M2 macrophage-laden vascular grafts orchestrate the optimization of the inflammatory microenvironment for abdominal aorta regeneration.

Abstract

The earliest tissue-engineered vascular grafts (TEVGs) applied clinically are biodegradable scaffolds laden with bone marrow mononuclear cells (BMCs). However, the inability to control BMCs fate after transplantation severely restricts their clinical use. To overcome this limitation, we developed a regenerative TEVG and investigated its role in modulating the immune microenvironment at arterial defects sites to enhance tissue regeneration. This TEVG was fabricated from a degradable elastomeric nanofiber scaffold combined with rBMCs, which had been induced to differentiate into regenerative M2 macrophages through in vitro culture. The resulting M2-derived extracellular matrix (ECM) dynamically modulated scaffold elasticity to match the biomechanical environment of the implantation site. When implanted into a rat abdominal aortic (rAA) defect model, the TEVGs, serving as interpositional artery grafts, could maintain the patency of abdominal artery blood circulation in rats and gradually transform into mature abdominal arteries within 12 months. However, the implanted rBMCs migrated away shortly after implantation. Instead, the scaffolds were initially repopulated by rat monocytes and subsequently gradually replaced by rat endothelial cells (ECs) and smooth muscle cells (SMCs). Further research revealed that the implanted M2 macrophages secrete IL-10 and IL-4, activating CD4⁺T cells and initiating the Th2 pathway. IL-4 derived from Th2 cells sustained the M2 macrophages phenotype, forming a positive feedback loop that boosted the regenerative microenvironment-key to restoring arterial function. These findings suggest that integrating BMCs into vascular grafts and regulating the extracellular microenvironment may offers a practical and efficient strategy for treating damaged and diseased arteries. STATEMENT OF SIGNIFICANCE: The earliest clinically applied tissue-engineered vascular grafts (TEVGs) are biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs), but the uncontrolled fate of BMCs after transplantation restricts their clinical use. This study developed a regenerative TEVG combining a degradable elastic nanofiber scaffold with in vitro-induced M2 macrophages. In a rat model, the TEVG maintained arterial patency and transformed into mature arteries within 12 months by activating an M2/Th2 immune positive feedback loop, offering a new strategy for arterial injury treatment.