Meningeal cells contribute to cortical neurogenesis in postnatal brain

Neurogenesis continues throughout life in mammalian brain (Eriksson et al., 1998; Gage, 2000) in two germinal niches: the subventricular zone lining the lateral ventricle and subgranular zone in the dentate gyrus of the hippocampus (Gage and Temple, 2013). Radial glial cells (Kriegstein and Alvarez-Buylla, 2009) are the neural stem cells that, during embryonic and postnatal development, give rise to various cell types including neuroblasts, neurons, oligodendrocytes, astrocytes and ependymal cells (Kriegstein and Alvarez-Buylla, 2009). In adult mice, newly formed neuroblasts migrate through the rostral migratory stream to the olfactory bulb, where they continually replace local interneurons (Imayoshi et al., 2008). Apart from these well-established neural stem niches, the existence of ectopic neural stem cell niches has been reported following injury (Pluchino et al., 2010), as well as in selected physiological conditions in the retina, cerebellum and olfactory bulb (Menezes et al., 1995; Ponti et al., 2008; Tropepe et al., 2000). Interestingly, several independent groups have recently identified a novel role for meninges as a potential niche harbouring endogenous stem cells with neural differentiation potential in the adult central nervous system (Bifari et al., 2009, 2015; Decimo et al., 2011; Nakagomi et al., 2011, 2012; Petricevic et al., 2011). Surprisingly, meningeal neural precursors are able to differentiate both in vitro and, after transplantation in vivo, into neurons with extremely high efficiency (Bifari et al., 2009; Decimo et al., 2011). Moreover, these cells can be activated by central nervous system parenchymal injuries, undergoing an extensive expansion of stem cells and progenitors (Nakagomi et al., 2012). Meningeal neural precursors contribute to neural parenchymal reaction after spinal cord injury, migrating to the perilesioned area, while expressing the same markers (nestin and DCX) that are transiently expressed by neural precursors within classic neurogenic niches (Decimo et al., 2011). The finding of this new cell population in the meninges, with stem cell features, provides new insights into the complexity of the parenchymal reaction to a traumatic injury and suggests a potential role for meningeal progenitor cells in the maintainance of brain homeostasis. However, the possible contribution of meningeal neural precursors to neurogenesis in physiological conditions has not previously been investigated. During the course of my studies, I explored the hypothesis that meningeal cells may contribute to neurogenesis in vivo. We were able to specifically tag meningeal cells in P0 pups and track them during time, combining injection of cell tracers in the meningeal subarachnoid space and transgenic mouse lines. We found that neurogenic meningeal cells migrate from their location outside the brain parenchyma, along the meningeal substructures, to the retrosplenial and visual motor cortices during the neonatal period. Subsequently, meningeal-derived cells differentiate into cortical neurons that are electrophysiologically functional, integrated in the existing network and responsive to pharmacological stimuli. In addition we found that these meningeal neurogenic cells belongs to the perivascular PDGFRß+ lineage and are mainly additive to the well-characterized neurogenic parenchymal radial glia. Although the developmental origin of these cells still has to be elucidated, our preliminary data indicate a possible neural crest-derivation. Thus, a reservoir of embryonic derived progenitors residing in the meninges contributes to postnatal cortical neurogenesis. These cells may have a role as endogenous stem cell pool that can be exploited in regenerative medicine for neurodegenerative diseases.