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Thioredoxin-1 regulates self-renewal and differentiation of murine hematopoietic stem cells through p53 tumor suppressor.

Publication ,  Journal Article
Jabbar, S; Mathews, P; Wang, X; Sundaramoorthy, P; Chu, E; Piryani, SO; Ding, S; Shen, X; Doan, PL; Kang, Y
Published in: Exp Hematol Oncol
October 31, 2022

BACKGROUND: Thioredoxin-1 (TXN1) is one of the major cellular antioxidants in mammals and is involved in a wide range of physiological cellular responses. However, little is known about the roles and the underlying molecular mechanisms of TXN1 in the regulation of hematopoietic stem/progenitor cells (HSPCs). METHODS: TXN1 conditional knockout mice (ROSA-CreER-TXN1fl/fl) and TXN1fl/fl control mice were used. The mice were treated with tamoxifen and the number and biological functions of HSPCs were measured by flow cytometry, PCR and western blot. Limiting dilution competitive transplantation with sorted HSCs and serial transplantations were performed to assess the effects of TXN1 knockout on HSC self-renewal and long-term reconstitutional capacity. RNA sequencing (RNA-seq) was performed to investigate the downstream molecular pathways of TXN1 deletion in murine HSPCs. CRISPR/Cas9 knockout experiments were performed in vitro in EML murine hematopoietic stem/progenitor cell line to investigate the effects of TXN1 and/or TP53 deletion on cell survival, senescence and colony forming units. TP53 protein degradation assay, CHiP PCR and PGL3 firefly/renilla reporter assay were performed. The effects of TXN1 on various molecular pathways relevant to HSC radiation protection were examined in vitro and in vivo. RESULTS: TXN1-TP53 tumor suppressor axis regulates HSPC biological fitness. Deletion of TXN1 in HSPCs using in vivo and in vitro models activates TP53 signaling pathway, and attenuates HSPC capacity to reconstitute hematopoiesis. Furthermore, we found that knocking out of TXN1 renders HSPCs more sensitive to radiation and treatment with recombinant TXN1 promotes the proliferation and expansion of HSPCs. CONCLUSIONS: Our findings suggest that TXN1-TP53 axis acts as a regulatory mechanism in HSPC biological functions. Additionally, our study demonstrates the clinical potential of TXN1 for enhancing hematopoietic recovery in hematopoietic stem cell transplant and protecting HSPCs from radiation injury.

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Published In

Exp Hematol Oncol

DOI

ISSN

2162-3619

Publication Date

October 31, 2022

Volume

11

Issue

1

Start / End Page

83

Location

England

Related Subject Headings

  • 3211 Oncology and carcinogenesis
  • 3201 Cardiovascular medicine and haematology
 

Citation

APA
Chicago
ICMJE
MLA
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Jabbar, S., Mathews, P., Wang, X., Sundaramoorthy, P., Chu, E., Piryani, S. O., … Kang, Y. (2022). Thioredoxin-1 regulates self-renewal and differentiation of murine hematopoietic stem cells through p53 tumor suppressor. Exp Hematol Oncol, 11(1), 83. https://doi.org/10.1186/s40164-022-00329-3
Jabbar, Shaima, Parker Mathews, Xiaobei Wang, Pasupathi Sundaramoorthy, Emily Chu, Sadhna O. Piryani, Shengli Ding, Xiling Shen, Phuong L. Doan, and Yubin Kang. “Thioredoxin-1 regulates self-renewal and differentiation of murine hematopoietic stem cells through p53 tumor suppressor.Exp Hematol Oncol 11, no. 1 (October 31, 2022): 83. https://doi.org/10.1186/s40164-022-00329-3.
Jabbar S, Mathews P, Wang X, Sundaramoorthy P, Chu E, Piryani SO, et al. Thioredoxin-1 regulates self-renewal and differentiation of murine hematopoietic stem cells through p53 tumor suppressor. Exp Hematol Oncol. 2022 Oct 31;11(1):83.
Jabbar, Shaima, et al. “Thioredoxin-1 regulates self-renewal and differentiation of murine hematopoietic stem cells through p53 tumor suppressor.Exp Hematol Oncol, vol. 11, no. 1, Oct. 2022, p. 83. Pubmed, doi:10.1186/s40164-022-00329-3.
Jabbar S, Mathews P, Wang X, Sundaramoorthy P, Chu E, Piryani SO, Ding S, Shen X, Doan PL, Kang Y. Thioredoxin-1 regulates self-renewal and differentiation of murine hematopoietic stem cells through p53 tumor suppressor. Exp Hematol Oncol. 2022 Oct 31;11(1):83.
Journal cover image

Published In

Exp Hematol Oncol

DOI

ISSN

2162-3619

Publication Date

October 31, 2022

Volume

11

Issue

1

Start / End Page

83

Location

England

Related Subject Headings

  • 3211 Oncology and carcinogenesis
  • 3201 Cardiovascular medicine and haematology