FOXO3A directs a protective autophagy program in haematopoietic stem cells

Warr. M. R., Binnewies M., Flach J., Reynaud D., Garg T., Malhotra R., Debnath J. and Passegué E.

(2013). Nature 494, 323-327.

Speaker: Chi-Hua Lee (李季樺)                                       Time:14:00~15:00, May. 1, 2013

Commentator: Dr. Ciou-Feng Lin (林秋烽 老師)   Location: Room 601

Abstract:

Haematopoietic stem cells (HSCs) play an important role in blood production and maintain high cellular turnover in the blood system. Although HSCs benefit the body through efficiently producing mature blood cells in young individuals, they often  accumulate damage with age, and develop serious or fatal diseases such as bone marrow failure syndromes and leukamias^[1]. Autophagy and apoptosis are two major stress-response mechanisms and result in different cellular outcomes. In addition to degradation, autophagy has a survival role in maintaining the nutrient and energy level in cells during metabolic starvation or stress, and the excessively damaged or dysfunctional cells can be eliminated by apoptosis^[2]. Currently, which signaling pathway is used by HSCs to combat stress in the body and whether autophagy plays a protective role remain elusive. In this paper, the authors found that only long-lived HSCs were able to induce a robust autophagic response upon metabolic stress. Furthermore, they validated that autophagy could protect HSCs from starvation-induced apoptosis. From previous studies, they further found two transcriptional regulators- FOXO3A and p53, both of which can trigger autophagy and apoptosis via inducing largely overlapping set of targets. FOXO3A which belongs to the forkheadfamily of transcriptional regulators is critical for HSCs self-renewal and acts downstream of the PTEN/PI3K/Akt pathway^[3]. Using FOXO3A^-/-, p53^-/- GEP-LC3 and double-knockout FOXO3A^-/- p53^-/- GEP-LC3 mice, they demonstrated that FOXO3A triggered a pro-autophagy gene expression profile (including LC3b, Gaba2, Atg4b and so on) for HSCs to mount a protective autophagic response under metabolic stress. Moreover, the authors confirmed that old HSCs showed nuclear FOXO3A expression and the same autophagy potential compared to young HSCs. In fact, autophagy contributes to the survival of old HSCs in response to reduced nutrient uptake and energy production. In conclusion, the authors demonstrated that old HSCs can induce an autophagy-mediated cytoprotective response through the expression of a FOXO3A-driven pro-autophagy gene expression profile, and therefore allow their survival.

References:

1.          Rossi, D. J., Jamieson, C. H. M. & Weissman, I. L. Stems cells and the pathways to aging and cancer. (2008). Cell 132, 681–696 .

2.  Danial, N. N. & Korsmeyer, S. J. Cell death: critical control points. (2004). Cell 116, 205–219.

3.          Miyamoto, K. et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. (2007). Cell Stem Cell 1, 101–112.