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
Affiliations
Claire Leveau
Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris;Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris
Tania Gajardo
Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris;Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris
Marie-Thérèse El-Daher
Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris;Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris
Nicolas Cagnard
Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris;Bioinformatic Platform, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris;Structure Fédérative de Recherche (SFR) Necker, INSERM US24/CNRS UMS 3633, Paris
Alain Fischer
Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris;Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades Immunology and Pediatric Hematology Department, Paris;Collège de France, Paris, France;INSERM UMR1163, Paris
Geneviève de Saint Basile
Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris;Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris;Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Centre d’Etudes des Déficits Immunitaires, Paris
Fernando E. Sepulveda
Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Imagine Institute, Paris;Université Paris Descartes -Sorbonne Paris Cité, Imagine Institute, Paris;Centre National de la Recherche Scientifique – CNRS, Paris, France
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.
