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Ttc7a controls HSC functions
estrogen receptor α (ERα) confers HSC resistance to pro- teotoxic stress by activating the Ire1α-Xbp1 branch of the UPR and promoting the cells’ reconstituting potential.24 In Ttc7a deficient HSC, expression levels of ER stress response genes were abnormally low, whereas the level of the Bip chaperone protein was increased. Furthermore, Ttc7a deficient HSC were less sensitive to stress induction than Ttc7a-proficient-HSC both in vitro and in vivo. A sim- ilar phenomenon was observed in mouse liver in which mild chronic ER stress decreases the mRNA level of Bip while maintaining its protein level. This response allows hepatocytes to avoid the overproduction of UPR effectors that could lead to apoptosis.45 It is, therefore, tempting to speculate that Ttc7a deficiency could be associated with mild chronic stress. In this context, the increased resist- ance of fsn HSC to tunicamycin could be caused by a cel- lular adaptive response aiming to increase the threshold of ER stress sensitivity, and ensure cell survival. Interestingly, HSC exposed to other sources of persistent cellular stress develop mechanisms of stress resistance resulting in increased self-renewal capacity and reconstitution poten- tial.46 Knowing that TTC7A stabilizes several interacting proteins, the role of additional components, altered as a consequence of Ttc7a deficiency, cannot be excluded. Ttc7a could represent a pivotal connection between ER stress regulation and the maintenance of HSC functions.
Along with an abnormally proliferative hematopoietic system, fsn mice develop hyperplasia of the epidermis and the gastric epithelium. Notably, stem cells from other tis- sues can similarly sense ER stress and activate the UPR
pathway to control self-renewal and differentiation. This has been shown for the intestinal epithelium in particular, and several lines of evidences support the concept where- by ER stress and UPR activity regulate the differentiation of intestinal stem cells.47 An attractive hypothesis would be that the other phenotypic manifestations that charac- terized Ttc7a deficiency might be due to perturbation of the ER stress response.
In summary, our results show that Ttc7a has a critical but previously unrecognized role as a regulator of HSC homeostasis and function through the regulation of the ER stress response.
Acknowledgments
We thank Gaël Ménasché, Annarita Miccio and Isabelle Andre-Schmutz for helpful comments and guidance; Olivier Pellé for help in cell sorting; the Necker histology and morphol- ogy facility [Structure Fédérative de Recherche (SFR) Necker] and the Cochin Genomic Platform for their services in histologi- cal and transcriptomic studies, respectively. This work was sup- ported by The French National Institutes of Health and Medical Research (INSERM), state funding from the Agence Nationale de la Recherche “Investissements d’avenir” program, la Fondation pour la Recherche Médicale (FRM project DEQ20150734354), and the Imagine Foundation. CL was supported by a fellowship from the Ministry of Education and FRM and MTED by a fellowship from the ANR, the FRM and the European Research Council (ERC). TG is a fellow of the International PhD program of the Imagine Institute funded by the Bettencourt Schueller Foundation.
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