Rat tracheal cartilage regeneration using mesenchymal stem cells derived from human iPS cells

Tracheal cartilage provides structural support to the airways to enable breathing. However, it can become damaged or impaired, sometimes requiring surgical resection and reconstruction. Previously, we clinically applied an artificial trachea composed of a polypropylene mesh and collagen sponge, with a favorable postoperative course. However, the artificial trachea presents a limitation, as the mesh is not biodegradable and cannot be used in pediatric patients. Compared to a polypropylene mesh, regenerated cartilage represents an ideal material for reconstruction of the damaged trachea. The use of mesenchymal stem cells (MSCs) as a source for cartilage regeneration has gained widespread acceptance, but challenges such as the invasiveness of harvesting and limited cell supply, persist. Therefore, we focused on the potential of human induced pluripotent stem cell (hiPSC)-derived mesenchymal stem cells (iMSCs) for tracheal cartilage regeneration. In this study, we aimed to regenerate tracheal cartilage on an artificial trachea as a preliminary step to replace the polypropylene mesh. iMSCs were induced from hiPSCs through neural crest cells and transplanted with a polypropylene mesh covered with a collagen sponge into the damaged tracheal cartilage in immunodeficient rats. Human nuclear antigen (HNA)-positive cells were observed in all six rats at 4 weeks and in six out of seven rats at 12 weeks after transplantation, indicating that transplanted iMSCs survived within the tracheal cartilage defects of rats. The HNA-positive cells co-expressed SOX9, and type II collagen was detected around HNA-positive cells in four of six rats at 4 weeks and in three of seven rats at 12 weeks after transplantation, reflecting cartilage-like tissue regeneration. These results indicate that the transplanted iMSCs could differentiate into chondrogenic cells and promote tracheal cartilage regeneration. iMSC transplantation thus represents a promising approach for human tracheal reconstruction.