Astrocytes within the neurogenic zones of the adult central nervous system (CNS) support the formation and maturation of neurons from progenitor cells throughout life. In contrast, astrocytes outside of neurogenic zones dedifferentiate and contribute to scar tissue formation after injury, creating a physical barrier to regenerating neurons. Moreover, reactive astrocytes can create a chemical barrier and be toxic for neurons after injury. Therefore, understanding the signaling pathways that switch astrocytes from neurogenesis-inhibitory to neurogenesis-supportive is a promising approach to reverse the progression of neurodegenerative diseases and traumatic CNS injuries.

The mammalian olfactory system shows robust neurogenesis throughout life, with neurosensory cells capable of renewal and differentiation. There is growing evidence that a distinct type of glia, olfactory ensheathing cells (OECs), regulate the astrocytic stress response in the olfactory bulb (OB) and is critical for the neuroregenerative properties of the olfactory system. Therefore, OECs can be leveraged as a tool to identify signals pertinent for maintaining neurorepair-promoting characteristics in astrocytes.

Exosomes are extracellular nanovesicles that serve intercellular communication. Our results show that an exosome secreted protein, Alpha-crystallin B chain (CryAB), plays an important role in astrocyte-OEC crosstalk. CryAB was shown to have protective roles for cells against stress conditions. In accordance, our results indicate that OEC-secreted, CryAB positive exosomes are taken up by astrocytes and this intercellular vesicle trafficking plays an anti-inflammatory role in astrocytes by moderating activity of pro-inflammatory factors.

OECs also support astrocyte differentiation via sustained fibroblast growth factor (FGF) signaling. FGFs are crucial factors in CNS development and injury response, and are targets for neuroregenerative strategies. Heparan sulfate proteoglycans (HSPGs) are cell-specific proteins that can be shed from the membrane and regulate FGF signaling in the donor cell. We show OEC-HSPGs differentially activate FGF receptor-1 (FGFR1) signaling in astrocytes and suppress reactivity. Moreover, our results suggest a mechanistic role for OEC-HSPGs in intracellular FGFR1 trafficking and its association with the transcriptional machinery in astrocytes. Together this work shows that OB OECs are integral components of one of the few neurogenic zones in the CNS. Mimicking OEC-astrocyte crosstalk in vivo may provide new approaches to ameliorating CNS injuries by targeting astrocytes.