Abstract
Substances that circulate in the blood following drug-induced bone marrow aplasia produce a biphasic curve of DNA synthesis in cells in liquid and semisolid cultures which reflect relative concentrations of these growth regulators of hematopoiesis. This net effect magnified by induced marrow failure in human, rat, and mouse is a sinusoidal curve that is the reciprocal of the WBC. Generated in the bone marrow, humoral stimulating activity (HSA) produces peak growth of colonies in agar (CFU-GM) during the proliferative phase of bone marrow recovery, whereas humoral inhibitory activity (HIA), present at the time of marrow maturation, suppresses colony growth. Split femurs from rats given cyclophosphamide (CY) and killed at regular intervals condition media that affect DNA synthesis in a fashion similar to that of HSA-HIA in the rats' sera. In Dexter cultures, HSA is derived from the adherent rather than the hematopoietic cell, whereas HIA is produced by that nonadherent cell. Animals treated with a lethal dose of busulfan (BU) produce large amounts of HSA in vivo until death. Those transplanted with adherent bone marrow cells depleted of hematopoietic cells on day 1 after BU also die, whereas those given nonadherent marrow cells survive and generate HIA at the time of bone marrow recovery. HSA and media conditioned by bone marrow stromal cells causes an increase in spleen colonies (CFU-S), as does HIA. These studies support the contention that the net effect of putative regulators of hematopoiesis, measured in the drug-perturbed state, consist of a constantly present stimulator emanating from bone marrow stroma, and a variable inhibitor produced by maturing hematopoietic bone marrow cells.
