Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300
Franziska Hettler,
Christina Schreck,
Sandra Romero Marquez,
Thomas Engleitner,
Baiba Vilne,
Theresa Landspersky,
Heike Weidner,
Renate Hausinger,
Ritu Mishra,
Rupert Oellinger,
Martina Rauner,
Ronald Naumann,
Christian Peschel,
Florian Bassermann,
Roland Rad,
Rouzanna Istvanffy,
Robert A.J. Oostendorp
Affiliations
Franziska Hettler
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich
Christina Schreck
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich
Sandra Romero Marquez
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich
Thomas Engleitner
Technical University of Munich, School of Medicine, Center for Translational Cancer Research (TranslaTUM), 81675 Munich, Germany; Technical University of Munich, School of Medicine, Institute of Molecular Oncology and Functional Genomics, Munich
Baiba Vilne
Bioinformatics Research Unit, Riga Stradins University, Riga, Latvia; netOmics, Riga
Theresa Landspersky
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich
Heike Weidner
Bone Lab Dresden, Department of Medicine III and Center for Healthy Aging, Technische Universitaet Dresden, Dresden
Renate Hausinger
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich
Ritu Mishra
Technical University of Munich, School of Medicine, Center for Translational Cancer Research (TranslaTUM), 81675 Munich, Germany; School of Medicine, Institute of Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich
Rupert Oellinger
Technical University of Munich, School of Medicine, Center for Translational Cancer Research (TranslaTUM), 81675 Munich, Germany; Technical University of Munich, School of Medicine, Institute of Molecular Oncology and Functional Genomics, Munich
Martina Rauner
Bone Lab Dresden, Department of Medicine III and Center for Healthy Aging, Technische Universitaet Dresden, Dresden
Ronald Naumann
Max Planck Institute of Molecular Cell Biology and Genetics, Transgenic Core Facility
Christian Peschel
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, 81675 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg
Florian Bassermann
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, 81675 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg
Roland Rad
Technical University of Munich, School of Medicine, Center for Translational Cancer Research (TranslaTUM), 81675 Munich, Germany; Technical University of Munich, School of Medicine, Institute of Molecular Oncology and Functional Genomics, 81675 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg
Rouzanna Istvanffy
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, 81675 Munich, Germany; Current address: Technical University of Munich, School of Medicine, Surgery Department, 81675 Munich
Robert A.J. Oostendorp
Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, 81675 Munich
Remodeling of the bone marrow microenvironment in chronic inflammation and in aging reduces hematopoietic stem cell (HSC) function. To assess the mechanisms of this functional decline of HSC and find strategies to counteract it, we established a model in which the Sfrp1 gene was deleted in Osterix+ osteolineage cells (OS1Δ/Δ mice). HSC from these mice showed severely diminished repopulating activity with associated DNA damage, enriched expression of the reactive oxygen species pathway and reduced single-cell proliferation. Interestingly, not only was the protein level of Catenin beta-1 (bcatenin) elevated, but so was its association with the phosphorylated co-activator p300 in the nucleus. Since these two proteins play a key role in promotion of differentiation and senescence, we inhibited in vivo phosphorylation of p300 through PP2A-PR72/130 by administration of IQ-1 in OS1Δ/Δ mice. This treatment not only reduced the b-catenin/phosphop300 association, but also decreased nuclear p300. More importantly, in vivo IQ-1 treatment fully restored HSC repopulating activity of the OS1Δ/Δ mice. Our findings show that the osteoprogenitor Sfrp1 is essential for maintaining HSC function. Furthermore, pharmacological downregulation of the nuclear b-catenin/phospho-p300 association is a new strategy to restore poor HSC function.