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Hematopoiesis
Ttc7a regulates hematopoietic stem cell functions while controlling the stress-induced response
Ferrata Storti Foundation
Haematologica 2020 Volume 105(1):59-70
Claire Leveau,1,2 Tania Gajardo,1,2 Marie-Thérèse El-Daher,1,2
Nicolas Cagnard,2,3,4 Alain Fischer,2,5,6,7 Geneviève de Saint Basile1,2,8,* and Fernando E. Sepulveda1,2,9,*
1Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris; 2Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris; 3Bioinformatic Platform, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris; 4Structure Fédérative de Recherche (SFR) Necker, INSERM US24/CNRS UMS 3633, Paris; 5Assistance Publique- Hôpitaux de Paris, Hôpital Necker-Enfants Malades Immunology and Pediatric Hematology Department, Paris; 6Collège de France, Paris, France; 7INSERM UMR1163, Paris; 8Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Centre d'Etudes des Déficits Immunitaires, Paris and 9Centre National de la Recherche Scientifique – CNRS, Paris, France
* These authors contributed equally to this work
ABSTRACT
The molecular machinery that regulates the balance between self- renewal and differentiation properties of hematopoietic stem cells (HSC) has yet to be characterized in detail. Here we found that the tetratricopeptide repeat domain 7 A (Ttc7a) protein, a putative scaffold pro- tein expressed by HSC, acts as an intrinsic regulator of the proliferative response and the self-renewal potential of murine HSC in vivo. Loss of Ttc7a consistently enhanced the competitive repopulating ability of HSC and their intrinsic capacity to replenish the hematopoietic system after serial cell transplantations, relative to wildtype cells. Ttc7a-deficient HSC exhibit a different transcriptomic profile for a set of genes controlling the cellular response to stress, which was associated with increased proliferation in response to chemically induced stress in vitro and myeloablative stress in vivo. Our results therefore revealed a previously unrecognized role of Ttc7a as a critical regulator of HSC stemness. This role is related, at least in part, to regulation of the endoplasmic reticulum stress response.
Introduction
In flaky skin (fsn) mice, the spontaneous insertion of early transposon into the gene for tetratricopeptide repeat domain 7 A (Ttc7a) is known to impair Ttc7a pro- tein expression.1,2 Consequently, fsn mice develop a proliferative lymphoid and myeloid disorder, with hyperplasia of the spleen and lymph nodes, elevated mono- cyte, granulocyte and lymphoid cell counts,3-6 and severe anemia.7 Moreover, fsn mice have a reduced lifespan and changes in the skin (epidermal hyperplasia and inflammation)8,9 and the intestinal tract (gastric papillomas).10 The marked pheno- typic alterations in fsn mice suggest that Ttc7a protein has one or more major reg- ulatory roles in the hematopoietic system, and, potentially, in other tissues of epithelial origin.
Ttc7a is a putative scaffolding protein as it contains nine tetratricopeptide repeats (TPR) domains that are predicted to interact with proteins containing their own TPR or other motifs.11 These TPR-containing proteins are involved in a variety of biological processes, including cell cycle control, protein trafficking, secretion and protein quality control. Indeed, TPR-containing proteins have been shown to bind chaperones such as Hsp90 and Hsp70, controlling their activity.12-14 Thus, Ttc7a is likely to be involved in a broad range of protein complexes and hence functions. In vitro studies have shown that the loss of Ttc7a causes inappropriate activation of RhoA-dependent effectors and thus disrupts cytoskeletal dynamics.15,16
Correspondence:
GENEVIÈVE DE SAINT BASILE
genevieve.de-saint-basile@inserm.fr
FERNANDO E. SEPULVEDA
fernando.sepulveda@inserm.fr
Received: September 18, 2018. Accepted: April 17, 2019. Pre-published: April 19, 2019.
doi:10.3324/haematol.2018.207100
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