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Scientists from the German Cancer Research Center (DKFZ) and the stem cell institute HI-STEM* in Heidelberg have succeeded for the first time in directly reprogramming human blood cells into a previously unknown type of neural stem cell. These induced stem cells are similar to those that occur 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 of our tissues: they can multiply indefinitely and then -- if they are pluripotent embryonic stem cells -- generate all conceivable cell types. In 2006, the Japanese scientist Shinya Yamanaka recognized that such cells could also be produced in the laboratory -- from mature body cells. Four genetic factors alone are sufficient to reverse the course of development and produce so-called induced pluripotent stem cells (iPS) that 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 applies in particular to for research in Germany, where the generation of human embryonic stem cells is not permitted. Stem cells have enormous potential both for basic research and for the development of regenerative therapies that aim to restore diseased tissue in patients. However, reprogramming is also associated with problems: For example, pluripotent cells can form germ line tumors, so-called teratomas.

Another possibility is not to completely turn back the course of development. For the first time, Trumpp's team has succeeded in reprogramming mature human cells in such a way that a defined type of induced neural stem cells is produced that can multiply almost indefinitely. "We used four genetic factors like Yamanaka, but different ones for our reprogramming," explains Marc Christian Thier, first author of the study. "We assumed that our factors would allow reprogramming to an early stage of development of the nervous system."

In the past, other research groups also reprogrammed connective tissue cells into mature nerve cells or neural precursor cells. However, these artificially produced nerve cells often could not be expanded and could therefore hardly be used for therapeutic purposes. "Often, it was a heterogeneous mixture of different cell types that might not exist in the body under physiological conditions," said Andreas Trumpp explaining the problems.

Together with stem cell researcher Frank Edenhofer from the University of Innsbruck and neuroscientist Hannah Monyer from DKFZ and the Heidelberg University Hospital, Trumpp and his team have succeeded in reprogramming different human cells: connective tissue cells of the skin or pancreas as well as peripheral blood cells. "The origin of the cells had no influence on the properties of the stem cells," said Thier. In particular, the possibility of extracting neural stem cells from the blood of patients without invasive intervention is a decisive advantage for future therapeutic approaches.

What is special about the reprogrammed cells of the Heidelberg researchers 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. "Corresponding cells exist 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 embryo.

These so called "induced Neural Plate Border Stem Cells" (iNBSCs) have a broad development potential. The iNBSCs of the Heidelberg scientists are expandable and multipotent and can develop in two different directions. On the one hand, they can take the path of development to mature nerve cells and their supplier cells, the glial cells, i.e. become cells of the central nervous system. On the other hand, they can also develop into cells of the neural crest, from which different cell types emerge, for example peripheral sensitive nerve cells or cartilage and bones of the skull.

The iNBSCs thus form an ideal basis for generating a broad range of different cell types for an individual patient. "These cells have the same genetic material as the donor and are therefore presumably recognized as "self" by the immune system and are not rejected," explains Thier.

The CRISPR/Cas9 gene scissors can be used to modify the iNBSC or repair genetic defects, as the scientists have shown in their experiments. "They are therefore of interesting both for basic research and the search for new active substances and for the development of regenerative therapies, for example in patients with diseases of the nervous system. However until we can use them in patients, a lot of research work will still be necessary," emphasizes Trumpp.

Date: December 21, 2018
Source: German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
Summary: Scientists have succeeded for the first time in directly reprogramming human blood cells into a previously unknown type of neural stem cell. These induced stem cells are similar to those that occur 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.

The steady production of sperm relies on the number of sperm stem cells in the testis remaining constant. Researchers including Asst. Prof. Yu Kitadate and Prof. Shosei Yoshida (developmental biologists at the National Institute for Basic Biology within the National Institutes of Natural Sciences in Japan) and Prof. Benjamin Simons (a theoretical physicist at the University of Cambridge in the UK) have revealed a novel mechanism for stem cell number control. Their results show that constant sperm stem cell numbers are achieved, in mouse testes, through a self-organized process in which they actively migrate and compete for a limited supply of self-renewal-promoting fibroblast growth factors (FGFs). This study was published on line in Cell Stem Cell on Nov. 20th, 2018.

To ensure a balance between the loss of differentiated cells and their replacement in long-lived multicellular organisms, it is critically important to keep the number of tissue stem cells constant. Failure to maintain stem cell number is thought to underlay the progression of ageing and disease. In tissues like the testis and ovary of the fruitfly Drosophila and intestine of mammalians, stem cells are clustered in their specialized home where self-renewal-promoting factors are abundant: the stem cell niche. In these tissues, stem cell numbers are controlled simply by the capacity of the niche. However, sperm stem cells are not clustered in mouse testis, but are highly motile and widely dispersed across the basement membrane. Yet, their density remains surprisingly uniform thus raising the question of how their numbers are regulated.

In this study, the researchers found that a subset of lymphatic endothelial (LE) cells produce FGFs (Fgf5, 8 and 4 in particular), which promote stem cell self-renewal.

Asst. Prof. Kitadate said, "The lymphatic endothelial cells in the testis were described via the use of electron microscopy in the 1970s, but had scant attention paid to them for a long time. By a stroke of good luck, our screening met these cells again and threw light on their hidden roles!"

Quantitative analyses of mice with increased or decreased FGF production revealed a simple mechanism: migratory stem cells uptake and consume FGFs. Stem cells which consume more FGFs are likely to duplicate, while those that consume less are inclined to differentiate. Under this framework, stem cells effectively compete with each other for a limited supply of FGFs, leading the stem cell number to automatically adjust to a particular value, depending on the rate of FGF supply. The discovery of a novel, and extremely simple, mechanism of stem cell number control based on "competition for self-renewal promoting factors (or mitogens)" advances our understanding of the regulation of stem cells in tissues without a canonical, anatomically definable stem cell niche -- a microenvironment sometimes called an "open niche."

Prof. Simons said, "As a general and robust mechanism of stem cell density control, these findings may have important implications for the regulation of stem cell density in other tissue types."

Prof. Yoshida said, "Sperm stem cells migrate in the testis to intake FGFs, just as cows move around the meadow to eat the grass which they live on. Interestingly, the dynamics of stem cells can be described using mathematics similar to that for ecosystem -- a fruit of my beloved interdisciplinary research team!"

Date: December 20, 2018
Source: National Institutes of Natural Sciences
Summary: Researchers have revealed a novel mechanism for stem cell number control.