Researchers in Australia have cracked the code to transform pluripotent stem cells into blood stem cells similar to the rare bone marrow cells that can make all types of blood and immune cells. The researchers say that this has enormous potential in treating people with diseases of the blood and blood-forming organs.
Researchers have taken a major step towards a medical revolution, enabling many critically ill people with leukaemia or bone marrow failure to be treated with bone marrow cells developed from the person’s own cells, such as skin cells.
Researchers from the Melbourne node of the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW Melbourne), Australia have made this breakthrough by figuring out how to convert pluripotent stem cells into blood stem cells that can generate a human blood system in a laboratory mouse while the researchers can show that the cells function normally.
The researchers hope that these blood stem cells can also be transplanted into a person’s bone marrow and create a complete blood system, including red blood cells to carry oxygen, white blood cells to fight infection and platelets to clot blood.
The breakthrough has attracted attention from around the world.
“We have been working on this for 25 years and have finally succeeded. Many laboratories around the world have been striving to solve this problem, but we are the first to produce blood in culture and make it work inside the human body. Many colleagues worldwide are contacting us now to learn more about the protocol. The interest is enormous,” explains a researcher leading the research, Elizabeth Ng, Associate Professor, Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW Melbourne and the Murdoch Children’s Research Institute, Parkville, Australia.
The research has been published in Nature Biotechnology.
Nobel Prize awarded for research on pluripotent stem cells in 2012
Researchers have been able to create pluripotent stem cells from adult human cells, such as skin cells, since Shinya Yamanaka’s 2006 research led to a Nobel Prize.
This requires turning on the stem cell programme in developed cells to make them develop back to a stage at which, in principle, they can develop into any kind of cell.
This type of stem cell is called an induced pluripotent stem cell, and the discovery of the cellular programme that causes mature cells to become induced pluripotent stem cells led to researchers John B. Gurdon and Shinya Yamanaka being awarded the Nobel Prize in 2012.
Although making stem cells from skin cells, blood cells or other cells has long been possible, researchers were unable to crack the code to transform induced pluripotent stem cells into bone marrow stem cells, known as haematopoietic stem cells.
The researchers solved this problem in the new study.
“We have spent 25 years developing the protocol that causes the induced pluripotent stem cells to become haematopoietic stem cells. Induced pluripotent stem cells are like early embryonic stem cells that can become all types of cells if they are given the right instructions in the form of growth factors. We have discovered these instructions,” says Andrew Elefanty, another researcher behind the study a the Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW Melbourne and the Murdoch Children’s Research Institute.
Several stages of development
The protocol involves several stages over two weeks.
First, the researchers make the induced pluripotent stem cells form small spheres called embryoid bodies that provide specific growth factors that cause the embryoid bodies to differentiate into the next stage, called mesoderm.
In the embryo, mesoderm forms bones, muscles, connective tissue, heart, blood vessels (endothelium) and blood cells.
The researchers then give the mesodermal cells specific growth factors and signalling molecules, causing them to develop into endothelial cells, which then give rise to blood cells. After two weeks, red blood cells begin to appear in the culture dish.
“Many others have tried to make functioning blood stem cells in the laboratory, but we are the first to succeed with human cells,” explains Elizabeth Ng.
Mice started forming blood with new bone marrow cells
The next step involved transplanting the cells grown in the laboratory into mice. The researchers injected the cells into a vein in the mice’s tail and then tested whether the cells migrated to the bone marrow, settled there and began to grow.
The researchers dyed the cells red or blue to make them easier to track in the mice and confirmed that the cells migrated to the bone marrow and began producing various blood cells there.
The researchers also examined the spleens of the mice and found millions of B cells and T cells produced by the laboratory-created blood stem cells.
“This proves that we cannot merely make blood cells in a culture dish but can also transplant them into a mouse and make them work there. The cells also look completely normal compared with transplanted umbilical cord blood cells,” says Elizabeth Ng.
Making litres of blood
Elizabeth Ng and Andrew Elefanty see great clinical potential in the discovery. Specifically, they envision that people with leukaemia or bone marrow failure can have their bone marrow or blood cells replaced with cells developed from their own tissue – a perfect genetic match.
However, this requires making more cells than those that fit in a petri dish. To solve this problem, the researchers are therefore testing bioreactors to produce patient-sized doses of blood stem cells for clinical use.
Elizabeth Ng explains that, in addition to being able to produce enough cells for different individual patients, the laboratory-created bone marrow cells also have another advantage of coming from the patients themselves.
“When patients receive cells from a donor, there is often a high risk that the patient’s immune system will react to the new cells because they are not a perfect match. The patient therefore needs immunosuppressive treatment, which has various side-effects, and the patient may become ill and the cells may not work properly. Since our cells come from the patients themselves, we hope to overcome all these problems,” notes Elizabeth Ng.
Aim to start human trials in five years
Elizabeth Ng and Andrew Elefanty say that the goal is to start the first human clinical trials in five years but that considerable work is needed to realise this.
The researchers must show that they can reproduce the results over and over and with cells from many people, that the cells are both safe and effective and that the production of blood stem cells can be scaled up effectively.
“We are collaborating with doctors who specialise in transplantation to help us to find patients for the first clinical trials, but we must first show that this treatment is safe. We need to identify the necessary steps to get there,” concludes Elizabeth Ng.
