Format

Send to

Choose Destination
Nat Cell Biol. 2016 Jun;18(6):607-18. doi: 10.1038/ncb3346. Epub 2016 Apr 25.

Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.

Author information

1
The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
2
Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
3
Division of Hematology, University Hospital and University of Zurich, 8091 Zurich, Switzerland.
4
Department of Cell Biology, Albert Einstein Medical College, Queens, New York 10461, USA.
5
Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK.

Abstract

Haematopoietic stem cells (HSCs) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory 'emergency' signal, directly accelerates cell division and myeloid differentiation of HSCs through precocious activation of a PU.1-dependent gene program. Although this effect is essential for rapid myeloid recovery following acute injury to the bone marrow, chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges such as transplantation. Importantly, these damaging effects are transient and fully reversible on IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and is likely to underlie deregulated blood homeostasis in chronic inflammation conditions.

PMID:
27111842
PMCID:
PMC4884136
DOI:
10.1038/ncb3346
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center