Teratoma-free cartilage regeneration using p21−/− iPSCs engineered with iCasp9

TL;DR

Researchers used modified stem cells to regenerate cartilage without causing tumors, offering a promising new approach for cartilage repair.

Contribution

The study introduces a safety mechanism using iCasp9 to eliminate tumor-forming stem cells while preserving their regenerative potential.

Findings

iCasp9 activator AP20187 prevented tumor formation in mice after iPSC transplantation.

Both p21−/− and p21+/+ iPSCs showed similar cartilage regeneration capabilities.

Tumor formation occurred when iCasp9 was not activated in transplanted iPSCs.

Abstract

Objective: Articular cartilage has limited regenerative capacity due to its lack of innervation, vascularization, and lymphatic vessels. As cartilage is devoid of nerves, injuries often go unnoticed until degeneration leads to pain, reduced function, and ultimately osteoarthritis (OA). Treatment options for cartilage injury, both surgical and nonsurgical, depend on factors like defect size, shape, depth, location, and patient age. Stem cells, particularly their ability to differentiate into chondrocytes, hold promise for cartilage repair, but no therapies have yet gained clinical approval. Recently, induced pluripotent stem cells (iPSCs) have emerged as a potential solution for cartilage regeneration. However, post-transplantation tumorigenesis remains a significant concern. To mitigate this risk, robust quality and safety protocols are needed, alongside safety mechanisms to control iPSC behavior after transplantation.

Design: The iCaspase9 (iCasp9) cell suicide system offers a promising solution, enabling selective elimination of genetically modified cells via apoptosis. We previously demonstrated that the efficiency of iCasp9-mediated killing increases in a p21 mutant background. Since p21 mutations also enhance cartilage repair, we investigated iCasp9-engineered p21−/− and wildtype (p21+/+) iPSCs in a mouse cartilage injury model.

Results: Without iCasp9 activation, both p21−/− and p21+/+ iPSCs formed tumors post-transplantation. In contrast, mice treated with the iCasp9 activator AP20187 showed no tumors. Both p21−/− and p21+/+ iPSCs demonstrated similar cartilage regeneration.

Conclusions: These findings suggest that iCasp9-mediated elimination of iPSCs can effectively mitigate tumor risks while preserving their therapeutic potential for cartilage repair.

Graphical Abstract

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