CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners

CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners

Summary: Bone marrow (BM) niche cells help to keep adult hematopoietic stem cells (HSCs) in a quiescent state via secreted factors and induction of cell-cycle inhibitors. Here, we demonstrate that the adapter protein CABLES1 is a key regulator of long-term hematopoietic homeostasis during stress and...

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Main Authors: Liang He, Florian Beghi, Viviane Baral, Mallorie Dépond, Yanyan Zhang, Virginie Joulin, Bo R. Rueda, Patrick Gonin, Adlen Foudi, Monika Wittner, Fawzia Louache
Format: Article
Language:English
Published: Elsevier 2019-08-01
Series:Stem Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2213671119302280
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language English
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author Liang He
Florian Beghi
Viviane Baral
Mallorie Dépond
Yanyan Zhang
Virginie Joulin
Bo R. Rueda
Patrick Gonin
Adlen Foudi
Monika Wittner
Fawzia Louache
spellingShingle Liang He
Florian Beghi
Viviane Baral
Mallorie Dépond
Yanyan Zhang
Virginie Joulin
Bo R. Rueda
Patrick Gonin
Adlen Foudi
Monika Wittner
Fawzia Louache
CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners
Stem Cell Reports
author_facet Liang He
Florian Beghi
Viviane Baral
Mallorie Dépond
Yanyan Zhang
Virginie Joulin
Bo R. Rueda
Patrick Gonin
Adlen Foudi
Monika Wittner
Fawzia Louache
author_sort Liang He
title CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners
title_short CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners
title_full CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners
title_fullStr CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners
title_full_unstemmed CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners
title_sort cables1 deficiency impairs quiescence and stress responses of hematopoietic stem cells in intrinsic and extrinsic manners
publisher Elsevier
series Stem Cell Reports
issn 2213-6711
publishDate 2019-08-01
description Summary: Bone marrow (BM) niche cells help to keep adult hematopoietic stem cells (HSCs) in a quiescent state via secreted factors and induction of cell-cycle inhibitors. Here, we demonstrate that the adapter protein CABLES1 is a key regulator of long-term hematopoietic homeostasis during stress and aging. Young mice lacking Cables1 displayed hyperproliferation of hematopoietic progenitor cells. This defect was cell intrinsic, since it was reproduced in BM transplantation assays using wild-type animals as recipients. Overexpression and short hairpin RNA-mediated depletion of CABLES1 protein resulted in p21Cip/waf up- and downregulation, respectively. Aged mice lacking Cables1 displayed abnormalities in peripheral blood cell counts accompanied by a significant reduction in HSC compartment, concomitant with an increased mobilization of progenitor cells. In addition, Cables1−/− mice displayed increased sensitivity to the chemotherapeutic agent 5-fluorouracil due to an abnormal microenvironment. Altogether, our findings uncover a key role for CABLES1 in HSC homeostasis and stress hematopoiesis. : Maintenance of hematopoietic stem cell quiescence is crucial for homeostasis. Using mutant mice and cross-transplant experiments, Louache and colleagues show that the adapter protein CABLES1 is required for stem cell quiescence under transplantation and regulates p21Cip/waf protein level. In addition, CABLES1 is a niche-based regulator of hematopoietic stem cell responses to proliferative stress and during aging. Keywords: CABLES1, cell cycle, p21, hematopoietic stem cell homeostasis, hematopoietic niches, mesenchymal stromal cells
url http://www.sciencedirect.com/science/article/pii/S2213671119302280
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spelling doaj-7cf200aa19294620af78bfbaeb9f80c22020-11-24T20:51:45ZengElsevierStem Cell Reports2213-67112019-08-01132274290CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic MannersLiang He0Florian Beghi1Viviane Baral2Mallorie Dépond3Yanyan Zhang4Virginie Joulin5Bo R. Rueda6Patrick Gonin7Adlen Foudi8Monika Wittner9Fawzia Louache10Institut National de la Santé et de la Recherche Médicale, Inserm UMRS1170, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. ChinaInstitut National de la Santé et de la Recherche Médicale, Inserm UMRS1170, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, FranceInstitut National de la Santé et de la Recherche Médicale, Inserm UMRS1170, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, FranceInstitut National de la Santé et de la Recherche Médicale, Inserm UMRS1170, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, FranceInstitut National de la Santé et de la Recherche Médicale, Inserm UMRS1170, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, FranceInstitut National de la Santé et de la Recherche Médicale, Inserm UMRS1170, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, FranceVincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, USAPlateforme d'Evaluation Préclinique, AMMICA UMS 3655/ US 23, Gustave Roussy, Villejuif, FranceParis-Saclay University, UFR Medicine, INSERM UMS 33, Andre Lwoff Institute, Paul Brousse Hospital, Villejuif, FranceInstitut National de la Santé et de la Recherche Médicale, Inserm UMRS1170, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France; CNRS, GDR 3697 MicroNiT, Tours, FranceInstitut National de la Santé et de la Recherche Médicale, Inserm UMRS1170, 114 Rue Edouard Vaillant, 94805 Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France; CNRS, GDR 3697 MicroNiT, Tours, France; Corresponding authorSummary: Bone marrow (BM) niche cells help to keep adult hematopoietic stem cells (HSCs) in a quiescent state via secreted factors and induction of cell-cycle inhibitors. Here, we demonstrate that the adapter protein CABLES1 is a key regulator of long-term hematopoietic homeostasis during stress and aging. Young mice lacking Cables1 displayed hyperproliferation of hematopoietic progenitor cells. This defect was cell intrinsic, since it was reproduced in BM transplantation assays using wild-type animals as recipients. Overexpression and short hairpin RNA-mediated depletion of CABLES1 protein resulted in p21Cip/waf up- and downregulation, respectively. Aged mice lacking Cables1 displayed abnormalities in peripheral blood cell counts accompanied by a significant reduction in HSC compartment, concomitant with an increased mobilization of progenitor cells. In addition, Cables1−/− mice displayed increased sensitivity to the chemotherapeutic agent 5-fluorouracil due to an abnormal microenvironment. Altogether, our findings uncover a key role for CABLES1 in HSC homeostasis and stress hematopoiesis. : Maintenance of hematopoietic stem cell quiescence is crucial for homeostasis. Using mutant mice and cross-transplant experiments, Louache and colleagues show that the adapter protein CABLES1 is required for stem cell quiescence under transplantation and regulates p21Cip/waf protein level. In addition, CABLES1 is a niche-based regulator of hematopoietic stem cell responses to proliferative stress and during aging. Keywords: CABLES1, cell cycle, p21, hematopoietic stem cell homeostasis, hematopoietic niches, mesenchymal stromal cellshttp://www.sciencedirect.com/science/article/pii/S2213671119302280

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