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Olfactory Neural Cells Can Become Multipotent Following Injury

by Amy E. Hamaker •

COMMENT: In this important study, researchers from Tufts University provide the first evidence that it is possible to regenerate stem cells of nasal tissue in mice, thus enlarging the population of adult stem cells. The adult stem cells regenerated in mice with injured nasal tissue. When those adult stem cells were transplanted into other mice, they were able to regenerate all the different cell types in the olfactory epithelium. The authors conclude: “If we can restore the population of stem cells in the olfactory epithelium by regenerating them or by administering the right drug as a nasal spray, we may be able to prevent deterioration in the sense of smell.”—Subinoy Das, MD

Can Ascl1+ and Neurog1+ neuronal progenitors in the olfactory epithelium (OE) become multipotent after injury, contributing significantly to tissue regeneration?

BOTTOM LINE

Adult OE progenitors that are normally fated and specified to make only neurons (Neurog1+GBCs) or only neurons and duct/gland cells (Ascl1+ GBCs) have the potential to acquire stem-like multipotency, increased proliferation, and a greater degree of self-renewal in response to epithelial damage.

Background: Adult neurogenesis in the OE is often seen as a unidirectional pathway during homeostasis and repair, resulting in the birth and differentiation of neurons and non-neuronal cells when epithelial repair requires them. At the apex are two multipotent stem cell populations: reserve horizontal basal cells (HBCs) and active globose basal cells (GBCs). Following direct epithelial lesion (surgical ablation of the olfactory bulb [OBX] and direct injury from olfactotoxins methyl bromide [MeBr] or methimazole [MTZ]), both stem cell pools contribute to regeneration.

Study design: Pulse-chase analysis using mice models.

Setting: Tufts University, Boston.

Synopsis: Two weeks after OBX, researchers found Ascl1-derived Sus cells, suggesting that Ascl1+ and Neurog1+ progenitor cells, previously specified to make neurons, became capable after injury of generating all OE cell types (except dormant HBC stem cells) for a limited time to participate in tissue regeneration without altering long-term stem cell balance. After MTZ injection, Ascl1+ GBC multipotency was much more pronounced, and a small but significant number of respiratory cells were generated. There were also statistically significant increases in non-neuronal cell generation as the injury became more severe. The newly multipotent progenitor cells were then transplanted to lesioned areas of the OE, maintaining multipotency based on the timing and the in situ injury environment. Transplanted Neurog1-eGFP+ cells harvested five days post-OBX retained multipotency, but those transplanted 14 days post-OBX were limited to generating Sus cells and olfactory sensory neurons (OSNs). Researchers also found that the transcription factor Sox2 must be present to induce the multipotency—knocking out Sox2 prevented non-neuronal cell generation two weeks after recombination and injury, keeping Neurog1+ or Ascl1+ GBCs from becoming multipotent. Single cell-level analysis identified the Ezh2 gene as a potential epigenetic regulator of induced multipotency. They found no apparent role for Notch signaling in modulating induced multipotency.

Citation: Lin B, Coleman JH, Peterson JN, et al. Injury induces endogenous reprogramming and dedifferentiation of neuronal progenitors to multipotency. Cell Stem Cell. 2017;21:761–774.