Clumps of mesenchymal stem cells/extracellular matrix complexes directly reconstruct the functional periodontal tissue in a rat periodontal defect model

Abstract

Periodontitis is an inflammatory disease characterized by tooth‐supporting periodontal tissue destruction, including the cementum, periodontal ligament, and alveolar bone. To regenerate the damaged periodontal tissue, mesenchymal stem cells (MSCs) have attracted much scientific and medical attention. Recently, we generated clumps of MSCs/extracellular matrix (ECM) complexes (C‐MSCs), which consist of cells and self‐produced ECM. C‐MSCs can be transplanted into lesion areas without artificial scaffold to induce tissue regeneration. To develop reliable scaffold‐free periodontal tissue regenerative cell therapy by C‐MSCs, this study investigated the periodontal tissue regenerative capacity of C‐MSCs and the behavior of the transplanted cells. Rat bone marrow‐derived MSCs were isolated from rat femur. Confluent cells were scratched using a micropipette tip and then torn off. The sheet was rolled to make a three‐dimensional round clump of cells, C‐MSCs. Then, ten C‐MSCs were grafted into a rat periodontal fenestration defect model. To trace the grafted cells in the defect, PKH26‐labeled cells were also employed. Micro‐CT and histological analyses demonstrated that transplantation of C‐MSCs induced successful periodontal tissue regeneration in the rat periodontal defect model. Interestingly, the majority of the cells in the reconstructed tissue, including cementum, periodontal ligaments, and alveolar bone, were PKH26 positive donor cells, suggesting the direct tissue formation by MSCs. This study demonstrates a promising scaffold‐free MSCs transplantation strategy for periodontal disease using C‐MSCs and offers the significance of multipotency of MSCs to induce successful periodontal tissue regeneration.

Distinctive Biological Properties between Mesenchymal Stem Cell Spheroids and Clumps of Mesenchymal Stem Cells/Extracellular Matrix Complexes in 3D Culture Systems

“…In fact, C-MSCs demonstrated good handleability, allowing for direct transplantation in bone or periodontal tissue defects. Notably, C-MSC transplantation without an artificial scaffold into the defects induced successful tissue regeneration via grafted cell differentiation at the defect sites [36,37], suggesting the stability of the grafted cells. Attempting such procedures using MSC spheroids of a diameter less than 500 µm might present challenges.…”

Current Application of iPS Cells in the Dental Tissue Regeneration

“…Recently, iPS cells have been differentiated into somatic stem cells before they were transplanted to decrease the risk of tumorigenesis. As MSCs are known to have a high ability to regenerate PDL tissue [ 64 , 65 , 66 ], several studies used iPS-derived MSCs for the regeneration of PDL tissue. Hynes et al reported the significant increase in PDL tissues and alveolar bone in a rat periodontal defect model when iPS-MSCs were transplanted with fibrinogen and thrombin clots, compared with the control group [ 63 ].…”