The protection of hematopoietic stem and progenitor cells and their environment is required for recovery from radiation-induced (RI) myelosuppression. To achieve this goal, we propose a new gene therapy strategy based on local and short-term synthesis and expression of Sonic hedgehog morphogene (Shh) at the niche level. We investigated the hematopoietic response of 8 Gy gamma-irradiated monkeys to a single intra-osseous injection of multipotent mesenchymal stem cells (adipocyte-derived stem cells/ASC) transduced with a Shh pIRES2 plasmid (3+/-0.4 × 10(6) cells/kg on day (D) 2; n=4). Control animals were injected with mock-ASCs (n=4). Two controls died from radiation toxicity on D19 and D196, whereas all Shh-ASC treated monkeys fully recovered. Thrombocytopenia (4.75+/-1.8 days versus 10+/-2.2 days, platelet count <20 × 10(9)/L), neutropenia (14.2 +/-1 days versus 17.7 +/-2.6 days, ANC count<0.5 × 10(9)/L) and anemia (15.5 +/-3.6 days versus 50.7 +/-31 days, Hb less than 10 g/dL) duration were reduced in Shh-ASC animals. Areas under the curve of platelets (P<0.05), ANCs (P=0.06) and RBC/Hb between D0 and D30 were higher in Shh-ASC injected animals. Globally this study suggests that Shh may represent a new factor to counteract RI-myelosuppression.