SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization
Abstract Background Hematopoietic stem cell (HSC) transplantation is widely recognized as an effective treatment for various malignant diseases. Enhancing HSC mobilization can improve transplantation outcomes and ultimately increase patient survival rates. Recent studies suggest that mild endoplasmi...
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BMC
2025-04-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04345-y |
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| author | Lijun Li Danhua Xu Xinxin Huang |
| author_facet | Lijun Li Danhua Xu Xinxin Huang |
| author_sort | Lijun Li |
| collection | DOAJ |
| description | Abstract Background Hematopoietic stem cell (HSC) transplantation is widely recognized as an effective treatment for various malignant diseases. Enhancing HSC mobilization can improve transplantation outcomes and ultimately increase patient survival rates. Recent studies suggest that mild endoplasmic reticulum (ER) stress promotes HSC self-renewal, anti-apoptotic, and anti-aging capabilities. This led us to investigate whether inducing mild ER stress could facilitate HSC mobilization. Methods The phenotype changes in cells treated with ER stress inducers and Sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibitors were assessed using flow cytometry. The efficacy of these agents on HSC mobilization was evaluated in C57Bl/6 mice, with colony forming unit (CFU) assays used for quantification. Knockdown Jurkat cell lines were constructed to validate the role of SERCA in the mobilization mechanism. Molecular and protein expression levels associated with the pathway were analyzed through quantitative reverse-transcription PCR and western blotting. Results Our findings revealed that BHQ, a SERCA inhibitor, efficiently enhanced HSC mobilization in vivo. Mechanistically, BHQ regulated the CaMKII-STAT3-CXCR4 pathway by suppressing SERCA activity. This inhibition led to a reduction in CXCR4 expression on the surface of HSCs, facilitating their migration from the bone marrow into peripheral circulation. Conclusions Our study provides novel insights into the role of the SERCA-ER stress pathway in HSC mobilization. By targeting SERCA activity with BHQ, we observed a significant enhancement in the mobilization of HSCs, facilitated by the modulation of the CaMKII-STAT3-CXCR4 signaling pathway. This research highlights the potential of utilizing mild ER stress as a strategy to promote HSC mobilization, with significant implications for improving stem cell-based therapies, including those used in HSC transplantation. |
| format | Article |
| id | doaj-art-0729ef660dbb467cbae0f21e218a81f4 |
| institution | OA Journals |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-0729ef660dbb467cbae0f21e218a81f42025-08-20T02:20:01ZengBMCStem Cell Research & Therapy1757-65122025-04-0116111510.1186/s13287-025-04345-ySERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilizationLijun Li0Danhua Xu1Xinxin Huang2Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, and The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan UniversityShanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, and The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan UniversityShanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, and The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan UniversityAbstract Background Hematopoietic stem cell (HSC) transplantation is widely recognized as an effective treatment for various malignant diseases. Enhancing HSC mobilization can improve transplantation outcomes and ultimately increase patient survival rates. Recent studies suggest that mild endoplasmic reticulum (ER) stress promotes HSC self-renewal, anti-apoptotic, and anti-aging capabilities. This led us to investigate whether inducing mild ER stress could facilitate HSC mobilization. Methods The phenotype changes in cells treated with ER stress inducers and Sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibitors were assessed using flow cytometry. The efficacy of these agents on HSC mobilization was evaluated in C57Bl/6 mice, with colony forming unit (CFU) assays used for quantification. Knockdown Jurkat cell lines were constructed to validate the role of SERCA in the mobilization mechanism. Molecular and protein expression levels associated with the pathway were analyzed through quantitative reverse-transcription PCR and western blotting. Results Our findings revealed that BHQ, a SERCA inhibitor, efficiently enhanced HSC mobilization in vivo. Mechanistically, BHQ regulated the CaMKII-STAT3-CXCR4 pathway by suppressing SERCA activity. This inhibition led to a reduction in CXCR4 expression on the surface of HSCs, facilitating their migration from the bone marrow into peripheral circulation. Conclusions Our study provides novel insights into the role of the SERCA-ER stress pathway in HSC mobilization. By targeting SERCA activity with BHQ, we observed a significant enhancement in the mobilization of HSCs, facilitated by the modulation of the CaMKII-STAT3-CXCR4 signaling pathway. This research highlights the potential of utilizing mild ER stress as a strategy to promote HSC mobilization, with significant implications for improving stem cell-based therapies, including those used in HSC transplantation.https://doi.org/10.1186/s13287-025-04345-yER stressSERCAHSCMobilizationCXCR4 |
| spellingShingle | Lijun Li Danhua Xu Xinxin Huang SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization Stem Cell Research & Therapy ER stress SERCA HSC Mobilization CXCR4 |
| title | SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization |
| title_full | SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization |
| title_fullStr | SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization |
| title_full_unstemmed | SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization |
| title_short | SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization |
| title_sort | serca mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization |
| topic | ER stress SERCA HSC Mobilization CXCR4 |
| url | https://doi.org/10.1186/s13287-025-04345-y |
| work_keys_str_mv | AT lijunli sercamediatedendoplasmicreticulumstressfacilitateshematopoieticstemcellmobilization AT danhuaxu sercamediatedendoplasmicreticulumstressfacilitateshematopoieticstemcellmobilization AT xinxinhuang sercamediatedendoplasmicreticulumstressfacilitateshematopoieticstemcellmobilization |