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

Adam C Wilkinson,Maiko Morita,Hiromitsu Nakauchi,Satoshi Yamazaki

doi:10.1016/j.exphem.2018.04.004

Adam C Wilkinson, Maiko Morita + Show 2 more

Open Access

https://doi.org/10.1016/j.exphem.2018.04.004

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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.

Highlights

Branched-chain amino acid depletion conditions bone marrow for hematopoietic stem cell transplantation avoiding amino acid imbalance-associated toxicity
The morbidity and mortality associated with traditional BM conditioning regimens, radiation and/or chemotherapy, currently limit the application of HSCT [5]
Through single-cell assays, we found that branched-chain amino acids (BCAAs) imbalance blocked hematopoietic stem cell (HSC) expansion through a combination of increasing cell death and inhibiting proliferation (Figures 1C and 1D)

Summary

Introduction

Branched-chain amino acid depletion conditions bone marrow for hematopoietic stem cell transplantation avoiding amino acid imbalance-associated toxicity. We reported that dietary valine depletion could be used to condition mice for HSCT [6]. When valine was reduced to »10% while the concentration of isoleucine/leucine (I/L) was simultaneously increased fivefold (valine-low, I/L-high), HSC expansion was blocked completely (Figures 1A and 1B).

Results

Conclusion