Branched-chain amino acid depletion conditions bone marrow for hematopoietic stem cell transplantation avoiding amino acid imbalance-associated toxicity

Exp Hematol. 2018 Jul;63:12-16.e1. doi: 10.1016/j.exphem.2018.04.004. Epub 2018 Apr 26.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / etiology
  • Animals
  • Bone Marrow / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Culture Media / chemistry
  • Culture Media / pharmacology
  • Culture Media / toxicity
  • Diet
  • Erythrocyte Count
  • Fetal Blood / cytology
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Isoleucine / administration & dosage*
  • Isoleucine / adverse effects
  • Isoleucine / pharmacology
  • Leucine / administration & dosage*
  • Leucine / adverse effects
  • Leucine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Radiation Chimera
  • Transplantation Conditioning / adverse effects
  • Transplantation Conditioning / methods*
  • Valine / administration & dosage*
  • Valine / adverse effects
  • Valine / pharmacology

Substances

  • Culture Media
  • Isoleucine
  • Leucine
  • Valine