FL CFC adhered to collagen IV. Further, alpha 2 beta 1 integrin on FL CFC was functional since their engag ement, either by adhesion to collagen IV or through blocking a2 antibodies, transmitted proliferation inhibitory signals. In contrast to alpha 4b and alpha 5 beta 1 integrin dependent adhesion, alpha 2 beta 1 dependent adhesi on of FL CFC to collagen IV was not enhanced after treatment with 8A2. The reason for this is not clear but suggests that alpha 2 integrins on FL CFC are maximally activated. This novel adhesive interaction with collagen TV, reminiscent of that described for CML progenitors, may have a role in the e xtramedullary localization of FL hematopoiesis or its developmental stage-s pecific regulation by its microenvironment. Studies to evaluate these possi bilities are underway. (C) 1999 International Society for Experimental Hema tology. Published by Elsevier Science Inc.