Details

Autor(en) / Beteiligte

• van Galen, Peter
• Kreso, Antonija
• Mbong, Nathan
• Kent, David G.
• Fitzmaurice, Timothy
• Chambers, Joseph E.
• Xie, Stephanie
• Laurenti, Elisa
• Hermans, Karin
• Eppert, Kolja
• Marciniak, Stefan J.
• Goodall, Jane C.
• Green, Anthony R.
• Wouters, Bradly G.
• Wienholds, Erno
• Dick, John E.

Titel

The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress

Ist Teil von

• Nature (London), 2014-06, Vol.510 (7504), p.268-272

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2014

Quelle

Psychology & Behavioral Sciences Collection

Beschreibungen/Notizen

• Molecular, pharmacological and functional data show that haematopoietic stem cells (HSCs) are predisposed to ER-stress-mediated apoptosis compared to closely related progenitors; a framework for understanding how stress signalling is coordinated within the hematopoietic hierarchy and integrated with stemness is provided, and may have implications for the improvement of clinical transplantation of HSCs. Haematopoietic stem-cell integrity Haematopoietic stem cells persist throughout the lifespan of an organism in order to maintain a capacity for blood self-renewal. The combination of longevity with the latent potential to proliferate presents the danger that inappropriate cell division could occur if the stem cells are damaged by stress of some kind. This paper describes a mechanism that clears stress-damaged stem cells from the blood. John Dick and colleagues show that haematopoietic stem cells are predisposed to endoplasmic-reticulum-stress-mediated apoptosis when compared to early progenitors. The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage 1 , 2 . Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of oncogenic mutations that increase the risk of leukaemogenesis 3 , 4 . Despite the importance of maintaining cell integrity throughout life, how the HSC pool achieves this and how individual HSCs respond to stress remain poorly understood. Many sources of stress cause misfolded protein accumulation in the endoplasmic reticulum (ER), and subsequent activation of the unfolded protein response (UPR) enables the cell to either resolve stress or initiate apoptosis 5 , 6 . Here we show that human HSCs are predisposed to apoptosis through strong activation of the PERK branch of the UPR after ER stress, whereas closely related progenitors exhibit an adaptive response leading to their survival. Enhanced ER protein folding by overexpression of the co-chaperone ERDJ4 (also called DNAJB9 ) increases HSC repopulation capacity in xenograft assays, linking the UPR to HSC function. Because the UPR is a focal point where different sources of stress converge, our study provides a framework for understanding how stress signalling is coordinated within tissue hierarchies and integrated with stemness. Broadly, these findings reveal that the HSC pool maintains clonal integrity by clearance of individual HSCs after stress to prevent propagation of damaged stem cells.