In a breakthrough study, scientists in Canada have made blood from skin directly without having to go through the middle step of changing a skin stem cell into a pluripotent stem cell, bringing closer the day when blood used in surgery or to treat cancer, anemia and other conditions, is made from a patch of the patient’s own skin.

The researchers, from McMaster University, Hamilton, Ontario, wrote about their work in a paper published in Nature on 7 November. A statement from the university suggests clinical trials could start in 2012.

Study leader Dr Mick Bhatia, scientific director of McMaster’s Stem Cell and Cancer Research Institute in the Michael G. DeGroote School of Medicine, and colleagues, managed to show it is possible to make blood from skin directly, that is without having to go through the intermediate step of transforming a human skin cell into a pluripotent stem cell (a cell that has the potential to become virtually any other type of human cell) then turning it into a blood stem cell.

“We have shown this works using human skin,” Bhatia told the press, explaining that now they know how it works they are confident they can improve the process.

“We’ll now go on to work on developing other types of human cell types from skin, as we already have encouraging evidence,” he added.

Previous studies have been able to show that it is possible to create neurons and heart muscle cells directly from fibroblast skin cells in mice, but this is the first study to show a direct conversion from skin cells to another type of cell in humans, and the first to achieve direct conversion to a stem cell, in this case for blood.

Over two years, Bhatia and colleagues repeated the conversion several times, using skin from young and old people, showing that age was not an issue.

Cynthia Dunbar, who heads the Molecular Hematopoiesis Section of the Hematology Branch of the National Heart, Lung and Blood Institute, in the National Institutes of Health in the United States called the discovery “exciting”, and told the press it will transform ideas of how to produce multipotent stem cells for making the various blood cell types used in regenerative medicine and research into human blood diseases.

“Bhatia’s approach detours around the pluripotent stem cell stage and thus avoids many safety issues, increases efficiency, and also has the major benefit of producing adult-type l blood cells instead of fetal blood cells, a major advantage compared to the thus far disappointing attempts to produce blood cells from human ESCs [embryonic stem cells] or IPSCs [induced pluripotent stem cells],” said Dunbar.

For the study, Bhatia and colleagues recovered skin fibroblasts, a type of cell that makes the “scaffolding” of connective tissue that gives skin its form, from several volunteers. They used a virus to insert the gene for OCT4 in the cells and then grew them in an infusion of cytokines (signalling proteins that communicate between cells, and also stimulate the immune system).

OCT4 is a protein that in humans is encoded by the POU5F1 gene, and is one of the factors that the Japanese team, led by Shinya Yamanaka, a professor at Kyoto University, used to reprogram adult skin fibroblasts into induced pluripotent (iPS) cells; this breakthrough was exciting because it showed for the first time that it was possible to make stem cells without having to use embryos. However, Yamanaka’s method requires that the fibroblast first transform into an embryonic-like pluripotent state, before it can then become a stem cell for another type of cell.

But Bhatia and his team found no evidence that the blood stem cells they made had gone through the embryonic-like pluripotent state, because they observed none of the gene expressions that characterize that state, and the mice that they used in the experiment did not develop teratomas, a type of tumor caused by pluripotent cells.

The blood stem cells went on to produce all three types of human blood cells: white blood cells, red blood cells and platelets. And further tests showed that they functioned correctly and the red blood cells even carried adult haemoglobin, not the fetal form:

“We note that adult haematopoietic programs are activated, consistent with bypassing the pluripotent state to generate blood fate: this is distinct from haematopoiesis involving pluripotent stem cells, where embryonic programs are activated,” wrote the researchers, who concluded that:

“These findings demonstrate restoration of multipotency from human fibroblasts, and suggest an alternative approach to cellular reprogramming for autologous cell-replacement therapies that avoids complications associated with the use of human pluripotent stem cells.”

One of the many advantages that scientists can see for producing stem cells without having to go through the pluripotent stage is that it would be safer, because it would eliminate the risk of tumors. However, this, and other factors still have to be tested.

So far, Bhatia and his team have proved the concept in mice, using human cells. The final test that would prove it works in humans is to do clinical trials in humans. Although Nature News reports that Bhatia said the “clinical side is going to be a lot of work”, a statement from McMaster University suggests trials could start as early as 2012.

Funds from the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Stem Cell Network and the Ontario Ministry of Research and Innovation paid for the research.

Alain Beaudet, president of the Canadian Institutes for Health Research, said that making blood from a patient’s own skin cells has the “potential of making bone marrow transplant HLA [human leukocyte antigen] and paucity of donors a thing of the past”.

Christine Williams, director of research for the Canadian Cancer Society Research Institute, said the breakthrough study “holds enormous promise for improved treatment of many types of cancer, including solid tumours and leukemias”.

“Direct conversion of human fibroblasts to multilineage blood progenitors.”
Eva Szabo, Shravanti Rampalli, Ruth M. Risueño, Angelique Schnerch, Ryan Mitchell, Aline Fiebig-Comyn, Marilyne Levadoux -Martin, Mickie Bhatia.
Nature, 7 November 2010.

Additional sources: McMaster University, Nature News, wikipedia.

Written by: Catharine Paddock, PhD