Skeletal Stem Cell-Schwann Cell Circuitry in Mandibular Repair

Abstract

SUMMARY Regenerative paradigms exhibit nerve dependency, including regeneration of the mouse digit tip and salamander limb. Denervation impairs regeneration and produces morphological aberrancy in these contexts, but the direct effect of innervation on the stem and progenitor cells enacting these processes is unknown. We devised a model to examine nerve dependency of the mouse skeletal stem cell (mSSC), the progenitor responsible for skeletal development and repair. We show that after inferior alveolar denervation, mandibular bone repair is compromised because of functional defects in mSSCs. We present mSSC reliance on paracrine factors secreted by Schwann cells as the underlying mechanism, with partial rescue of the denervated phenotype by Schwann cell transplantation and by Schwann-derived growth factors. This work sheds light on the nerve dependency of mSSCs and has implications for clinical treatment of mandibular defects.

Neuronal substrates alter the migratory responses of nonmyelinating Schwann cells to controlled brain‐derived neurotrophic factor gradients

“…Regenerative strategies rely strongly upon the local migration of replacement and/or supplemental cells (Mishra, Pena, Redenti, & Vazquez, ; Thakur et al, ), which requires detailed knowledge of cell migratory capacity and response(s). Although cell replacement therapies using terminal SCs remain elusive (Couve, Lovera, Suzuki, & Schmachtenberg, ), SC migration has been reported to aid axonal regeneration and synaptic SC–MN connections during transplantation of SCs, individually and in combination with different stem‐like cells and biomaterials (Ban et al, ; Hyung et al, ; Jones et al, ; Xia et al, ; Xie et al, ; Yang et al, ; Zeng et al, ; Zhang et al, ). As a result, our study examined the concurrent use of neurotrophin gradients and neuronal substrates to stimulate migratory behaviors of nmSCs via both chemical stimulus and haptotactic pathways (Figure ).…”

“…Although numerous projects highlight neuron–muscle interactions for motility (Chhabra et al, ; Huie, Almeida, & Ferguson, ; Webster, ), only a handful of NMJ studies use models that include glia to leverage the significant roles of these cells in NMJ function and repair (Brosius Lutz & Barres, ; Du, Chen, Tseng, Eisenberg, & Firestein, ; Hyung, Jung, Cho, & Jeon, ). SC inclusion is vital to regenerative therapies because adult SCs of the peripheral NS possess remarkable regenerative abilities (Jessen & Mirsky, ; Kim, Mindos, & Parkinson, ), including de/differentiation (Arthur‐Farraj et al, ), migration to sites of injury (Ji et al, ; Sohn, Jo, & Park, ), and glial bridging to synapse with adjacent functional neurons (Jones et al, ; Mousavi et al, ). Terminal SCs of the NMJ are active, nonmyelinating, synaptic partners that modulate cell–cell communication essential to motor function and recovery (Griffin & Thompson, ; Negro et al, ).…”

Sensory nerve‐deficient microenvironment impairs tooth homeostasis by inducing apoptosis of dental pulp stem cells

“…The microenvironment where MSCs reside in modulates the biological behavior of MSCs 10 . For example, 3D scaffolds promote cell survival and regenerative capacity 39 .…”

“…Studies have illustrated that denervation impedes cellular behaviour in various tissues, 8,9 but whether and how denervation impairs odontogenic stromal/stem cells responsible for tooth homeostasis remains elusive. The rodent lower incisor as an independent organ grow continuously, offering an excellent model to address the relationship between nerve and odontogenic stromal/stem cells 10 . Additionally, dental pulp stromal/stem cells (DPSCs) as a kind of mesenchymal stromal/stem cells (MSCs) in tooth can differentiate into odontoblasts and pulp cells participating in tooth homeostasis and regeneration 11‐13 .…”

Skeletal stem cells: insights into maintaining and regenerating the skeleton

“…Nerve cells may also influence repair. For example, it has been shown that Shh emanating from nerves maintains tooth incisor stem cells, and that Schwann cells from nerves in the mandible potentially provide important paracrine factors for bone repair in the jaw (Jones et al, 2019;Zhao et al, 2018). The influence of cells from the immune system may also be crucial.…”