Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia
Abstract Background Cancer cachexia is a wasting syndrome that is quite common in terminal-stage cancer patients. Cancer-related anemia is one of the main features of cancer cachexia and mostly results in a poor prognosis. The disadvantages of the current therapies are obvious, but few new treatment...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-020-02120-9 |
| _version_ | 1828948295866646528 |
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| author | Boyan Wang Yi Wang Hainan Chen Senyu Yao Xiaofan Lai Yuan Qiu Jianye Cai Yinong Huang Xiaoyue Wei Yuanjun Guan Tao Wang Jiancheng Wang Andy Peng Xiang |
| author_facet | Boyan Wang Yi Wang Hainan Chen Senyu Yao Xiaofan Lai Yuan Qiu Jianye Cai Yinong Huang Xiaoyue Wei Yuanjun Guan Tao Wang Jiancheng Wang Andy Peng Xiang |
| author_sort | Boyan Wang |
| collection | DOAJ |
| description | Abstract Background Cancer cachexia is a wasting syndrome that is quite common in terminal-stage cancer patients. Cancer-related anemia is one of the main features of cancer cachexia and mostly results in a poor prognosis. The disadvantages of the current therapies are obvious, but few new treatments have been developed because the pathological mechanism remains unclear. Methods C57BL/6 mice were subcutaneously injected with Lewis lung carcinoma cells to generate a cancer-related anemia model. The treated group received daily intraperitoneal injections of SB505124. Blood parameters were determined with a routine blood counting analyzer. Erythroid cells and hematopoietic stem/progenitor cells were analyzed by flow cytometry. The microarchitecture changes of the femurs were determined by micro-computed tomography scans. Smad2/3 phosphorylation was analyzed by immunofluorescence and Western blotting. The changes in the hematopoietic stem cell niche were revealed by qPCR analysis of both fibrosis-related genes and hematopoietic genes, fibroblastic colony-forming unit assays, and lineage differentiation of mesenchymal stromal cells. Results The mouse model exhibited hematopoietic suppression, marked by a decrease of erythrocytes in the peripheral blood, as well as an increase of immature erythroblasts and reduced differentiation of multipotent progenitors in the bone marrow. The ratio of bone volume/total volume, trabecular number, and cortical wall thickness all appeared to decrease, and the increased osteoclast number has led to the release of latent TGFβ and TGFβ signaling over-activation. Excessive TGFβ deteriorated the hematopoietic stem cell niche, inducing fibrosis of the bone marrow as well as the transition of mesenchymal stromal cells. Treatment with SB505124, a small-molecule inhibitor of TGFβ signaling, significantly attenuated the symptoms of cancer-related anemia in this model, as evidenced by the increase of erythrocytes in the peripheral blood and the normalized proportion of erythroblast cell clusters. Meanwhile, hindered hematopoiesis and deteriorated hematopoietic stem cell niche were also shown to be restored with SB505124 treatment. Conclusion This study investigated the role of TGFβ released by bone remodeling in the progression of cancer-related anemia and revealed a potential therapeutic approach for relieving defects in hematopoiesis. |
| first_indexed | 2024-12-14T05:45:10Z |
| format | Article |
| id | doaj.art-be482fd51d0c493ba40c226677da0c70 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-14T05:45:10Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj.art-be482fd51d0c493ba40c226677da0c702022-12-21T23:14:54ZengBMCStem Cell Research & Therapy1757-65122021-01-0112111710.1186/s13287-020-02120-9Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemiaBoyan Wang0Yi Wang1Hainan Chen2Senyu Yao3Xiaofan Lai4Yuan Qiu5Jianye Cai6Yinong Huang7Xiaoyue Wei8Yuanjun Guan9Tao Wang10Jiancheng Wang11Andy Peng Xiang12Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen UniversityCenter for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityCore Facility of Center, Zhongshan School of Medicine, Sun Yat-Sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityScientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen UniversityAbstract Background Cancer cachexia is a wasting syndrome that is quite common in terminal-stage cancer patients. Cancer-related anemia is one of the main features of cancer cachexia and mostly results in a poor prognosis. The disadvantages of the current therapies are obvious, but few new treatments have been developed because the pathological mechanism remains unclear. Methods C57BL/6 mice were subcutaneously injected with Lewis lung carcinoma cells to generate a cancer-related anemia model. The treated group received daily intraperitoneal injections of SB505124. Blood parameters were determined with a routine blood counting analyzer. Erythroid cells and hematopoietic stem/progenitor cells were analyzed by flow cytometry. The microarchitecture changes of the femurs were determined by micro-computed tomography scans. Smad2/3 phosphorylation was analyzed by immunofluorescence and Western blotting. The changes in the hematopoietic stem cell niche were revealed by qPCR analysis of both fibrosis-related genes and hematopoietic genes, fibroblastic colony-forming unit assays, and lineage differentiation of mesenchymal stromal cells. Results The mouse model exhibited hematopoietic suppression, marked by a decrease of erythrocytes in the peripheral blood, as well as an increase of immature erythroblasts and reduced differentiation of multipotent progenitors in the bone marrow. The ratio of bone volume/total volume, trabecular number, and cortical wall thickness all appeared to decrease, and the increased osteoclast number has led to the release of latent TGFβ and TGFβ signaling over-activation. Excessive TGFβ deteriorated the hematopoietic stem cell niche, inducing fibrosis of the bone marrow as well as the transition of mesenchymal stromal cells. Treatment with SB505124, a small-molecule inhibitor of TGFβ signaling, significantly attenuated the symptoms of cancer-related anemia in this model, as evidenced by the increase of erythrocytes in the peripheral blood and the normalized proportion of erythroblast cell clusters. Meanwhile, hindered hematopoiesis and deteriorated hematopoietic stem cell niche were also shown to be restored with SB505124 treatment. Conclusion This study investigated the role of TGFβ released by bone remodeling in the progression of cancer-related anemia and revealed a potential therapeutic approach for relieving defects in hematopoiesis.https://doi.org/10.1186/s13287-020-02120-9Cancer-related anemiaCachexiaErythropoiesisHematopoietic stem cells nicheMesenchymal stromal cellsTGFβ |
| spellingShingle | Boyan Wang Yi Wang Hainan Chen Senyu Yao Xiaofan Lai Yuan Qiu Jianye Cai Yinong Huang Xiaoyue Wei Yuanjun Guan Tao Wang Jiancheng Wang Andy Peng Xiang Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia Stem Cell Research & Therapy Cancer-related anemia Cachexia Erythropoiesis Hematopoietic stem cells niche Mesenchymal stromal cells TGFβ |
| title | Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia |
| title_full | Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia |
| title_fullStr | Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia |
| title_full_unstemmed | Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia |
| title_short | Inhibition of TGFβ improves hematopoietic stem cell niche and ameliorates cancer-related anemia |
| title_sort | inhibition of tgfβ improves hematopoietic stem cell niche and ameliorates cancer related anemia |
| topic | Cancer-related anemia Cachexia Erythropoiesis Hematopoietic stem cells niche Mesenchymal stromal cells TGFβ |
| url | https://doi.org/10.1186/s13287-020-02120-9 |
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