sri By Sridhar Radhakrishnan, Ph.D..

Summary:

Upon transplantation, Hematopoietic Stem Cells (HSCs) can expand and differentiate into any mature hematopoietic cell type. This ability of donor HSCs to reform a recipient's hematopoietic system is key to the success of HSC transplantation (HSCT) and thus, this is an area of great interest. For donor HSCs to engraft, the recipient bone marrow niche must first be emptied and this is normally done in rodent models via myeloablative irradiation or chemotherapy. However, myeloablative conditioning can cause severe complications, unexpected side-effects and even mortality.

Two groups have shown the role that branched chain amino acids (BCAAs, valine, isoleucine and leucine) play in the expansion and maintenance of HSCs. Taya et al, 2016, showed using a valine-deficient diet (A05080209), within a week, HSC frequency fell dramatically and thereby emptied the mouse bone marrow niche. Within 2 weeks, these researchers showed that long-term donor-HSC engraftment could be done using a diet without the need for chemoirradiative myeloablation. Wilkinson et al., 2018, improved over this model by using a diet deficient in all 3 BCAAs (A16081601). Such a BCAA deficient diet was as effective as the valine deficient diet in emptying the HSCs from the bone marrow niche, in addition, it also minimized the systemic toxicities and was safer and better tolerated than the valine deficient diet.

The ease of modifying purified diets, with amino acids as the protein source, allowed to make such formulations that could be used in lieu of complex procedures like myeloablation and could make the process of HSCs engraftment an easy procedure in rodents.

References:

1. Yuki Taya, Yasunori Ota, Adam C. Wilkinson, Ayano Kanazawa, Hiroshi Watarai, Masataka Kasai, Hiromitsu Nakauchi, Satoshi Yamazaki. Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation, Science, Dec 2016, 1152-115

2. Adam C. Wilkinson, Maiko Morita, Hiromitsu Nakauchi, Satoshi Yamazaki. Branched-chain amino acid depletion conditions bone marrow for hematopoietic stem cell transplantation avoiding amino acid imbalance-associated toxicity, Experimental Hematology, 63, 2018, Pages 12-16.e1

Diets

A05080209 – Valine deficient diet
A16081601 – Valine, Leucine and Isoleucine Deficient diet