Abstract
Articular cartilage damage does not heal spontaneously and causes joint dysfunction. The implantation of induced pluripotent stem cell (iPSC)-derived cartilage (iPS-Cart) is one candidate treatment to regenerate the damaged cartilage. However, concerns of tumorigenicity are associated with iPS-Cart, because the iPSC reprogramming process and long culture time for cartilage induction could increase the chance of malignancy. We evaluated the tumorigenic risks of iPS-Cart using HeLa cells as the reference. Spike tests revealed that contamination with 100 HeLa cells in 150 mg of iPS-Cart accelerated the cell growth rate. On the other hand, 150 mg of iPS-Cart without HeLa cells reached growth arrest and senescence after culture, suggesting less than 100 tumorigenic cells, assuming they behave like HeLa cells, contaminated iPS-Cart. The implantation of 10,000 or fewer HeLa cells into joint surface defects in the knee joint of nude rat did not cause tumor formation. These in vitro and in vivo studies collectively suggest that the implantation of 15 g or less iPS-Cart in the knee joint does not risk tumor formation if assuming that the tumorigenic cells in iPS-Cart are equivalent to HeLa cells and that nude rat knee joints are comparable to human knee joints in terms of tumorigenicity. However, considering the limited immunodeficiency of nude rats, the clinical amount of iPS-Cart for implantation needs to be determined cautiously.
Highlights
Cartilage consists of chondrocytes embedded in abundant cartilage extracellular matrix (ECM)
Induced pluripotent stem cells (PSCs) are somatic cells that have been reprogrammed to a PSC state, but unlike other PSCs such as embryonic stem cells (ESCs), they are free from ethical issues such as the sacrifice of embryos
The other is the long culture period needed to induce cartilage from PSCs and the process of cell reprogramming during the generation of induced pluripotent stem cell (iPSC), which are associated with an increased probability of iPS-Cart cells becoming malignant
Summary
Cartilage consists of chondrocytes embedded in abundant cartilage extracellular matrix (ECM). Cell growth analysis indicated that cell numbers increased constantly for up to 32 days and 40 days and more slowly after those times in culture with HeLa 0 and HeLa 10, respectively (Fig. 1d).
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