RT Journal Article
SR Electronic
T1 Peripheral Nerve Single Cell Analysis Identifies Mesenchymal Ligands that Promote Axonal Growth
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0066-20.2020
DO 10.1523/ENEURO.0066-20.2020
A1 Jeremy S. Toma
A1 Konstantina Karamboulas
A1 Matthew J. Carr
A1 Adelaida Kolaj
A1 Scott A. Yuzwa
A1 Neemat Mahmud
A1 Mekayla A. Storer
A1 David R. Kaplan
A1 Freda D. Miller
YR 2020
UL http://www.eneuro.org/content/early/2020/04/29/ENEURO.0066-20.2020.abstract
AB Peripheral nerves provide a supportive growth environment for developing and regenerating axons and are essential for maintenance and repair of many non-neural tissues. This capacity has largely been ascribed to paracrine factors secreted by nerve-resident Schwann cells. Here, we used single cell transcriptional profiling to identify ligands made by different injured rodent nerve cell types and have combined this with cell surface mass spectrometry to computationally model potential paracrine interactions with peripheral neurons. These analyses show that peripheral nerves make many ligands predicted to act on peripheral and central nervous system neurons, including known and previously uncharacterized ligands. While Schwann cells are an important ligand source within injured nerves, more than half of the predicted ligands are made by nerve-resident mesenchymal cells, including the endoneurial cells most closely associated with peripheral axons. At least three of these mesenchymal ligands, ANGPT1, CCL11 and VEGFC, promote growth when locally applied on sympathetic axons. These data therefore identify an unexpected paracrine role for nerve mesenchymal cells and suggest that multiple cell types contribute to creating a highly pro-growth environment for peripheral axons.SIGNIFICANCE STATEMENT This work expands our understanding of the cellular sources of ligands in the injured peripheral nerve that are potentially important for promoting axon growth. Here, we used single cell RNA sequencing (scRNA-seq) to reveal that Schwann cells and, surprisingly, nerve mesenchymal cells are primary sources of ligands in the injured nerve. We then combined injured nerve scRNA-seq data with proteomic and transcriptomic data from sensory and sympathetic neurons and used a systems-biology/modeling approach to predict novel mesenchymal cell-derived factors that may promote peripheral axon growth. We tested some of these predictions and found three factors, ANGPT1, CCL11 and VEGFC, that promoted outgrowth of cultured sympathetic axons, supporting a potential role for mesenchymal-derived factors in axon growth.