Stem cell factor (SCF) synergizes with megakaryocyte colony stimulating activity in post-irradiated aplastic plasma in stimulating human megakaryocytopoiesis.
Plasma obtained from lethally irradiated animals contains a megakaryocyte (MK) growth factor which has recently been identified as the ligand for the c-mpl receptor and has been named thrombopoietin (TPO). We demonstrate that post-irradiation aplastic canine plasma (PICS-J) and plasma from a human subject (ML) who was accidentally exposed to lethal irradiation, contain high levels of this activity, which support both MK proliferation and maturation in a dose-dependent manner. These plasma were far more active in stimulating human MK colony formation than other types of thrombocytopenic plasma or a number of exogenously added human recombinant cytokines and their combinations. The addition of stem cell factor (SCF), which alone has a minimal stimulatory affect, to post lethal-irradiation plasma provided a synergistic stimulation of megakaryocytopoiesis both in colony assays and liquid cultures. In colony assays, the combination of SCF with PICS-J or ML almost doubled the number of burst forming units (BFU-MK) and provided a 1.5-fold increase in colony forming units (CFU-MK). A 1.6-fold increase in the number of CD34+ BM cell-derived MK colonies was also elicited. In liquid cultures, the presence of both SCF and PICS-J or ML induced the appearance of a high proportion of CD34+ (6.56% vs 0.6% control) and CD41+ (3.5% vs 1.2% control) cells after 3 days in culture. By day 10, 66.8 x 10(4) CD41+ cells and 29.8 x 10(4) CD34+ cells were derived from 2 x 10(6) BMMC originally seeded. We propose that these unique plasma, which do not contain elevated level of IL-6, IL-3, GM-CSF, IL-1 beta, erythropoietin or SCF, probably contain high levels of TPO. The addition of SCF to the post-irradiation plasma provides a synergistic stimulation of megakaryocytopoiesis which may become relevant for future clinical application.
Deutsch
V R
VR
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.
Eldor
A
A
Olson
T
T
Barak
V
V
Pick
M
M
Nagler
A
A
D000741:Anemia, Aplastic / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology*; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D004285:Dogs; D004357:Drug Synergism; D058851:GPI-Linked Proteins; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects* / Q000528:radiation effects; D008562:Membrane Glycoproteins; D000090204:Mesothelin; D011506:Proteins / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental; D018788:Radioactive Hazard Release; D019089:Stem Cell Factor / Q000494:pharmacology*; D014916:Whole-Body Irradiation / Q000009:adverse effects
D001798:Blood Proteins; D003115:Colony-Stimulating Factors; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D019089:Stem Cell Factor; D000090204:Mesothelin