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TY - JOUR

T1 - Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity

AU - Kim, Kyung Mok

AU - Mura-Meszaros, Anna

AU - Tollot, Marie

AU - Krishnan, Murali Shyam

AU - Gründl, Marco

AU - Neubert, Laura

AU - Groth, Marco

AU - Rodriguez-Fraticelli, Alejo

AU - Svendsen, Arthur Flohr

AU - Campaner, Stefano

AU - Andreas, Nico

AU - Kamradt, Thomas

AU - Hoffmann, Steve

AU - Camargo, Fernando D.

AU - Heidel, Florian H.

AU - Bystrykh, Leonid V.

AU - de Haan, Gerald

AU - von Eyss, Björn

N1 - Funding Information: B.v.E. was supported by grants from the DFG (EY 120/1-1), Else Kröner-Fresenius Foundation (2016_A58) and the German Cancer Aid (Deutsche Krebshilfe; 70113138). The FLI is a member of the Leibniz Association and is financially supported by the Federal Government of Germany and the State of Thuringia. F.H.H. was supported in part by grants of the German Research Council (DFG), (HE6233/4-1 and 4-2) and by the Thuringian state program ProExzellenz (RegenerAging - FSU-I-03/14) of the Thuringian Ministry for Economics, Science and Digital Society (TMWWDG). G.d.H. was supported by the Landsteiner Foundation for Blood Transfusion Research. A.E.R.-F. is a Special Fellow of the Leukemia and Lymphoma Society (3391-19). A.E.R.-F. received the support of a fellowship from ”la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 847648. The fellowship code is LCF/BQ/ES08/11520137. BM-HPC#5 cells were a kind gift from Leif Carlsson. The DNA Sequencing and the Flow Cytometry and the of the FLI are gratefully acknowledged. We would like to thank all the members of the von Eyss lab, von Maltzahn lab, Rudolph lab, and Kaether lab for helpful discussion and Christin Ritter and Tom Hünniger and all the animal care takers at FLI for excellent technical support. Some of the figures were created with BioRender.com. Funding Information: B.v.E. was supported by grants from the DFG (EY 120/1-1), Else Kröner-Fresenius Foundation (2016_A58) and the German Cancer Aid (Deutsche Krebshilfe; 70113138). The FLI is a member of the Leibniz Association and is financially supported by the Federal Government of Germany and the State of Thuringia. F.H.H. was supported in part by grants of the German Research Council (DFG), (HE6233/4-1 and 4-2) and by the Thuringian state program ProExzellenz (RegenerAging - FSU-I-03/14) of the Thuringian Ministry for Economics, Science and Digital Society (TMWWDG). G.d.H. was supported by the Landsteiner Foundation for Blood Transfusion Research. A.E.R.-F. is a Special Fellow of the Leukemia and Lymphoma Society (3391-19). A.E.R.-F. received the support of a fellowship from ”la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 847648. The fellowship code is LCF/BQ/ES08/11520137. BM-HPC#5 cells were a kind gift from Leif Carlsson. The DNA Sequencing and the Flow Cytometry and the of the FLI are gratefully acknowledged. We would like to thank all the members of the von Eyss lab, von Maltzahn lab, Rudolph lab, and Kaether lab for helpful discussion and Christin Ritter and Tom Hünniger and all the animal care takers at FLI for excellent technical support. Some of the figures were created with BioRender.com. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - Specific functions of the immune system are essential to protect us from infections caused by pathogens such as viruses and bacteria. However, as we age, the immune system shows a functional decline that can be attributed in large part to age-associated defects in hematopoietic stem cells (HSCs)—the cells at the apex of the immune cell hierarchy. Here, we find that the Hippo pathway coactivator TAZ is potently induced in old HSCs and protects these cells from functional decline. We identify Clca3a1 as a TAZ-induced gene that allows us to trace TAZ activity in vivo. Using CLCA3A1 as a marker, we can isolate “young-like” HSCs from old mice. Mechanistically, Taz acts as coactivator of PU.1 and to some extent counteracts the gradual loss of PU.1 expression during HSC aging. Our work thus uncovers an essential role for Taz in a previously undescribed fail-safe mechanism in aging HSCs.

AB - Specific functions of the immune system are essential to protect us from infections caused by pathogens such as viruses and bacteria. However, as we age, the immune system shows a functional decline that can be attributed in large part to age-associated defects in hematopoietic stem cells (HSCs)—the cells at the apex of the immune cell hierarchy. Here, we find that the Hippo pathway coactivator TAZ is potently induced in old HSCs and protects these cells from functional decline. We identify Clca3a1 as a TAZ-induced gene that allows us to trace TAZ activity in vivo. Using CLCA3A1 as a marker, we can isolate “young-like” HSCs from old mice. Mechanistically, Taz acts as coactivator of PU.1 and to some extent counteracts the gradual loss of PU.1 expression during HSC aging. Our work thus uncovers an essential role for Taz in a previously undescribed fail-safe mechanism in aging HSCs.

UR - http://www.scopus.com/inward/record.url?scp=85137155076&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-32970-1

DO - 10.1038/s41467-022-32970-1

M3 - Article

C2 - 36057685

VL - 13

JO - Nature communications

JF - Nature communications

SN - 2041-1723

IS - 1

M1 - 5187

ER -