Reconstruction of the lymphatic system by transplantation of a centrifuge-based bioengineered lymphatic tissue.

Abstract

The increase in cancer incidence has accelerated the need for secondary lymphedema treatments after lymphadenectomy (LD) because lymph nodes cannot be regenerated. We demonstrate that bioengineered tissues with a lymphatic network containing lymphatic endothelial cells and mesenchymal stem/stromal cells (MSCs) fabricated by a centrifugal cell stacking technique effectively treat secondary lymphedema. Centrifuge-based bioengineered lymphatic tissues (CeLyTs) with MSCs outside the tissue, prepared using mouse or human cells, survive long after transplantation and restore lymphatic flow in LD mice. CeLyTs transplanted into LD mice form a lymph node-like structure and suppress lymphedema in LD mice for 100 days post-transplantation, in contrast to conventional standard treatments including compression therapy. Lymph node-like structures composed of transplant- and host-derived cells, including immune cells, generate immune responses to an immunostimulant CpG1018. Here we show CeLyTs composed of lymphatic endothelial cells and MSCs reconstruct a lymph node and may represent a promising therapy for secondary lymphedema.