Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA; Department of Haematology, University of Cambridge, Cambridge, UK.
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Exp Hematol. 2018 Jul;63:12-16.e1. doi: 10.1016/j.exphem.2018.04.004. Epub 2018 Apr 26.
Hematopoietic stem cells (HSCs) are used clinically in bone marrow (BM) transplantation due to their unique ability to reform the entire hematopoietic system. Recently, we reported that HSCs are highly sensitive to valine, one of the three branched-chain amino acids (BCAAs) in addition to isoleucine and leucine. Dietary depletion of valine could even be used as a conditioning regimen for HSC transplantation. Here, we report that HSCs are highly sensitive to the balance of BCAAs, with both proliferation and survival reduced by BCAA imbalance. However, low but balanced BCAA levels failed to rescue HSC maintenance. Importantly, in vivo depletion of all three BCAAs was significantly less toxic than depletion of valine only. We demonstrate that BCAA depletion can replace valine depletion as a safer alternative to BM conditioning. In summary, by determining HSC metabolic requirements, we can improve metabolic approaches to BM conditioning.
造血干细胞（HSCs）因其独特的能力能够重建整个造血系统，因此在骨髓（BM）移植中被临床应用。最近，我们报道 HSCs 对除异亮氨酸和亮氨酸之外的三种支链氨基酸（BCAAs）之一缬氨酸非常敏感。甚至可以用缬氨酸缺乏的饮食来作为 HSC 移植的预处理方案。在这里，我们报告 HSCs 对 BCAAs 的平衡非常敏感，BCAA 失衡会导致增殖和存活减少。然而，低但平衡的 BCAAs 水平未能挽救 HSC 的维持。重要的是，体内耗尽所有三种 BCAAs 比仅耗尽缬氨酸的毒性要小得多。我们证明，BCAA 耗竭可以替代缬氨酸耗竭，成为 BM 调理的更安全选择。总之，通过确定 HSC 的代谢需求，我们可以改进代谢方法来进行 BM 调理。
