Mesenchymal Stem Cell Sheet Engineering: Refining Cell Delivery Strategies in Regenerative Medicine

Mesenchymal stem cells (MSCs) have been widely investigated in regenerative medicine owing to their immunomodulatory activity, paracrine signaling, and multilineage differentiation potential. However, accumulating clinical and preclinical evidence indicates that conventional MSC therapies based on single-cell injection often produce transient benefits due to rapid post-transplant cell loss and poor engraftment. These observations suggest that the limited efficacy of MSC therapy is not determined solely by cell type or disease context but may also be influenced by the delivery strategy. In this review, we focus on MSC-based cell sheet studies as an approach to improve cell retention and therapeutic persistence. Building on the clinical validation of cell sheet technology, we critically summarize preclinical evidence across distinct tissue environments. Preclinical studies in cardiac and cutaneous repair models demonstrate that MSC sheets enhance cell retention, sustain paracrine signaling, and promote tissue-level regeneration. Together, these findings highlight that effective MSC sheet therapy requires organ-specific, cell-source-dependent design strategies rather than a uniform approach across tissues. Finally, we propose that the MSC sheet engineering represents not a technical adjustment, but a conceptual shift from transient cell delivery toward structurally integrated, tissue-level regeneration engineering.