MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS
Abstract Background Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Elucidating the mechanism underlying the dysfunction of MDS-HSCs is crucial for exploring t...
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BMC
2025-02-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04154-3 |
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| author | Chunlai Yin Xue Yan Jinyi Ren Cheng Zhang Jiaqing Liu Zilong Wang Jing Liu Weiping Li Xia Li |
| author_facet | Chunlai Yin Xue Yan Jinyi Ren Cheng Zhang Jiaqing Liu Zilong Wang Jing Liu Weiping Li Xia Li |
| author_sort | Chunlai Yin |
| collection | DOAJ |
| description | Abstract Background Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Elucidating the mechanism underlying the dysfunction of MDS-HSCs is crucial for exploring the pathogenesis of the syndrome. While previous studies have implicated mesenchymal stem cells (MSCs), a principal component of the bone marrow (BM) microenvironment, in the inhibition of normal hematopoiesis, the precise molecular mechanisms have not been fully elucidated. In this study, we investigated the effects of MSCs from MDS patients on hematopoietic functions of HSCs from a metabolic perspective. Methods MSCs were isolated from BM of MDS patients. The proliferation, apoptosis, differentiation and support for hematopoiesis of these cells were analyzed using CCK-8 assay, FC and induction medium and CFU (colony forming units) assay, respectively. Expression levels of metabolic molecules were used as indicators to screen MSCs with different metabolic pathways and were detected by RT-PCR and Western blotting. Exosome derived from MSCs were isolated from the culture supernatant and confirmed by Transmission Electron Microscope, Dynamic Light Scattering and Western blotting. The effects of these exosomes on HSCs were analyzed using the same methods as those used to assess MSCs function. Results Our findings demonstrated that MDS-MSCs exhibited significant functional impairments, including reduced proliferation, impaired differentiation, diminished support for hematopoiesis, and increased apoptosis. Notably, we observed an upregulation of lipid metabolism in these MSCs, which appears to contribute to their dysfunction. Intriguingly, the aberrant lipid metabolic profile can be effectively reversed by the administration of etomoxir (ETO), an inhibitor of carnitine palmitoyltransferase 1A (CPT-1A). Furthermore, MSCs with enhanced lipid metabolism could transmit this dysfunction to HSCs through the secretion of exosomes that are enriched in CPT-1A. Conclusions We suggest that the MDS BM microenvironment disrupts MSCs metabolism by increasing the expression of CPT-1A, which impairs the ability to support normal HSCs. Interestingly, the suppressive effect is mediated by exosomes rich in CPT-1A, which derived from MSCs. These findings provide novel insights into MDS MSCs-metabolism-Exosome axis in ineffective hematopoiesis and offer new strategies for the treatment of MDS. |
| format | Article |
| id | doaj-art-f6d7d4e5f3ca4befaa2fb7228abd9d3e |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj-art-f6d7d4e5f3ca4befaa2fb7228abd9d3e2025-02-09T12:15:31ZengBMCStem Cell Research & Therapy1757-65122025-02-0116111410.1186/s13287-025-04154-3MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDSChunlai Yin0Xue Yan1Jinyi Ren2Cheng Zhang3Jiaqing Liu4Zilong Wang5Jing Liu6Weiping Li7Xia Li8Department of Immunology, College of Basic Medical Science, Dalian Medical UniversityDepartment of Immunology, College of Basic Medical Science, Dalian Medical UniversityDepartment of Immunology, College of Basic Medical Science, Dalian Medical UniversityDepartment of Immunology, College of Basic Medical Science, Dalian Medical UniversityDepartment of Immunology, College of Basic Medical Science, Dalian Medical UniversityDepartment of Immunology, College of Basic Medical Science, Dalian Medical UniversityCollege of Pharmacy, Dalian Medical UniversityDepartment of Hematology, the Second Hospital of Dalian Medical UniversityDepartment of Immunology, College of Basic Medical Science, Dalian Medical UniversityAbstract Background Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Elucidating the mechanism underlying the dysfunction of MDS-HSCs is crucial for exploring the pathogenesis of the syndrome. While previous studies have implicated mesenchymal stem cells (MSCs), a principal component of the bone marrow (BM) microenvironment, in the inhibition of normal hematopoiesis, the precise molecular mechanisms have not been fully elucidated. In this study, we investigated the effects of MSCs from MDS patients on hematopoietic functions of HSCs from a metabolic perspective. Methods MSCs were isolated from BM of MDS patients. The proliferation, apoptosis, differentiation and support for hematopoiesis of these cells were analyzed using CCK-8 assay, FC and induction medium and CFU (colony forming units) assay, respectively. Expression levels of metabolic molecules were used as indicators to screen MSCs with different metabolic pathways and were detected by RT-PCR and Western blotting. Exosome derived from MSCs were isolated from the culture supernatant and confirmed by Transmission Electron Microscope, Dynamic Light Scattering and Western blotting. The effects of these exosomes on HSCs were analyzed using the same methods as those used to assess MSCs function. Results Our findings demonstrated that MDS-MSCs exhibited significant functional impairments, including reduced proliferation, impaired differentiation, diminished support for hematopoiesis, and increased apoptosis. Notably, we observed an upregulation of lipid metabolism in these MSCs, which appears to contribute to their dysfunction. Intriguingly, the aberrant lipid metabolic profile can be effectively reversed by the administration of etomoxir (ETO), an inhibitor of carnitine palmitoyltransferase 1A (CPT-1A). Furthermore, MSCs with enhanced lipid metabolism could transmit this dysfunction to HSCs through the secretion of exosomes that are enriched in CPT-1A. Conclusions We suggest that the MDS BM microenvironment disrupts MSCs metabolism by increasing the expression of CPT-1A, which impairs the ability to support normal HSCs. Interestingly, the suppressive effect is mediated by exosomes rich in CPT-1A, which derived from MSCs. These findings provide novel insights into MDS MSCs-metabolism-Exosome axis in ineffective hematopoiesis and offer new strategies for the treatment of MDS.https://doi.org/10.1186/s13287-025-04154-3Myelodysplastic syndromeMesenchymal stem cellHematopoietic stem cellCPT-1AExosome |
| spellingShingle | Chunlai Yin Xue Yan Jinyi Ren Cheng Zhang Jiaqing Liu Zilong Wang Jing Liu Weiping Li Xia Li MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS Stem Cell Research & Therapy Myelodysplastic syndrome Mesenchymal stem cell Hematopoietic stem cell CPT-1A Exosome |
| title | MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS |
| title_full | MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS |
| title_fullStr | MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS |
| title_full_unstemmed | MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS |
| title_short | MSCs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal CTP-1A in MDS |
| title_sort | mscs with upregulated lipid metabolism block hematopoietic stem cell differentiation via exosomal ctp 1a in mds |
| topic | Myelodysplastic syndrome Mesenchymal stem cell Hematopoietic stem cell CPT-1A Exosome |
| url | https://doi.org/10.1186/s13287-025-04154-3 |
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