Secretion of Shh by a Neurovascular Bundle Niche Supports Mesenchymal Stem Cell Homeostasis in the Adult Mouse Incisor

Abstract

Mesenchymal stem cells (MSCs) are typically defined by their in vitro characteristics, and as a consequence the in vivo identity of MSCs and their niches are poorly understood. To address this issue, we used lineage tracing in a mouse incisor model and identified the neurovascular bundle (NVB) as an MSC niche. We found that NVB sensory nerves secrete Shh protein, which activates Gli1 expression in periarterial cells that contribute to all mesenchymal derivatives. These periarterial cells do not express classical MSC markers used to define MSCs in vitro. In contrast, NG2+ pericytes represent an MSC subpopulation derived from Gli1+ cells; they express classical MSC markers and contribute little to homeostasis but are actively involved in injury repair. Likewise, incisor Gli1+ cells but not NG2+ cells exhibit typical MSC characteristics in vitro. Collectively, we demonstrate that MSCs originate from periarterial cells and are regulated by Shh secretion from a NVB.

Roles for Hedgehog signaling in adult organ homeostasis and repair

“…SHH signaling was also recently shown to play an important role in the maintenance of dentin, the mesenchymal compartment of the incisor, which is located under the outer enamel surface (Zhao et al, 2014). The study showed that dentin turnover is dependent on HHresponding periarterial mesenchymal stem cells, which also contribute to dentin repair after injury.…”

“…The role of peripheral nerves in delivering signaling factors such as HH to regulate normal and regenerate non-neuronal tissues is only just beginning to emerge (Brownell et al, 2011;Zhao et al, 2014). Given this role of the nervous system in delivering HH ligands and the involvement of HH signaling in the developing enteric system (Liu and Ngan, 2013), it is interesting to speculate that HH released by nerves is also involved in transducing the signaling pathway in the GI system.…”

“…Much like in the skin, the HH ligand that maintains the GLI1+ stem cell population is secreted by nerves in the neighboring neurovascular bundle. HH inhibitor administration revealed that, as in the incisor epithelium, the pathway is not required to support stem cell maintenance, survival or progenitor proliferation, but is necessary for the differentiation of odontoblasts (Zhao et al, 2014).…”

“…A recent report on prostate cancer development revealed that nerve fibers innervating the prostate act as a positive regulator of cancer progression (Magnon et al, 2013). It will be interesting to determine whether any HH proteins are delivered to the prostate through peripheral nerves as is the case in the adult skin and rodent incisors (Brownell et al, 2011;Zhao et al, 2014) (Fig. 3C).…”

Different angiogenic potentials of mesenchymal stem cells derived from umbilical artery, umbilical vein and wharton’s jelly

“…However, whether arteries, veins, and capillaries represent different MSC niches remains largely unknown. A recent study suggested that mouse incisor MSCs were localized around arterioles alone and not veins or capillaries and were regulated by the neurovascular bundle niche [38]. This finding may give a possible explanation as to why UCA-PSCs had a slight advantage over UCV-PSCs in terms of angiogenic capacity.…”