Successful stem cell transplants without chemotherapy or radiotherapy?

The fundamental purpose of a stem cell transplant in blood cancer is to cure the cancer by removing the source of the cancer cells. To understand why this works, we need to explore how blood cells are made.

Every blood cell you have in your body comes from a haematopoietic (“blood-producing”) stem cell, which is found in the bone marrow – the soft spongy centre of bone. Stem cells produce other blood cells by dividing into two. Some of the cells made in that division will be stem cells too, but others will become different types of stem cell – myeloid or lymphoid. These cells in turn divide into other types, eventually making all the different types of blood cell – a process called stem cell differentiation

However, when someone has blood cancer, the process of making blood cells gets stuck. Instead of healthy blood cells, the stem cells make faulty blood cells that are unable to carry out their usual tasks, like fighting infections. However, it is possible to remove these leukaemia stem cells which have created the faulty cells and replace them with healthy stem cells using a stem cell transplant, curing the cancer.

In order for a stem cell transplant to work this cure, the original set of stem cells has to be destroyed to make room for the new stem cells in a procedure called bone marrow conditioning. Currently, conditioning is achieved through high dose radiotherapy to the whole body, or intensive chemotherapy. However, both these processes can damage healthy cells as well as cancer cells, so for people who are already frail or ill, the conditioning procedure may be too dangerous to carry out, ruling out the possibility of a stem cell transplant. There are also unpleasant long-term side effects like infertility and increased risk of developing a second cancer.

Because of these drawbacks of the current conditioning regimen, Dr Wilkinson and his colleagues started looking at other ways to condition bone marrow – and they may have found a way to do it through dietary changes.

Amino acids are a group of molecules that join together to form proteins. These proteins have a wide variety of functions in the human body – e.g. passing messages within and between cells, repairing damage, and making copies of DNA during the process of cell division. Many amino acids can be made by our bodies from scratch, but there are nine essential amino acids that we have to get from food. Without these amino acids, many systems in our body start to malfunction, including the immune system, brain and kidneys.

Professor Hiromitsu Nakauchi, who is working with Dr Wilkinson at Stanford University, previously found that ‘depleting’ (making unavailable) one of the essential amino acids, valine, stops stem cells from growing and from functioning properly – which might offer another way to condition bone marrow. However, it wasn’t clear what other side effects this might have on the body, or whether depleting other essential amino acids might have the same effect. Dr Wilkinson therefore set out to find out the answers to these questions.

First, they looked at what happened to stem cells in a cell culture – essentially, a petri dish filled with the right chemicals for stem cells to grow and divide (which scientists call ‘expansion’). As in our bone marrow, stem cells that divide in cell culture can create more stem cells or grow into other cell types. In the earlier experiments by Professor Nakauchi, stem cells taken from mice were put into cell cultures that had everything they needed, except the amino acid valine. They survived but couldn’t divide or grow.

In the current research, the team replicated this experiment and found the same effect, but they also tried expanding stem cells in a cell culture that was low in valine and two other related amino acids, leucine and isoleucine. Valine, leucine and isoleucine all belong to a group of amino acids called branched-chain amino acids (BCAAs). In the cell culture with low BCAAs, the mouse stem cells grew just as they normally would. However, after a week in cell culture, there were no longer any stem cells – they had differentiated into other types of blood cell.

Next, they tried human stem cells: in both the no-BCAA cell culture and the no-valine cell culture, the human stem cells didn’t expand at all. This was a promising result, because it suggests that there might be multiple different ways to deplete amino acids and condition human bone marrow. But what would the effects be in living creatures, rather than a petri dish?

The researchers gave two groups of mice a specialised diet: one group received a diet with no BCAAs, while the other received a diet that only lacked valine (the ‘imbalanced’ diet). Both diets reduced the number of stem cells in the bone marrow, but the no-BCAA diet was safer than the imbalanced diet: mice receiving the imbalanced diet had more side effects (like anaemia) and did not live as long as the mice receiving the no-BCAA diet.

The researchers also tried giving mice a stem cell transplant after they had been on each of these diets and found that in both cases, nearly all the blood cells present after the stem cell transplant were from the donor, not the recipient – that is, the transplants had been successful.

Dr Wilkinson is pleased with these results, and thinks they could be very helpful for people needing stem cell transplants in the future: “We hope this research will lead to safer ways to condition bone marrow for stem cell transplants and maybe even new ways to treat leukaemia. We are currently looking into whether leukaemia stem cells also depend on BCAAs to survive.”

As mice stem cells and human stem cells respond differently to depletion of BCAAs, the way humans respond to these diets and to stem cell transplants may be quite different from the way mice respond. The team’s planned next work is to look at whether there might be a potential for using this dietary technique for conditioning bone marrow in humans. They are also looking at what’s happening within stem cells that causes this reaction to a lack of BCAAs. “By better understanding why stem cells require valine, we are hoping to identify cell pathways that could be targeted with drugs for bone marrow conditioning,” Dr Wilkinson says.

You can read more about Dr Wilkinson’s research in Experimental Hematology.

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