Dataset Information

Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques.

ABSTRACT: It has been demonstrated that mesenchymal stem cells (MSCs) differentiated from human embryonic stem cells (hESCs), name EMSCs, can treat a variety of autoimmune and inflammatory diseases, with similar efficacies to those achieved with MSCs derived from somatic tissues such as bone marrow (BMSCs). The chance increases even higher for EMSCs, than somatic tissue derived MSCs?, to become a cell drug as the former can be produced in large scale from an unlimited hESC line with easier quality control and less biosafety concern. We have further demonstrated that both human ESCs and EMSCs, after aggregation to form spheroids, can tolerate hypoxic and ambient conditions (AC) for over 4 and 10 days, respectively, without loss of their viability and alteration of their functions. Based on these advantages, we decided to test whether EMSC spheroids, made in large quantity and delivered through a long-term distance at AC, can treat osteoarthritis spontaneously developed in rhesus macaques (M. mulatta) monkeys as well as the allogenic MSCs. Methods: Xenogeneic AC-transported EMSC spheroids or allogenic BMSCs were injected into the articular cavity of both knees of the monkeys at 3 animals per group. Another two macaques were injected the same way with saline as controls. Results: Both EMSCs and BMSCs groups showed significant amelioration indicated by the reduction of swelling joint size and amplification of keen flare angle post-treatment, compared to the control group. Examinations via X-ray and MRI also indicated the decrease of inflammation and osteophyma, and recovery of the synovium and cartilage in both treated groups. No sign of allergy or graft versus host disease was observed in the animals. Conclusion: Our results demonstrate that human EMSC spheroids can prevent the osteoarthtitis progression and ameliorate osteoarthritis in the rhesus macaques as well as allogenic BMSCs, and this study shall help advance the clinical application of EMSCs.

SUBMITTER: Jiang B

PROVIDER: S-EPMC6771254 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques.

Jiang Bin B Fu Xufeng X Yan Li L Li Shanshan S Zhao Dongliang D Wang Xiaoyan X Duan Yanchao Y Yan Yaping Y Li Enqin E Wu Kunhua K Inglis Briauna Marie BM Ji Weizhi W Xu Ren-He RH Si Wei W

Theranostics 20190821 22

It has been demonstrated that mesenchymal stem cells (MSCs) differentiated from human embryonic stem cells (hESCs), name EMSCs, can treat a variety of autoimmune and inflammatory diseases, with similar efficacies to those achieved with MSCs derived from somatic tissues such as bone marrow (BMSCs). The chance increases even higher for EMSCs, than somatic tissue derived MSCs, to become a cell drug as the former can be produced in large scale from an unlimited hESC line with easier quality control ...[more]

PMID: 31588237

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Project description:Liver fibrosis is a disease that causes high morbidity and has become a major health problem. Liver fibrosis can lead to the end stage of liver diseases (livercirrhosisand hepatocellularcarcinoma). Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, the shortage of organ donors, high cost of medical surgery, immunological rejection and transplantation complications severely hamper liver transplantation therapy. Mesenchymal stem cells (MSCs) have been regarded as promising cells for clinical applications in stem cell therapy in the treatment of liver diseases due to their unique multipotent differentiation capacity, immunoregulation and paracrine effects. Although liver fibrosis improvements by MSC transplantation in preclinical experiments as well as clinical trials have been reported, the in vivo fate of MSCs after transportation and their therapeutic mechanisms remain unclear. In this present study, we isolated MSCs from the bone marrow of rhesus macaques. The cells exhibited typical MSC markers and could differentiate into chondrocytes, osteocytes, and adipocytes, which were not affected by labeling with enhanced green fluorescent protein (EGFP). The harvested MSCs respond to interferon-? stimulation and have the ability to inhibit lymphocyte proliferation in vitro. EGFP-labeled MSCs (1 × 106 cells) were transplanted into mice with carbon tetrachloride-induced liver fibrosis via tail vein injection. The ability of the heterogenic MSC infusion to ameliorate liver fibrosis in mice was evaluated by a blood plasma chemistry index, pathological examination and liver fibrosis-associated gene expression. Additionally, a small number of MSCs that homed and engrafted in the mouse liver tissues were evaluated by immunofluorescence analysis. Our results showed that the transplantation of heterogenic MSCs derived from monkey bone marrow can be used to treat liver fibrosis in the mouse model and that the paracrine effects of MSCs may play an important role in the improvement of liver fibrosis.

Project description:BackgroundOur group has developed a novel method for spontaneous spheroid formation using a specific low-adherence culture plate with around 90° water contact angle. In this study, this method was applied for oral mucosa-derived cells. First, the feasibility of spontaneous spheroid formation was tested. Next, the characteristics of spontaneous spheroids from oral mucosa- and skin-derived cells were compared with special focus on the stemness and neuronal differentiation capability.MethodsOral mucosal cells were obtained from the palate and buccal mucosa of C57BL/6J mice. Similarly, skin cells were obtained from the back of the same mouse strain. Passage 2-3 cells were inoculated into the specific low-adherence culture plates to form spontaneous spheroids. The effect of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and B27 supplement on spheroid formation and maintenance was assessed. Immunofluorescence and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were performed to investigate the expression of pluripotency markers, cell proliferation and apoptosis markers, and neurogenic differentiation markers.ResultsUsing this culture plate, spontaneous spheroid formation was feasible. This process depended on the presence of serum but was independent of the additives such as bFGF, EGF, and B27 supplement, although they improved the efficiency and were essential for spheroid maintenance. This result was confirmed by the higher expression of Caspase7 in the spheroids cultured without the additives than that with the additives. The spheroids from oral mucosa-derived cells expressed stem cell markers, such as Sox2, SSEA1, Oct4, Nanog, and Nestin. The expression of Sox2 in spheroids from oral mucosal cells was higher than that in spheroids from skin-derived cells. Both spheroid-forming cell types had the ability to differentiate into neural and Schwann cells after neurogenic induction, although significantly higher MAP 2, MBP, Nestin, and Nurr1 gene expression was noted in the cells from oral mucosa-derived spheroids.ConclusionsThe results showed that spontaneous spheroids from oral mucosa-derived cells contain highly potent stem cells, which were as good as skin-derived stem cells. The high expression of certain neuronal marker genes suggests an advantage of these cells for regeneration therapy for neuronal disorders.

Dataset Information

Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques.

Publications

Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques.

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