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Cell Rep. 2016 Dec 6;17(10):2584-2595. doi: 10.1016/j.celrep.2016.11.031.

Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation.

Author information

1
Section of Pediatric Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA.
2
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Statistics, Rice University, Houston, TX 77030, USA.
4
Institute of Biosciences & Technology, College of Medicine Texas A&M University Health Science Center, Houston, TX 77030, USA.
5
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Statistics, Rice University, Houston, TX 77030, USA; Systems Engineering Group, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland.
7
Section of Pediatric Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; BCM Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: kyk@bcm.edu.

Abstract

Chronic infections affect a third of the world's population and can cause bone marrow suppression, a severe condition that increases mortality from infection. To uncover the basis for infection-associated bone marrow suppression, we conducted repeated infection of WT mice with Mycobacterium avium. After 4-6 months, mice became pancytopenic. Their hematopoietic stem and progenitor cells (HSPCs) were severely depleted and displayed interferon gamma (IFN-γ) signaling-dependent defects in self-renewal. There was no evidence of increased HSPC mobilization or apoptosis. However, consistent with known effects of IFN-γ, transcriptome analysis pointed toward increased myeloid differentiation of HSPCs and revealed the transcription factor Batf2 as a potential mediator of IFN-γ-induced HSPC differentiation. Gain- and loss-of-function studies uncovered a role for Batf2 in myeloid differentiation in both murine and human systems. We thus demonstrate that chronic infection can deplete HSPCs and identify BATF2 as a mediator of infection-induced HSPC terminal differentiation.

KEYWORDS:

bone marrow failure; chronic infection; hematopoietic stem cell; interferon gamma; pancytopenia; terminal differentiation

PMID:
27926863
PMCID:
PMC5161248
DOI:
10.1016/j.celrep.2016.11.031
[Indexed for MEDLINE]
Free PMC Article

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