Antibodies turn hematopoietic cells into nerve stem cells
The result of a happy accident was the discovery by scientists of the Scripps Research Institute, working under the leadership of Professor Richard A. Lerner, of antibodies that ensure the transformation of bone marrow stem cells into precursor cells of brain neurons.
Antibodies are Y-shaped molecules synthesized by immune cells B-lymphocytes. Already in the 80s of the last century, specialists learned how to produce the antibodies they needed using cell cultures in the laboratory.
In the late 80s, Lerner and his colleagues took part in the development of the first technologies for creating large libraries of antibodies and quickly identifying antibodies specific to a given target. Last year, they proposed a new method for creating antibodies, implying their production in mammalian cells, occurring simultaneously with the production of receptors or other target molecules specific to them. This allows researchers to quickly determine not only which antibodies from the library bind to the molecule of interest to them, but also, for example, which of them activate the target molecule, changing the functions of the cell.
At the early stages of testing the technique, the developers used it to screen antibodies capable of activating a receptor for granulocyte colony stimulating factor (G-CSF) expressed on the surface of hematopoietic cells of the bone marrow and leukocytes. Drugs that stimulate the activity of G-CSF are often used to restore hematopoiesis in patients who have undergone antitumor chemotherapy and / or radiotherapy.
Very soon, the researchers were able to isolate an antibody clone that activates the receptor for G-CSF and, accordingly, stimulates the proliferation of leukocytes. However, further testing on the culture of hematopoietic bone marrow cells showed that, unlike the G-CSF protein itself, which stimulates the differentiation of these cells into mature leukocytes, antibodies to the G-CSF receptor had a completely unexpected effect. Stem cells proliferated, but at the same time they stretched and adhered to the bottom of the culture plate. A detailed study of the resulting cells showed that they are the precursor cells of neurons.
Typical morphology of cells obtained with the help of antibodies. A and B are individual cells that adhered to the surface of the cover glass after two weeks of treatment with G–CSF agonist antibodies. White arrows indicate growth cones. C is a bipolar morphology inherent in some cells after 10 days of cultivation. The arrows point to long axons (pictures from the PNAS article).
Currently, specialists have at their disposal methods for converting bone marrow stem cells into other types of cells, however, they require deprogramming cells into a state similar to that of embryonic cells, followed by exposure to complex complexes of growth factors that guide their differentiation in the right direction. Therefore, the direct transformation or transdifferentiation of hematopoietic bone marrow cells into nerve cells by activating a single receptor is a very significant achievement.
Scientists have not yet been able to decipher the mechanism by which antibodies have such an unexpected effect on the G-CSF receptor. They assume that the duration of their contact with the receptor is longer than the duration of the contact of the growth factor itself, and that this somehow changes the signaling mechanism triggered by the receptor.
Specialists involved in the development of drugs are increasingly paying attention to the fact that even minor differences in the nature of binding and activation of a particular receptor can lead to completely different biological effects. This significantly complicates the tasks facing them, while at the same time greatly expanding the range of opportunities that lie before them.
Article by Jia Xie et al. Autocrine signaling based selection of combinatorial antibodies that transdifferentiate human stem cells is published in the journal Proceedings of the National Academy of Sciences.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Scripps Research Institute:
Scripps Research Institute Scientists Find Antibody that Transforms Bone Marrow Stem Cells Directly into Brain Cells.
24.04.2013