Sensory and motor fibroblasts have different protein expression patterns and exert different growth promoting effects on sensory and motor neurons.

Functional reconstruction after peripheral nerve injury depends on the ability of the regenerated sensory and motor axons to re-innervate the suitable target organs. Therefore, it is essential to explore the cellular mechanisms of peripheral nerve-specific regeneration. In a previous study, we found that sensory and motor fibroblasts can guide Schwann cells to migrate towards the same phenotype. In the present paper, we analyzed the different effects of sensory and motor fibroblasts on sensory or motor neurons. The fibroblasts and neurons co-culture assay showed that compared with motor fibroblasts, sensory fibroblasts promote the neurite outgrowth of sensory neurons on a larger scale, and vice versa. Furthermore, a higher proportion of sensory or motor fibroblasts migrated towards their respective (sensory or motor) neurons. Meanwhile, a comparative proteomic approach was applied to obtain the protein expression profiles of sensory and motor fibroblasts. Among a total of 2597 overlapping proteins identified, we counted 148 differentially expressed items, of those 116 had a significantly higher expression in sensory fibroblasts, and 32 had a significantly greater expression in motor fibroblasts. Functional categorization revealed that differentially expressed proteins were involved in regeneration, axon guidance and cytoskeleton organization, all of which might play a critical role in peripheral nerve-specific regeneration. After nerve crush injury, ITB1 protein expression decreased significantly in motor nerves and increased in sensory nerves. In vitro, ITB1 significantly promoted axonal regeneration of sensory neurons, but had no significant effect on motor neurons. Overall, sensory and motor fibroblasts express different proteins and exert different growth promoting effects on sensory and motor neurons. This comparative proteomic database of sensory and motor fibroblasts could provide future directions for in-depth research on peripheral nerve-specific regeneration. Data are available via ProteomeXchange with identifier PXD034827.

Activin A Secreted From Peripheral Nerve Fibroblasts Promotes Proliferation and Migration of Schwann Cells.

The peripheral nervous system has remarkable regenerative capabilities. Schwann cells and fibroblasts are known to play crucial roles in these processes. In this study, we delineated the differential effects of peripheral nerve fibroblasts and cardiac fibroblasts on Schwann cells. We found that peripheral nerve fibroblasts significantly promoted Schwann cell proliferation and migration compared with cardiac fibroblasts. The cytokine array results identified 32 of 67 proteins that were considered differentially expressed in peripheral nerve fibroblasts versus cardiac fibroblasts. Among them, 25 were significantly upregulated in peripheral nerve fibroblasts compared with cardiac fibroblasts. Activin A, the protein with the greatest differential expression, clearly co-localized with fibroblasts in the in vivo sciatic never injury rat model. In vitro experiments proved that activin A secreted from nerve fibroblasts is the key factor responsible for boosting proliferation and migration of Schwann cells through ALK4, ALK5, and ALK7. Overall, these findings suggest that peripheral nerve fibroblasts and cardiac fibroblasts exhibit different patterns of cytokine secretion and activin A secreted from peripheral nerve fibroblasts can promote the proliferation and migration of Schwann cells.