HONG KONG — Scientists in Japan have identified an essential amino acid that is vital for the maintenance of hematopoietic stem cells (HSCs) in mice. That is a key finding that may lead to the development of a safer, more targeted pre-treatment regimen for bone marrow transplantation (BMT) in humans and possibly even a new approach to cancer therapy.
BMTs from immunologically matched, healthy donors are used to treat a wide array of serious diseases, notably cancers of the blood or bone marrow such as multiple myeloma or leukemia.
The procedure, however, involves a high degree of risk.
Before new HSCs are introduced, in order to prevent an immune reaction, cells in the bone marrow microenvironment, or niche, must first be destroyed using radiation or chemotherapy, a procedure known as myeloablation. Those cells include the multipotent HSCs that give rise to all other blood cell types, together with any cancer or cancer stem cells.
Unfortunately, especially in younger patients, myeloablation can result in severe complications, including secondary cancers, endocrine system disorders, infertility and even death. Hence there is an urgent need for a gentler conditioning technique that might result in much safer BMTs.
In their study reported in the Oct. 20, 2016 edition of Science, researchers led by Hiromitsu Nakauchi and Satoshi Yamazaki, professors in the Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine at the University of Tokyo, investigated the possibility of a nonmyeloablative approach to HSC transplantation in mice.
"It had previously been reported that rats fed a low-protein diet developed severe granulocytopenia or anemia that was corrected by the administration of purified amino acids," explained Nakauchi, who is concurrently a professor with the Department of Genetics of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University.
"Based on these findings, we hypothesized that specific amino acids may be indispensable for the bone marrow niche and influence the fate of HSCs," he told BioWorld Today.
Therefore, Nakauchi and colleagues studied cultures of HSCs that were each lacking a single amino acid, in order to determine whether any of the amino acids were essential for HSC maintenance.
They discovered that HSC replication was severely impaired in the absence of valine, an essential amino acid involved in protein synthesis. Similar impairment was found in immunodeficient chimeric mice harboring human blood cells, suggesting valine also has a critical role in human HSC maintenance.
"Both mouse and human HSCs failed to proliferate when cultured in valine-depleted conditions," said Nakauchi, noting that in mice fed a valine-restricted diet, "HSC frequency fell dramatically within one week."
In addition, when the mice were fed a diet lacking valine, they were shown to experience a significant reduction in both white blood cell and red blood cell numbers, while platelet counts were unaffected.
Importantly, however, the researchers demonstrated that when the mice were fed a valine-free diet for four weeks and were then suddenly reintroduced to the amino acid, half of the animals died. Autopsy revealed that the mortality was consistent with that due to refeeding syndrome, a form of metabolic shock associated with the reinstitution of nutrition in starvation conditions. The gradual reintroduction of the amino acid to the diet following deprivation is therefore essential.
In subsequent experiments evaluating that approach to preparing the body for BMT, the researchers found that a valine-free diet followed by its gradual reintroduction after stem cell transplantation was successful, with most mice benefiting from long-term transplantation of healthy donor HSCs.
"These findings indicate a critical role for valine in HSC maintenance," said Nakauchi, suggesting that dietary valine restriction may also reduce the complications associated with BMT. However, he also pointed out that more work needs to be done to determine whether that approach might also be safe and effective in humans.
"It still requires more preclinical studies, in order to confirm the safety and efficiency of this approach using animal models. Hopefully, there will be a clinical trial within a few years," Nakauchi said.
Meanwhile, "we would like to know whether a similar amino acid dependency exists in leukemic stem cells or in other cancer stem cells, which might open up a totally novel approach to cancer therapy."