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August 06, 2020

Guidelines for safe stem cell cartilage therapies

The Noriyuki Tsumaki laboratory estimates the amount of its iPS cell cartilage product can be transplanted safely into humans.

In preparation for new clinical research that they are expected to begin next year, CiRA researchers report the maximum amount of cartilage prepared from iPS cells that will not grow into tumors after transplantation into rats. The study provides guidelines for the amount of cartilage to be transplanted into human patients.

Ever since joining CiRA, professor and orthopedic surgeon Noriyuki Tsumaki has dedicated his research to studying and treating cartilage diseases with iPS cell technology.

"Cartilage has poor regenerative properties. When patients injure their cartilage, like with knee trauma, the pain remains because the cartilage does not heal and can develop into more serious cases like osteoarthritis," he explains.

Standard care involves rehabilitation or, in more serious cases, cartilage transplant. The cartilage used in this transplant can come from the patient (autografts) or from third-party donors (allografts). Autografts are safest but require an additional invasion to acquire the new cartilage. Plus, depending on the size of the cartilage trauma, a sufficient amount cannot be procured. With enough donors, enough allograft can be prepared, but the quality can vary, which is why not all patients recover well.

Tsumaki's research team has therefore been preparing cartilage from iPS cells that are of clinical grade (iPS-Cart). Because these iPS cells are abundant and of high quality, the scientists can prepare enough cartilage for a patient.

However, whenever using stem cells, one worry remains.

"One major concern with stem cell therapies is malignant tumors. If the transplant is contaminated with highly proliferating transformed cells, then malignant tumors are a serious risk," says Tsumaki.

To quantify this risk and provide guidelines for the first in-human transplant of a cartilage product made from iPS cells, the Tsumaki team mixed their iPS-Cart with HeLa cells, a type of malignant tumor cell commonly used in biomedical experiments and recommended by the WHO to test the tumorgenicity of a biological material, and injected the mixture into rat knee joints.

Contamination with 100,000 HeLa cells caused tumors in some rats, but contamination with 10,000 HeLa cells did not. Extrapolating this result to humans suggested that about 15 g of iPS-Cart would be safe.

"15 grams would file a defect of about 68 cm2. That's bigger than most defects we see in the clinic," says Tsumaki.

At the same time, the study emphasized that HeLa cells and rats only provide an estimation of how iPS cell products will behave in humans and that its results should be viewed as one piece of the information used to decide the maximum amount that can be safely transplanted.

Paper Details
  • Journal: Scientific Reports
  • Title: Quality assessment tests for tumorigenicity of human iPS cell-derived cartilage
  • Authors: Yoshiaki Takei1,2, Miho Morioka1, Akihiro Yamashita1, Tomohito Kobayashi1, Nobuyuki Shima1 and Noriyuki Tsumaki1
  • Author Affiliations:
    1. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
    2. Regenerative Medicine Technology Department, Healthcare R&D Center, Asahi KASEI Corporation, Tokyo, Japan
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