In mammalian adult brains, neural stem cells are only present in few specific parts, so called niches. Only these niches are capable of generating new neurons. For the first time, researchers defined the proteome of these niches, the entire set of expressed proteins, and compared it to other regions of the brain. The findings help to identify key regulators for neurogenesis, an important step towards activating neurogenesis after brain injuries.
What distinguishes neural stem cell niches from other parts of the brain? Why do only these niches contain neural stem cells and the rest of the brain does not? So far, we did not know what gives the niches their special function. Also, little was known about factors allowing the integration of new neurons into existing networks in the adult brain. A comparison of the proteome of neural stem cell niches and the region in which new neurons integrate with the remaining part of the brain, aimed to shed light about the unique niche environment allowing neurogenesis in the otherwise non-permissive adult mammalian brain.
Defining the niche characteristics
In a first step, Magdalena Götz and her team characterized the proteome of these specific brain regions. They used the largest neural stem cell niche in the subependymal zone of the brain and the olfactory bulb as this is the region where newly-generated neurons from the subependymal zone migrate, differentiate and integrate. They then compared this proteome to the cerebral cortex, an area where neither neurogenesis nor integration of new neurons occurs as in most parts of the adult mammalian brain. As a result, the team found that the proteome of the neurogenic niche evokes a niche-specific extracellular matrix architecture. One of the most important characteristics was the high solubility of the extracellular matrix. Other characteristic proteins however, such as those of the multifunctional enzyme transglutaminase 2, are hardly soluble meaning strongly cross-linked. Using pharmacological inhibitors as well as genetic experiments, the team was able to show that transglutaminase 2 is crucial for the regulation of neurogenesis. Furthermore, due to its cross-linking properties, the enzyme may contribute to the unique stiffness of the neural stem cell niche in otherwise soft brain tissue.
Turning the injured brain region into a neural stem cell niche
Having established the differences between the proteome of a neurogenic and a non-neurogenic site is a key step. It could help to find ways to convert the one to the other. Equally important for future cell replacement therapies is the generation of a beneficial environment for the integration of new neurons in the cerebral cortex by activating factors from the olfactory bulb, an area where new neurons are constantly being integrated. Next, the researchers want to compare these proteomes to the environment after brain injury. Their aim is to create new neurons after brain injury by turning the injured region into a neurogenic stem cell niche. Injured tissue demonstrates alternative phenotypes, that may create additional barriers for activating neurogenesis: “One of our collaborators at the University of Cambridge showed that scar tissue in the brain is particularly soft – a trait that is hostile to the function of neurogenesis. Overcoming this hurdle and generating a beneficial environment for repair will be the next steps of our research”, says Götz.
Magdalena Götz is Head of the Division Physiological Genomics at the Biomedical Center of the Ludwig-Maximilians-University Munich and leads the Institute of Stem Cell Research at Helmholtz Zentrum München.
J. Kjell et al., 2020: Defining the adult neural stem cell niche proteome identifies key regulators of adult neurogenesis. Cell Stem Cell, DOI: 10.1016/j.stem.2020.01.002
Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,500 staff members. It is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.
The Institute of Stem Cell Research (ISF) investigates the basic molecular and cellular mechanisms of stem cell maintenance and differentiation. From that, the ISF then develops approaches in order to replace defect cell types, either by activating resting stem cells or by re-programming other existing cell types to repair themselves. The aim of these approaches is to stimulate the regrowth of damaged, pathologically changed or destroyed tissue.