Reinjection of ex vivo-expanded primate bone marrow mononuclear cells strongly reduces radiation-induced aplasia.
To assess the therapeutic efficacy of ex vivo-expanded hematopoietic cells in the treatment of radiation-induced pancytopenia, we have set up a non-human primate model. Two ex vivo expansion protocols for bone marrow mononuclear cells (BMMNC) were studied. The first consisted of a 7-day culture in the presence of stem cell factor (SCF), Flt3-ligand, thrombopoietin (TPO), interleukin-3 (IL-3), and IL-6, which induced preferentially the expansion of immature hematopoietic cells [3.1 +/- 1.4, 10.0 +/- 5.1, 2.2 +/- 1.9, and 1.0 +/- 0.3-fold expansion for mononuclear cells (MNC), colony-forming units-granulocyte-macrophage (CFU-GM), burst-forming units erythroid (BFU-E), and long-term culture initiating cells (LTC-IC) respectively]. The second was with the same cytokine combination supplemented with granulocyte colony-stimulating factor (G-CSF) with an increased duration of culture up to 14 days and induced mainly the production of mature hematopoietic cells (17.2 +/- 11.7-fold expansion for MNC and no detectable BFU-E and LTC-IC), although expansion of CFU-GM (13.7 +/- 18.8-fold) and CD34+ cells (5.2 +/- 1.4-fold) was also observed. Results showed the presence of mesenchymal stem cells and cells from the lymphoid and the megakaryocytic lineages in 7-day expanded BMMNC. To test the ability of ex vivo-expanded cells to sustain hematopoietic recovery after radiation-induced aplasia, non-human primates were irradiated at a supralethal dose of 8 Gy and received the product of either 7-day (24 h after irradiation) or 14-day (8 days after irradiation) expanded BMMNC. Results showed that the 7-day ex vivo-expanded BMMNC shortened the period and the severity of pancytopenia and improved hematopoietic recovery, while the 14 day ex vivo-expanded BMMNC mainly produced a transfusion-like effect during 8 days, followed by hematopoietic recovery. These results suggest that ex vivo expanded BMMNC during 7 days may be highly efficient in the treatment of radiation-induced aplasia.
Institut de Radioprotection et de Sûreté Nucléaire, Département de Protection de la santé de l'Homme et de Dosimétrie, Section Autonome de Radiobiologie Appliquée à la Médecine, Fontenay-aux-Roses, France. jean-marc.bertho@irsn.fr
Jean-Marc
JM
Bertho
Johanna
J
Frick
Christelle
C
Demarquay
Armelle
A
Lauby
Emilie
E
Mathieu
Nicolas
N
Dudoignon
Nelly
N
Jacquet
François
F
Trompier
Alain
A
Chapel
Christophe
C
Joubert
Manuel
M
Lopez
Jocelyne
J
Aigueperse
Norbert-Claude
NC
Gorin
Patrick
P
Gourmelon
Dominique
D
Thierry
D000818:Animals; D001854:Bone Marrow Cells; D018929:Cell Culture Techniques / Q000379:methods; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000637:transplantation*; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000097:blood; D010198:Pancytopenia / Q000209:etiology / Q000628:therapy*; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D008565:Membrane Proteins; C084881:flt3 ligand protein