The neurovascular unit (NVU) consists of cerebral endothelial cells that interact with pericytes, astrocytes, neurons, microglial cells and extracellular matrix to form the blood-brain barrier. This functional barrier regulates molecular movement into and out of the brain. The brain vasculature has a key role in brain development, homeostasis, and disease. Recently, the project team identified a novel perivascular cell population with exceptional neuronal differentiation potential. These perivascular meningeal stem cells (PMSCs) are activated by injury, which increases their self-renewal proliferation and migration properties. The main hypothesis of the EU-funded STEM-ACTIVATION (Perivascular meningeal stem cells: a new player in the neurovascular unit. Characterization, modulation and therapeutic potential of perivascular meningeal stem cell activation in neurological disord) project was that finding the key metabolic modulator of PMSC could yield novel therapies for neurological disorders. Researchers evaluated the in vitro activation/differentiation regulation of PMSCs via the candidate key metabolic modulator enzyme PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3). They found a clear shift from glycolytic to oxidative metabolism in proliferating cells. They also demonstrated that PFKFB3 regulates glycolysis, which is necessary for the activation of PMSC proliferation and migration. In addition, project members investigated the developmental origin of PMSCs and their possible contribution to neurogenesis in vivo. Using a transgenic mouse model, researchers established that PMSCs migrate to the cortex and contribute to postnatal cerebral cortical neurogenesis. Lineage tracing approaches indicated that these cells have a neural crest origin and they generate a subpopulation of excitatory neurons in cortical layers I-IV. In conclusion, the main discovery of the STEM-ACTIVATION initiative was the identification of the role of the distinct pool of meningeal cells in cerebral cortical neurogenesis. The results of this work were presented in several top level journal publications. Targeting the metabolism of PMSCs could help treat many neurological disorders such as stroke and Alzheimer's.
Neurovascular unit, perivascular meningeal stem cells, STEM-ACTIVATION, cortical neurogenesis