TY - JOUR
T1 - Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300
AU - Hettler, Franziska
AU - Schreck, Christina
AU - Marquez, Sandra Romero
AU - Engleitner, Thomas
AU - Vilne, Baiba
AU - Landspersky, Theresa
AU - Weidner, Heike
AU - Hausinger, Renate
AU - Mishra, Ritu
AU - Oellinger, Rupert
AU - Rauner, Martina
AU - Naumann, Ronald
AU - Peschel, Christian
AU - Bassermann, Florian
AU - Rad, Roland
AU - Istvanffy, Rouzanna
AU - Oostendorp, Robert A.J.
N1 - Funding Information:
We thank Alina Wagner for excellent technical assistance as well as Mauricio Testanera and Theresa Mayo (Technical University of Munich, Gynecology) for critical reading of the manuscript. We also thank Matthias Schiemann, Lynette Henkel, Immanuel Andrä, Corinne Angerpointner, and Susanne Dürr (Flow Cytometry Unit CyTUM, Institut für Mikrobiologie, Immunologie und Hygiene, Technical University of Munich) for cell sorting and help with fluorescent microscopy. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant n. FOR 2033 B3, SFB 1243 A09, OO 8/16 and 8/18 to RO, and BA 2851/6-1 and SFB 1335 Project-ID 360372040 to FB, and the European Research Commission project BCM-UPS, grant #682473 to FB.
Funding Information:
This work was funded by the Deutsche Forschungsgemein-schaft (DFG, German Research Foundation) grant n. FOR 2033 B3, SFB 1243 A09, OO 8/16 and 8/18 to RO, and BA 2851/6-1 and SFB 1335 Project-ID 360372040 to FB, and the European Research Commission project BCM-UPS, grant #682473 to FB.
Publisher Copyright:
©2023 Ferrata Storti Foundation.
PY - 2023/2
Y1 - 2023/2
N2 - 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 (b-catenin) 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.
AB - 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 (b-catenin) 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.
UR - http://www.scopus.com/inward/record.url?scp=85147234157&partnerID=8YFLogxK
U2 - 10.3324/haematol.2022.280760
DO - 10.3324/haematol.2022.280760
M3 - Article
C2 - 35950533
AN - SCOPUS:85147234157
SN - 0390-6078
VL - 108
SP - 490
EP - 501
JO - Haematologica
JF - Haematologica
IS - 2
ER -