Trial Results Suggest Safety of Trisomy 7 MSCs in Treating Meniscus Injuries

Previous research from the laboratory of Ichiro Sekiya (Tokyo Medical and Dental University, Tokyo, Japan) described the development of a mesenchymal stem cell (MSC)-based therapy for the treatment of meniscus injuries [1]. Importantly, MSCs can often display trisomy of chromosome 7 in older donors [2-7], which can prompt tumor formation [8]. In their recent STEM CELLS Translational Medicine article, researchers from the Sekiya group now report on the proportion of synovial MSCs with trisomy 7 in patients undergoing cell therapy, the relative safety of MSCs with trisomy 7, and the rate of tumor formation in patients at five years after cell therapy [9]. Overall, Mizuno et al. establish that the presence of trisomy 7 in transplanted synovial MSCs may not entail any significant problems from a safety point of view.

An initial analysis of the autologous synovial MSCs employed in the transplants using G-bands and digital karyotyping encountered trisomy 7 in three of the ten patients; in these cases, between 5 and 10% of synovial MSCs showed trisomy 7. Interestingly, a transcriptional comparison of MSCs with and without trisomy 7 failed to encounter the differential expression of representative oncogenes (i.e., CDKN1A, CDKN2A, MYC, and KIT) or chromosome 7-resident genes (i.e., EGFR, HGF, IL6, PPIA, and CAV2); furthermore, subsequent whole-genome sequencing, DNA methylation analysis, and proliferation assays also failed to detect significant differences between the two cell populations. Looking beyond safety, an assessment of in vitro analysis highlighted a similar degree of chondrogenic potential in MSCs with and without trisomy 7.

Subsequent in vivo confirmatory analysis demonstrated a lack of tumorigenic potential of human synovial MSCs with trisomy 7 after transplantation into mouse knees. Meanwhile, the five-year follow-ups of the ten human patients found that the meniscus tear became obscured after three years (by magnetic resonance imaging), but also underscored a lack of serious adverse events (including tumorigenesis), including in the three patients who received MSCs with trisomy 7.

While the results of this study strongly suggest the safety of autologous synovial MSC transplantation into the knee as a therapy for meniscus injuries, the authors do note some limitations with their study. The most critical limitation they highlight relates to the relatively small amount of MSCs containing trisomy 7, which may inhibit the detection of some phenotypes.

For more on the safety and efficacy of MSC therapy and the impact of trisomy 7, stay tuned to the Stem Cells Portal!

References

1. Sekiya I, Koga H, Otabe K, et al., Additional Use of Synovial Mesenchymal Stem Cell Transplantation Following Surgical Repair of a Complex Degenerative Tear of the Medial Meniscus of the Knee: A Case Report. Cell Transplantation 2019;28:1445-1454.
2. Kinne RW, Liehr T, Beensen V, et al., Mosaic chromosomal aberrations in synovial fibroblasts of patients with rheumatoid arthritis, osteoarthritis, and other inflammatory joint diseases. Arthritis Research & Therapy 2001;3:319.
3. Dahlén A, Broberg K, Domanski HA, et al., Analysis of the distribution and frequency of trisomy 7 in vivo in synovia from patients with osteoarthritis and pigmented villonodular synovitis. Cancer Genetics and Cytogenetics 2001;131:19-24.
4. Broberg K, Limon J, Pålsson E, et al., Clonal chromosome aberrations are present in vivo in synovia and osteophytes from patients with osteoarthritis. Human Genetics 1997;101:295-298.
5. Weiss KR, Georgescu HI, Gollin SM, et al., Trisomy 7 in synovial fibroblasts obtained from arthritic joints. Inflammation Research 1999;48:132-133.
6. Castellanos MV, Hernández JM, Ramos L, et al., Chromosomal abnormalities are related to location and grade of osteoarthritis. Osteoarthritis and Cartilage 2004;12:982-985.
7. Stumm M, Boger E, Gaissmaier CG, et al., Genomic chondrocyte culture profiling by array-CGH, interphase-FISH and RT-PCR. Osteoarthritis and Cartilage 2012;20:1039-1045.
8. Ly P, Kim SB, Kaisani AA, et al., Aneuploid human colonic epithelial cells are sensitive to AICAR-induced growth inhibition through EGFR degradation. Oncogene 2013;32:3139-3146.
9. Mizuno M, Endo K, Katano H, et al., Transplantation of human autologous synovial mesenchymal stem cells with trisomy 7 into the knee joint and 5 years of follow-up. STEM CELLS Translational Medicine 2021;10:1530-1543.