Cell Sheet Technology as a Platform for Functional Regeneration.

Cell sheet technology has evolved into a unique scaffold-free and biomaterial-free regenerative medicine platform that enables transplantation of intact cellular constructs while preserving extracellular matrix and cell-cell interactions. Clinical applications of cell sheet technology have demonstrated successful tissue and organ regeneration in the cornea, esophagus, heart, cartilage, and retina. More recently, the therapeutic scope of cell sheet technology has expanded beyond tissue replacement toward stem cell-based regenerative therapy, in which paracrine signaling, anti-fibrotic activity, and microenvironment remodeling play important roles. In this review, we use the term "functional regeneration" as an integrative therapeutic framework of a regenerative medicine platform capable of promoting the regenerative processes that modify disease pathophysiology and may alter the natural history of a disease, irrespective of complete anatomical reconstitution. Liver cirrhosis is a representative target disease for this concept of functional regeneration because the functional regenerative therapy that reverses progressive fibrosis and restores hepatic function has the opportunity to prevent the onset of hepatocellular carcinoma. This review discusses the evolution of cell sheet technology, the biological basis of stem cell-based functional regeneration, and the development of KCS-003, a cell sheet-based therapeutic product manufactured from mesenchymal stem/stromal cells preconditioned with IC-2, which has potent anti-fibrotic action and promotes liver regeneration. In addition, clinical investigations, including corneal and retinal reconstitution, esophageal regeneration, cartilage repair, and cardiac patches, were shown as representative clinical cases of cell sheet technology.