Transplantation of Human Autologous Synovial Mesenchymal Stem Cells with Trisomy 7 into the Knee Joint and 5 Years of Follow-up

Mizuno, Mitsuru; Endo, Kentaro; Katano, Harutaka; Amano, Naoki; Nomura, Masaki; Hasegawa, Yoshinori; Ozeki, Nobutake; Koga, Hideyuki; Takasu, Naoko; Ohara, Osamu; Morio, Tomohiro; Sekiya, Ichiro

doi:10.1002/sctm.20-0491

Cited by 17 publications

(14 citation statements)

References 53 publications

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“…Total RNA was extracted from synovial MSCs and HUVECs using an RNeasy Mini Kit (Qiagen N.V.). RNA sequencing was performed as described previously [ 25 ]. Briefly, the RNA concentration and quality were determined using a Quantus Fluorometer (Promega Co., WI, USA) and an Agilent 2100 Bioanalyzer, respectively.…”

Section: Methodsmentioning

confidence: 99%

Cell membrane fluidity and ROS resistance define DMSO tolerance of cryopreserved synovial MSCs and HUVECs

et al. 2022

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Objectives Synovial mesenchymal stem cells (MSCs) have high freeze–thaw tolerance, whereas human umbilical vein endothelial cells (HUVECs) have low freezing tolerance. The differences in cell type-specific freeze–thaw tolerance and the mechanisms involved are unclear. This study thus aimed to identify the biological and physical factors involved in the differences in freeze–thaw tolerance between MSCs and HUVECs. Materials and methods For biological analysis, MSC and HUVEC viability after freeze-thawing and alteration of gene expression in response to dimethyl sulfoxide (DMSO, a cryoprotectant) were quantitatively evaluated. For physical analysis, the cell membrane fluidity of MSCs and HUVECs before and after DMSO addition was assessed using a histogram for generalized polarization frequency. Results HUVECs showed lower live cell rates and higher gene expression alteration related to extracellular vesicles in response to DMSO than MSCs. Fluidity measurements revealed that the HUVEC membrane was highly fluidic and sensitive to DMSO compared to that of MSCs. Addition of CAY10566, an inhibitor of stearoyl-coA desaturase (SCD1) that produces highly fluidic desaturated fatty acids, decreased the fluidity of HUVECs and increased their tolerance to DMSO. The combination of CAY10566 and antioxidant glutathione (GSH) treatment improved HUVEC viability from 57 to 69%. Membrane fluidity alteration may thus contribute to pore-induced DMSO influx into the cytoplasm and reactive oxygen species production, leading to greater cytotoxicity in HUVECs, which have low antioxidant capacity. Conclusions Differences in freeze–thaw tolerance originate from differences in the cell membranes with respect to fluidity and antioxidant capacity. These findings provide a basis for analyzing cell biology and membrane-physics to establish appropriate long-term preservation methods aimed at promoting transplantation therapies.

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Section: Methodsmentioning

confidence: 99%

Cell membrane fluidity and ROS resistance define DMSO tolerance of cryopreserved synovial MSCs and HUVECs

et al. 2022

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“…Synovial mesenchymal stem cells also harbor a trisomy 7. One can suppose that there is a link between the synovial hyperproliferation, EGFR pathway and TGCT ( 38 , 40 ). The effect of trisomy 5 is uncertain.…”

Section: Genetic Similarities and Differences Between Tgct Ra And Sar...mentioning

confidence: 99%

Update on Tenosynovial Giant Cell Tumor, an Inflammatory Arthritis With Neoplastic Features

2022

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Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction and bone erosion. Even if many treatments were developed with success in the last decades, some patients fail to respond, and disease chronicity is still a burden. Mechanisms involved in such resistance may include molecular changes in stromal cells. Other explanations can come from observations of tenosynovial giant cell tumor (TGCT), first considered as an inflammatory arthritis, but with unusual neoplastic features. TGCT leads to synovium hypertrophy and hyperplasia with hemosiderin deposition. It affects young adults, resulting in secondary osteoarthritis and increased morbidity. TGCT shows clinical, histological and genetic similarities with RA but affecting a single joint. However, the monoclonality of some synoviocytes, the presence of translocations and rare metastases also suggest a neoplastic disease, with some features common with sarcoma. TGCT is more probably in an intermediate situation between an inflammatory and a neoplastic process, with a main involvement of the proinflammatory cytokine CSF-1/CSF1R signaling axis. The key treatment option is surgery. New treatments, derived from the RA and sarcoma fields, are emerging. The tyrosine kinase inhibitor pexidartinib was recently FDA-approved as the first drug for severe TGCT where surgery is not an option. Options directly targeting the excessive proliferation of synoviocytes are at a preclinical stage.

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“…Most studies that have evaluated the oncogenic potential of MSC had a short follow-up, usually only one or two months, which may not be sufficient to detect potential long term oncogenic effects [7,11,12]. In the clinical setting, MSC with trisomy 5 [7] or trisomy 7 [31] has already been injected into humans that were followed up for two and five years, respectively, with no signs of tumor formation. In a recent study, MSCs harboring trisomy 5 were reported incapable of generating colonies in soft agar, therefore lacking the ability of transformed cells to grow in an anchorage independent manner [32].…”

Section: Stem Cells Internationalmentioning

confidence: 99%

Preclinical Evaluation of the Tumorigenic and Immunomodulatory Properties of Human Bone Marrow Mesenchymal Stromal Cell Populations with Clonal Trisomy 5

Marodin

Godoy

Alves-Paiva

et al. 2022

Stem Cells International

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Cytogenetic aberrations may emerge in human mesenchymal stromal cells (MSC) during ex vivo expansion for cell therapy. We have detected clonal trisomy 5 in two distinct autologous MSC products expanded from bone marrow which, based on the current quality control criteria, could not be released for clinical use. Although a safety concern, it is still unclear to what extent recurrent aneuploidies detected in MSC products may affect the threshold for neoplastic transformation or the medicinal properties of these cells. We have carried out an exploratory preclinical study to evaluate these MSC products with clonal trisomy 5, regarding their oncogenic and immunomodulatory potential. Cell population growth in vitro was reduced in MSC cultures with clonal trisomy 5 compared with the population growth of their euploid MSC counterparts, based on a lower cumulative population doubling level, reduced cell proliferation index, and increased senescence-associated beta-galactosidase activity. Subcutaneous injection of clinically relevant amount of MSC population, either with or without clonal trisomy 5, did not generate tumors in immunodeficient mice within a follow-up period of six months. Most importantly, MSC population with clonal trisomy 5 kept immunomodulatory properties upon interferon gamma (IFNγ) licensing, displaying overexpression of IDO, CXCL9, CXCL10, and CXCL11, in a similar fashion than that of IFNγ-licensed euploid MSC. Our findings suggest that bone marrow MSC products with clonal trisomy 5 may retain their therapeutic potential, based on poor tumor initiating capability and preserved immunomodulatory potency. This preclinical evidence may further support the definition of release criteria of autologous MSC products for cell therapy under critical clinical scenarios. This trial is registered with Clinical Study registration number: RBR-29x2pr.

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Transplantation of Human Autologous Synovial Mesenchymal Stem Cells with Trisomy 7 into the Knee Joint and 5 Years of Follow-up

Cited by 17 publications

References 53 publications

Cell membrane fluidity and ROS resistance define DMSO tolerance of cryopreserved synovial MSCs and HUVECs

Cell membrane fluidity and ROS resistance define DMSO tolerance of cryopreserved synovial MSCs and HUVECs

Update on Tenosynovial Giant Cell Tumor, an Inflammatory Arthritis With Neoplastic Features

Preclinical Evaluation of the Tumorigenic and Immunomodulatory Properties of Human Bone Marrow Mesenchymal Stromal Cell Populations with Clonal Trisomy 5

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