Ttc7a regulates hematopoietic stem cell functions while controlling the stress-induced response

Claire Leveau; Tania Gajardo; Marie-Thérèse El-Daher; Nicolas Cagnard; Alain Fischer; Geneviève de Saint Basile; Fernando E Sepulveda

doi:10.3324/haematol.2018.207100

Ttc7a regulates hematopoietic stem cell functions while controlling the stress-induced response

Haematologica. 2020 Jan;105(1):59-70. doi: 10.3324/haematol.2018.207100. Epub 2019 Apr 19.

Authors

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 Basile^{8

2

9}, Fernando E Sepulveda^{8

2

10}

Affiliations

¹ Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris.
² Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris.
³ Bioinformatic Platform, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris.
⁴ Structure Fédérative de Recherche (SFR) Necker, INSERM US24/CNRS UMS 3633, Paris.
⁵ Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades Immunology and Pediatric Hematology Department, Paris.
⁶ Collège de France, Paris, France.
⁷ INSERM UMR1163, Paris.
⁸ Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris genevieve.de-saint-basile@inserm.fr fernando.sepulveda@inserm.fr.
⁹ Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Centre d'Etudes des Déficits Immunitaires, Paris.
¹⁰ Centre National de la Recherche Scientifique - CNRS, Paris, France.

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 protein 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cell Proliferation
Hematopoietic Stem Cells*
Mice
Proteins*

Substances

Proteins