2. Academic Validation
  3. SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization

SERCA-mediated endoplasmic reticulum stress facilitates hematopoietic stem cell mobilization

  • Stem Cell Res Ther. 2025 Apr 24;16(1):208. doi: 10.1186/s13287-025-04345-y.
Lijun Li # 1,  Danhua Xu # 1,  Xinxin Huang 2
Affiliations

Affiliations

  • 1 Shanghai 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 University, Shanghai, 200032, China.
  • 2 Shanghai 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 University, Shanghai, 200032, China. xinxinhuang@fudan.edu.cn.
  • # Contributed equally.
PMID: 40275396 DOI: 10.1186/s13287-025-04345-y
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.

Keywords

CXCR4; ER stress; HSC; Mobilization; SERCA.

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