Immunoregulatory dendritic cells in traumatic injury and biomaterial implantation

Introduction:: After injury and biomaterial implantation there is a large influx of immune cells to prevent infection and clean up damaged tissue. In this response to tissue damage there is a disruption in homeostasis and release of self-antigen. The balance between recruiting enough inflammation to prevent infection and clear damaged tissue, while being inhibitory enough to prevent autoimmunity and subsequent tissue damage is a critical process to understand for development of future therapeutics.


Materials and Methods:: We utilized a murine model of volumetric muscle loss (VML) for injury and subsequent biomaterial implantation. The VML is generated through surgical excision of a 3mm portion of the quadriceps muscle group that is backfilled with a particulate decellularized extracellular matrix (ECM) scaffold, polyethylene (PE), or a surgical saline control. Muscles are excised at 3-, 7-, 21-, and 42-days post-injury for analysis via flow cytometry, histopathology, and transcriptomics. Data were analyzed via FlowJo, R, GraphPad Prism, and MatLab.


Results, Conclusions, and Discussions:: Early in response to injury, pro-regenerative materials (ECM) induce the recruitment of eosinophils, whereas pro-fibrotic materials (PE) recruit neutrophils. In both material microenvironments there is a strong presence of macrophages accompanied by a small but prevalent population of dendritic cells. These dendritic cells are largely cDC1s in ECM treatment (by the expression of CD103 and XCR1) but double negative suggesting pDC or mDC phenotype in PE treatment. Evaluating these dendritic cells closer in ECM treated mice, we find high levels of CD206 and CD301b, and though they lack the canonical CD8a marker -- they are ablated in BATF3-knockout mice suggesting that they are cross-presenting dendritic cells. These trauma-associated dendritic cells are accompanied by CD4+ and CD8+ regulatory T cells. In the absence of tDCs peripheral CD4+ T cell activation increases in the draining lymph node and circulating blood. Furthermore, tissue architecture changes in BATF3-knockout mice showing increased white fat and fibrosis in muscle tissue, accompanied by increases in Adiponectin and Collagen I gene expression, and heterotrophic ossification, accompanied by increases in Acvr1, a gene associated with a human disease, FOP, characterized by excessive post-trauma ossification. Interestingly, there are increases in myogenesis genes, suggesting tDCs and BATF3 are major regulators of post-trauma tissue development. Mechanistically, these cells are recruited by NK cells that secrete XCL-1 and an increase in E-Cadherin in injured muscle tissue.


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