Increased plasma levels of stromal-derived factor-1 (SDF-1/CXCL12) enhance human thrombopoiesis and mobilize human colony-forming cells (CFC) in NOD/SCID mice

• Published in: Experimental hematology 2004-03, Vol.32 (3), p.300-307
• Main Authors: Perez, Lia E, Alpdogan, Onder, Shieh, Jae-Hung, Wong, Donald, Merzouk, Ahmed, Salari, Hassan, O'Reilly, Richard J, van den Brink, Marcel R.M, Moore, Malcolm A.S
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Blood Platelets - cytology; Cell Differentiation - drug effects; Chemokine CXCL12; Chemokines, CXC - agonists; Chemokines, CXC - blood; Chemokines, CXC - genetics; Chemokines, CXC - pharmacology; Drug Evaluation, Preclinical; Fetal Blood - cytology; Genetic Vectors - genetics; Hematopoiesis - drug effects; Hematopoietic Stem Cell Mobilization - methods; Humans; Megakaryocytes - drug effects; Mice; Mice, Inbred NOD; Mice, SCID; Radiation Chimera; Recombinant Fusion Proteins - physiology; Thrombopoietin - genetics; Thrombopoietin - pharmacology; Transduction, Genetic; Transplantation, Heterologous
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2003.12.005

Stromal-derived factor-1 (SDF-1/CXCL12) is chemotactic for lympho/hematopoietic stem cells. We have previously shown that increasing peripheral blood (PB) levels of SDF-1 with adenovectors expressing human SDF-1 complementary DNA (ad-SDF-1) leads to hematopoietic stem cell mobilization as well as migration of megakaryocytes and thrombocytosis in mice. Herein, we studied the in vivo effects of ad-SDF-1 and of an analogue peptide of SDF-1 (CTCE-0214) on human hematopoiesis in a xenotransplant model. Sublethally irradiated (300 cGY) NOD/SCID mice transplanted with human cord blood mononuclear cells (CB MNC) were injected with ad-SDF-1 (10 9 plaque forming units, IV, ×1) or CTCE-0214 (10 mg/kg/dose, IV q 24 hours ×7). Effects on megakaryocytopoiesis (CD41 + cells and platelets) as well as stem cell mobilization were monitored. CB MNC in NOD/SCID mice are able to differentiate into CD41 + cells and platelets, peaking at week 9 at a mean of 3.7×10 3/μL. IV injection of ad-SDF-1 increased human CD41 + cells by day 4 in PB and was followed by an increase in human platelet production by day 5, with return to baseline by day 30. Human colony-forming cells (CFC) were mobilized from bone marrow to spleen (by day 6–13) and to PB (by day 13). Human CD34 + and CD33 + cells were mobilized by this treatment as well. A novel SDF-1 peptide agonist (CTCE-0214) also mobilized human CFC and enhanced human thrombopoiesis. SDF-1 and its analogue may be of clinical value in stimulating platelet recovery after chemo/radiation treatment as well as in stem cell mobilization.