Researchers from the German Cancer Research Center (DKFZ) and the HI-STEM * stem cell institute in Heidelberg have succeeded for the first time in direct reprogramming of human blood cells to a previously unknown type of neural stem cell. These induced stem cells are similar to those occurring during the early embryonic development of the central nervous system. They can be modified and multiplied indefinitely in the culture dish and can represent an important basis for the development of regenerative therapies.
Stem cells are considered to be the all-rounders in our tissues: they can multiply infinitely and then – if they are pluripotent embryonic stem cells – generate all possible cell types. In 2006, Japanese scientist Shinya Yamanaka acknowledged that such cells could also be produced in the laboratory – from mature body cells. Only four genetic factors are sufficient to reverse the development and produce so-called induced pluripotent stem cells (iPS) which have identical properties to embryonic stem cells. Yamanaka was awarded the Nobel Prize for Medicine in 2012 for this discovery.
"This was a major breakthrough for stem cell research," said Andreas Trumpp, German Cancer Research Center (DKFZ) and director of HI-STEM in Heidelberg. "This is especially true for research in Germany, where the generation of human embryonic stem cells is not allowed. Stem cells have great potential for both basic research and for the development of regenerative therapies aimed at restoring disease tissue in patients. However, reprogramming is also associated with problems: For example, pluripotent cells can form germline types, so-called teratoms.
Another option is not to fully reverse the trend. For the first time, Trump's team has succeeded in reprogramming mature human cells in such a way as to create a defined type of induced neural stem cells that can reproduce almost indefinitely. "We used four genetic factors such as Yamanaka, but different for our reprogramming," explains Marc Christian Thier, first author of the study. "We assumed our factors would allow reprogramming to an early stage of the development of the nervous system."
Previously, other research groups have reprogrammed connective tissue cells in mature nerve cells or neural precursor cells. However, these artificially produced nerve cells were often unable to expand and could therefore hardly be used for therapeutic purposes. "It was often a heterogeneous mixture of different cell types that might not exist in the body under physiological conditions," said Andreas Trumpp, who explained the problems.
Together with stem cell researcher Frank Edenhofer from the University of Innsbruck and neuroscientific Hannah Monyer from DKFZ and Heidelberg University Hospital, Trump and his team have succeeded in reprogramming various human cells: connective tissue cells in the skin or pancreas and peripheral blood cells. "The origin of the cells had no influence on the properties of the stem cells," said Thier. In particular, the ability to recover neural stem cells from the patient's blood without invasive intervention is a key benefit to future therapeutic approaches.
What is special about the reprogrammed Heidelberg researchers cells is that they are a homogeneous cell type that resembles a stage of neural stem cells that occurs during the embryonic development of the nervous system. "Similar cells are found in mice and probably also in humans during early embryonic brain development," said Thier. "We have described here a new neural stem cell type in the mammalian fetus.
These so-called "induced neural plate bundle cells" (iNBSCs) have a wide development potential. Heidelberg researchers' iNBSCs are expandable and multipotent and can be developed in two different directions. On the one hand, they can take the pathway to mature nerve cells and their supplier cells, the glial cells, ie. become cells in the central nervous system. On the other hand, they may also develop into cells in the neural crown from which various cell types emerge, for example, peripheral sensitive nerve cells or cartilage and skull bones.
The INBSCs are thus an ideal basis for generating a wide variety of different cell types for an individual patient. "These cells have the same genetic material as the donor and are therefore presumably considered" self "by the immune system and are not rejected," explains Thier.
CRISPR / Cas9 gene scissors can be used to alter iNBSC or repair genetic defects shown by the researchers in their experiments. "They are therefore interesting both for basic research and the search for new active substances and for the development of regenerative therapies, eg in patients with diseases of the nervous system. But until we can use them in patients, there will still be a lot of research," emphasizes Trump.