Sensory nerves in the spotlight of the stem cell niche

Abstract

Niches are specialized tissue microenvironments that control stem cells functioning. The bone marrow mesenchymal stem cell niche defines a location within the marrow in which mesenchymal stem cells are retained and produce new cells throughout life. Deciphering the signaling mechanisms by which the niche regulates stem cell fate will facilitate the use of these cells for therapy. Recent studies, by using state-of-the-art methodologies, including sophisticated in vivo inducible genetic techniques, such as lineage-tracing Cre/loxP mediated systems, in combination with pharmacological inhibition, provide evidence that sensory neuron is an important component of the bone marrow mesenchymal stem cell niche. Strikingly, knockout of a specific receptor in sensory neurons blocked stem cell function in the bone marrow. The knowledge arising from these discoveries will be crucial for stem cell manipulation in the future. Here, we review recent progress in our understanding of sensory nerves biology in the stem cell niche.

Keywords: genetic depletion; mesenchymal stem cells; microenvironment; niche; sensory nerves.

FIGURE 1

Schematic illustration summarizing the findings from genetic deletion of EP4 specifically from sensory nerve fibers in the bone marrow mesenchymal stem cell (BMSC) niche. Sensory fibers innervate the bone marrow BMSC niche. (Right) Sensory nerves maintain MSC number in the bone marrow, which differentiate normally into osteoblasts. (Left) In contrast, genetic ablation of EP4 from sensory innervations reduces the number of BMSCs, likewise their capacity to self‐renew and to differentiate into the osteogenic lineage. This leads to inhibited osteogenesis and induced adipogenesis ⁹²

FIGURE 2

Sensory nerves role in the hair follicle melanocyte stem cell (MeSC) niche. Two main stem cell populations are present in the hair follicle bulge: MeSCs and hair follicle stem cells (HFSCs). MeSCs generate new pigmented hair. Zhang and colleagues revealed that hyperactivation of sympathetic nerves leads to MeSCs activation, proliferation, and consequently elimination from their niche, leading to hair discoloration. ¹²⁶ Interestingly, resinoferatoxin (RTX), which causes sensory nerve denervation as well, was used to induce stress. Adrb2, β2‐adrenergic receptor; NE, norepinephrine

FIGURE 3

Sensory nerves' possible roles in the tumor microenvironment. Sensory neuronal projections infiltrate the tumor microenvironment. The study of Prazeres and colleagues indicates that sensory nerves block cancer progression. ¹²⁴ Cellular and molecular mechanisms by which sensory nerves influence cancer development remain uncertain. Future works should examine whether sensory nerves regulate tumor‐associated mesenchymal stem cells (MSCs), cancer stem cells, or/and dormant tumor cells