FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells

Abstract

Little is known about whether autophagic mechanisms are active in hematopoietic stem cells (HSCs) or how they are regulated. FIP200 (200-kDa FAK-family interacting protein) plays important roles in mammalian autophagy and other cellular functions, but its role in hematopoietic cells has not been examined. Here we show that conditional deletion of FIP200 in hematopoietic cells leads to perinatal lethality and severe anemia. FIP200 was cell-autonomously required for the maintenance and function of fetal HSCs. FIP200-deficient HSC were unable to reconstitute lethally irradiated recipients. FIP200 ablation did not result in increased HSC apoptosis, but it did increase the rate of HSC proliferation. Consistent with an essential role for FIP200 in autophagy, FIP200-null fetal HSCs exhibited both increased mitochondrial mass and reactive oxygen species. These data identify FIP200 as a key intrinsic regulator of fetal HSCs and implicate a potential role for autophagy in the maintenance of fetal hematopoiesis and HSCs.

Autophagy is required for self-renewal and differentiation of adult human stem cells

“…Moreover, as the results of this study suggest, adult stem cells appear to be not only able to tolerate a certain degree of stress but also to be ready to initiate regeneration and repair of tissues that were damaged as a consequence of cytotoxic treatment. Our observations are in agreement with recent reports demonstrating impaired production of lymphoid and myeloid progenitors in mice with autophagy-deficient HSC [1,2]. However, in these previous experimental mouse studies, the defect in differentiation might have been due to insufficient stem cell maintenance.…”

“…For instance, FIP200 (200 kDa focal adhesion kinase family interacting protein) was shown to be essential not only for the induction of autophagy, but also for the maintenance and function of HSC in vivo [1]. Moreover, HSC lacking autophagy-related gene (ATG) 7, another essential autophagy protein, were also unable to survive under in vivo conditions [2].…”

“…Moreover, etoposide-exposed stem cells were able to self-renew and to differentiate after removal but not in the presence of the stressor ( Figure 1H and 1I). Simi Although it was recently shown that autophagy is required for the maintenance of mouse HSC [1,2], it remained unclear whether other adult stem cells would also depend on intact autophagic pathways. The data reported here point to the possibility that autophagy represents an essential process that ensures the maintenance of adult stem cells in general.…”

Autophagy Regulates Homeostasis of Pluripotency-Associated Proteins in hESCs

“…Two hESC lines (CHA15-hESC [23], passages 55-85, and H9, passages 50-80) and a human induced pluripotent stem cell (iPSC) line [24] (passages [25][26][27][28][29][30][31][32][33][34][35] were used in this study. They were maintained on Mitomycin C (Sigma-Aldrich, St. Louis, MO, http://www.sigmaaldrich.com)-treated mouse embryonic fibroblasts (mct-MEFs) in the ESC medium at 37 C and 5% CO 2 in air.…”

The relevance of Nrf2 pathway and autophagy in pancreatic cancer cells upon stimulation of reactive oxygen species

“…With the increased ROS, cancer cells induce antioxidant programs to set a new redox balance, resulting in cellular adaptation. Studies have shown that autophagic inhibitor (chloroquine) caused accumulated ROS in cells, and downstream of Atg1, FIP200-(Atg17 homologue) knockout livers, and Atg5-and Atg7-knockout cells both increase ROS production [25][26][27][28][29][30]. On the basis of these results, we hypothesized that there is a possibility that autophagy inhibition not only leads to accumulation of p62 to activate Nrf2 pathway by a noncanonical way but also increase ROS production to directly activate Nrf2 pathway.…”