Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but the large number of HSCs required limits its widespread use. Host conditioning and donor cell composition are known to affect HSCT outcomes. However, the specific role that the posttransplantation signaling environment plays in donor HSC fate is poorly understood. To mimic clinical HSCT, we injected human umbilical cord blood (UCB) cells at different doses and compositions into immunodeficient NOD/SCID/IL-2Rgc-null (NSG) mice. Surprisingly, higher UCB cell doses inversely correlated with stem and progenitor cell engraftment. This observation was attributable to increased donor cell–derived inflammatory signals. Donor T cell–derived tumor necrosis factor–α (TNFα) was specifically found to directly impair the survival and division of transplanted HSCs and progenitor cells. Neutralizing donor T cell–derived TNFα in vivo increased short-term stem and progenitor cell engraftment, accelerated hematopoietic recovery, and altered donor immune cell compositions. This direct effect of TNFα on transplanted cells could be decoupled from the indirect effect of alleviating graft-versus-host disease (GVHD) by interleukin-6 (IL-6) blockade. Our study demonstrates that donor immune cell–derived inflammatory signals directly influence HSC fate, and provides new clinically relevant strategies to improve engraftment efficiency during HSCT.

同种异体造血干细胞移植（HSCT）是一种治疗方法，但是所需的大量HSC限制了其广泛应用。已知宿主调节和供体细胞组成会影响HSCT结果。但是，人们对移植后信号传导环境在供体HSC命运中所起的特定作用了解甚少。为了模拟临床HSCT，我们将不同剂量和成分的人脐带血（UCB）细胞注射到免疫缺陷的NOD / SCID / IL-2Rgc-null（NSG）小鼠中。令人惊讶的是，较高的UCB细胞剂量与干细胞和祖细胞植入成反比。该观察结果归因于供体细胞衍生的炎症信号增加。特别发现供体T细胞来源的肿瘤坏死因子-α（TNFα）直接损害移植的HSC和祖细胞的存活和分裂。在体内中和供体T细胞衍生的TNFα会增加短期干细胞和祖细胞的植入，加速造血恢复，并改变供体免疫细胞的组成。TNFα对移植细胞的直接作用可以与白介素6（IL-6）阻断减轻移植物抗宿主病（GVHD）的间接作用分离。我们的研究表明，供体免疫细胞衍生的炎症信号直接影响HSC的命运，并提供新的临床相关策略以提高HSCT期间的植入效率。加速造血恢复，并改变供体免疫细胞组成。TNFα对移植细胞的直接作用可以与白介素6（IL-6）阻断减轻移植物抗宿主病（GVHD）的间接作用分离。我们的研究表明，供体免疫细胞衍生的炎症信号直接影响HSC的命运，并提供新的临床相关策略以提高HSCT期间的植入效率。加速造血恢复，并改变供体免疫细胞组成。TNFα对移植细胞的直接作用可以与白介素6（IL-6）阻断减轻移植物抗宿主病（GVHD）的间接作用分离。我们的研究表明，供体免疫细胞衍生的炎症信号直接影响HSC的命运，并提供新的临床相关策略以提高HSCT期间的植入效率。