期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 9, 期 421, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aag3214
关键词
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资金
- Human Frontier Science program
- Leukemia and Lymphoma Society
- Canadian Stem Cell Network
- Canadian Institutes of Health Research
- Ontario Institute for Cancer Research
- Terry Fox Foundation
- Ontario Institute for Regenerative Medicine postdoctoral fellowship
- Swiss Initiative in Systems Biology Transition Postdoc fellowship
- Canadian Blood and Marrow Transplantation David Smyth fellowship
- Sears Cancer Research fellowship
- Garron Family Cancer Centre Research fellowship
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-alpha (TNF alpha) was specifically found to directly impair the survival and division of transplanted HSCs and progenitor cells. Neutralizing donor T cell-derived TNF alpha in vivo increased short-term stem and progenitor cell engraftment, accelerated hematopoietic recovery, and altered donor immune cell compositions. This direct effect of TNF alpha 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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