Research ArticleTransplantation

Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell–mediated TNFα signaling

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Science Translational Medicine  20 Dec 2017:
Vol. 9, Issue 421, eaag3214
DOI: 10.1126/scitranslmed.aag3214

TNFα tampers with stem cell success

Most stem cell transplantation procedures are performed with unrelated donor/recipient pairs. One source of stem cells is umbilical cord blood, but the number of cells derived from this source can be limiting. Wang et al. examined factors that affect proliferation, engraftment, and differentiation of human umbilical cord stem cells in a preclinical model. They found that donor T cell production of TNFα was harmful to stem cell health. In the future, inhibiting TNFα after stem cell transplantation could lead to improved patient outcomes.


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.

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