Paracrinally stimulated expansion of early human hemopoietic progenitors by stroma-generated cyclic ADP-ribose.

Abstract

SPECIFIC AIMSCoexpression of transmembrane NAD+-exporting activity (via connexin 43 hemichannels) and of ectocellular ADP-ribosyl cyclase activity (via CD38 and BST-1) on stromal cells in the bone marrow microenvironment potentially enables the extracellular production of cyclic ADP-ribose (cADPR) in the hemopoietic tissue. We previously demonstrated that cADPR stimulates the proliferation of human committed hemopoietic progenitors (HP), the colony forming cells (CFC); the major aim of the present work was to study the effect of cADPR on the most immature HP, i.e., the long-term culture initiating cells (LTC-IC), which include the HP capable of repopulating the irradiated host.PRINCIPAL FINDINGS1. Exogenously added cADPR induces an in vitro expansion of LTC-ICPretreatment of cord blood-derived mononuclear cells (CB MNC) with cADPR (100 μM for 24 h) induced a significant increase (P<0.04) of the LTC-IC frequency over ADP-ribose (ADPR) -treated controls; median values were 69 vs. 39 LTC-IC/106 MNC, respecti...