Abstract
BackgroundRecent physiological and experimental data highlight the role of the sensory nervous system in bone repair, but its precise role on angiogenesis in a bone regeneration context is still unknown. Our previous work demonstrated that sensory neurons (SNs) induce the osteoblastic differentiation of mesenchymal stem cells, but the influence of SNs on endothelial cells (ECs) was not studied.MethodsHere, in order to study in vitro the interplay between SNs and ECs, we used microfluidic devices as an indirect co-culture model. Gene expression analysis of angiogenic markers, as well as measurements of metalloproteinases protein levels and enzymatic activity, were performed.ResultsWe were able to demonstrate that two sensory neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), were involved in the transcriptional upregulation of angiogenic markers (vascular endothelial growth factor, angiopoietin 1, type 4 collagen, matrix metalloproteinase 2) in ECs. Co-cultures of ECs with SNs also increased the protein level and enzymatic activity of matrix metalloproteinases 2 and 9 (MMP2/MMP9) in ECs.ConclusionsOur results suggest a role of sensory neurons, and more specifically of CGRP and SP, in the remodelling of endothelial cells extracellular matrix, thus supporting and enhancing the angiogenesis process.2_7KgRKy4YATrqDcNKG8uBVideo abstract
Highlights
Recent physiological and experimental data highlight the role of the sensory nervous system in bone repair, but its precise role on angiogenesis in a bone regeneration context is still unknown
Sensory neuron (SN) emit neurites towards Endothelial cell (EC), closely interacting In order to analyse the impact of SNs on ECs function, a new microfluidic device was engineered for co-culturing both cell types (Fig. 1a-b)
The present study reveals that SNs have a direct effect on ECs functions in view of angiogenesis and extracellular matrix (ECM) remodelling through the upregulation of expression of VegfA, Col4, Angpt1 and Mmp2 (Fig. 2)
Summary
Recent physiological and experimental data highlight the role of the sensory nervous system in bone repair, but its precise role on angiogenesis in a bone regeneration context is still unknown. The focus on skeletal neurobiology emerged with a series of sensory denervation experimental models performed mainly in rats [10, 11] and confirmed the role of peripheral innervation in the regulation of bone tissue development and regeneration. Tomlinson and colleagues demonstrated that sensory nerves coordinate the vascularization and ossification of developing endochondral bone and that, when blocking specific sensory innervation and inhibiting specific functional sensory signalling, vascular invasion of the primary ossification centre was strongly impaired [22]. The understanding of the neuro-vascular interplay, in a bone regeneration context, will open new avenues on therapeutic approaches that can sustain/modulate angiogenesis, a key process in bone remodelling and repair
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