The olfactory epithelium maintains stem and progenitor cells that support the neuroepithelium’s life-long capacity to reconstitute after injury. However, the identity of the stem cells – and their regulation – remain poorly defined. The transcription factors Pax6 and Sox2 are characteristic of stem cells in many tissues, including the brain. Therefore, we assessed the expression of Pax6 and Sox2 in normal olfactory epithelium and during epithelial regeneration after methyl bromide lesion or olfactory bulbectomy. Sox2 is found in multiple kinds of cells in normal epithelium, including sustentacular cells, horizontal basal cells, and some globose basal cells. Pax6 is co-expressed with Sox2 in all these, but is also found in duct/gland cells as well as olfactory neurons that innervate necklace glomeruli. Most of the Sox2/Pax6-positive globose basal cells are actively cycling, but some express the cyclin-dependent kinase inhibitor p27Kip1, and are presumably mitotically quiescent. Among globose basal cells, Sox2 and Pax6 are co-expressed by putatively multipotent progenitors (labeled by neither anti-Mash1 nor anti-Neurog1) and neuron-committed transit amplifying cells (which express Mash1). However, Sox2 and Pax6 are expressed by only a minority of immediate neuronal precursors (Neurog1- and NeuroD1-expressing). The assignment of Sox2 and Pax6 to these categories of globose basal cells is confirmed by a temporal analysis of transcription factor expression during the recovery of the epithelium from methyl bromide-induced injury. Each of the Sox2/Pax6-colabeled cell types is at a remove from the birth of neurons; thus, suppressing their differentiation may be among the roles of Sox2/Pax6 in the olfactory epithelium.

Aging is the biggest risk factor for several neurodegenerative diseases. Parabiosis experiments have established that old mouse brains are improved by exposure to young mouse blood. Previously, our lab showed that delivery of Growth Differentiation Factor 11 (GDF11) to the bloodstream increases the number of neural stem cells and positively affects vasculature in the subventricular zone of old mice. Our new study demonstrates that GDF11 enhances hippocampal neurogenesis, improves vasculature and increases markers of neuronal activity and plasticity in the hippocampus and cortex of old mice. Our experiments also demonstrate that systemically delivered GDF11, rather than crossing the blood brain barrier, exerts at least some of its effects by acting on brain endothelial cells. Thus, by targeting the cerebral vasculature, GDF11 has a very different mechanism from that of previously studied circulating factors acting to improve central nervous system (CNS) function without entering the CNS.