Yu-Hua Chao1,2,3, Chiao-Wen Lin4,5, Hui-Hsien Pan1,2,3, Shun-Fa Yang3,6, Te-Fu Weng7, Ching-Tien Peng7,8, Kang-Hsi Wu7,9. 1. Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan. 2. School of Medicine, Chung Shan Medical University, Taichung, Taiwan. 3. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan. 4. Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan. 5. Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan. 6. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan. 7. Division of Pediatric Hematology/Oncology, Children's Hospital, China Medical University, Taichung, Taiwan. 8. Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan. 9. School of Post-baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan.
Abstract
BACKGROUND: Although immune-mediated pathogenesis is considered an important aspect of severe aplastic anemia (SAA), its underlying mechanisms remain unclear. Mesenchymal stem cells (MSCs) are essential to the formation of specialized microenvironments in the bone marrow (BM), and MSC insufficiency can trigger the development of SAA. METHODS: To find MSC alterations in the SAA BM, we compared BM MSCs from five children with SAA and five controls. Peripheral blood mononuclear cells (PBMCs) were cocultured with MSCs to evaluate the supportive effects of MSCs on hematopoiesis. Cytometric bead array immunoassay was used to determine cytokine excretion by MSCs. The immune functions of MSCs and their conditioned medium (CM) were evaluated by PBMC proliferation assays. RESULTS: SAA MSCs were characterized by a high percentage of cells in the abnormal sub-G1 phase of the cell cycle, which suggests an increased rate of apoptosis in SAA MSCs. In comparison with control MSCs, PBMCs cocultured with SAA MSCs displayed significantly reduced PBMC proliferation (P = 0.009). Aberrant cytokine profiles were secreted by SAA MSCs, with increased concentrations of interleukin-6, interferon-γ, tumor necrosis factor-α, and interleukin-1β in the CM. PBMC proliferation assays demonstrated additional immunosuppressive effects of SAA MSCs (P = 0.016) and their CM (P = 0.013). CONCLUSIONS: Our data revealed increased apoptosis and PBMC suppression of SAA MSCs. The alterations of MSCs may contribute to the formation of functionally abnormal microenvironments in SAA BM.
BACKGROUND: Although immune-mediated pathogenesis is considered an important aspect of severe aplastic anemia (SAA), its underlying mechanisms remain unclear. Mesenchymal stem cells (MSCs) are essential to the formation of specialized microenvironments in the bone marrow (BM), and MSC insufficiency can trigger the development of SAA. METHODS: To find MSC alterations in the SAA BM, we compared BM MSCs from five children with SAA and five controls. Peripheral blood mononuclear cells (PBMCs) were cocultured with MSCs to evaluate the supportive effects of MSCs on hematopoiesis. Cytometric bead array immunoassay was used to determine cytokine excretion by MSCs. The immune functions of MSCs and their conditioned medium (CM) were evaluated by PBMC proliferation assays. RESULTS:SAA MSCs were characterized by a high percentage of cells in the abnormal sub-G1 phase of the cell cycle, which suggests an increased rate of apoptosis in SAA MSCs. In comparison with control MSCs, PBMCs cocultured with SAA MSCs displayed significantly reduced PBMC proliferation (P = 0.009). Aberrant cytokine profiles were secreted by SAA MSCs, with increased concentrations of interleukin-6, interferon-γ, tumor necrosis factor-α, and interleukin-1β in the CM. PBMC proliferation assays demonstrated additional immunosuppressive effects of SAA MSCs (P = 0.016) and their CM (P = 0.013). CONCLUSIONS: Our data revealed increased apoptosis and PBMC suppression of SAA MSCs. The alterations of MSCs may contribute to the formation of functionally abnormal microenvironments in SAA BM.
Authors: Khaled Atmar; Adam J Tulling; Arjan C Lankester; Marije Bartels; Frans J Smiers; Mirjam van der Burg; Alexander B Mohseny Journal: Front Immunol Date: 2022-03-09 Impact factor: 7.561