Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300.

Autor:	Hettler F; Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich., Schreck C; Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich., Marquez SR; Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich., Engleitner T; 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., Vilne B; Bioinformatics Research Unit, Riga Stradins University, Riga, Latvia; netOmics, Riga., Landspersky T; Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich., Weidner H; Bone Lab Dresden, Department of Medicine III and Center for Healthy Aging, Technische Universitaet Dresden, Dresden., Hausinger R; Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology-Oncology, Munich., Mishra R; 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., Oellinger R; 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., Rauner M; Bone Lab Dresden, Department of Medicine III and Center for Healthy Aging, Technische Universitaet Dresden, Dresden., Naumann R; Max Planck Institute of Molecular Cell Biology and Genetics, Transgenic Core Facility., Peschel C; Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, 81675 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg., Bassermann F; Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, 81675 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg., Rad R; 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., Istvanffy R; 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., Oostendorp RAJ; Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, 81675 Munich. robert.oostendorp@tum.de.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2023 Feb 01; Vol. 108 (2), pp. 490-501. Date of Electronic Publication: 2023 Feb 01.
DOI:	10.3324/haematol.2022.280760
Abstrakt:	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.
Databáze:	MEDLINE
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