TY - JOUR
T1 - Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging
AU - Bogeska, Ruzhica
AU - Mikecin, Ana Matea
AU - Kaschutnig, Paul
AU - Fawaz, Malak
AU - Büchler-Schäff, Marleen
AU - Le, Duy
AU - Ganuza, Miguel
AU - Vollmer, Angelika
AU - Paffenholz, Stella V.
AU - Asada, Noboru
AU - Rodriguez-Correa, Esther
AU - Frauhammer, Felix
AU - Buettner, Florian
AU - Ball, Melanie
AU - Knoch, Julia
AU - Stäble, Sina
AU - Walter, Dagmar
AU - Petri, Amelie
AU - Carreño-Gonzalez, Martha J.
AU - Wagner, Vinona
AU - Brors, Benedikt
AU - Haas, Simon
AU - Lipka, Daniel B.
AU - Essers, Marieke A.G.
AU - Weru, Vivienn
AU - Holland-Letz, Tim
AU - Mallm, Jan Philipp
AU - Rippe, Karsten
AU - Krämer, Stephan
AU - Schlesner, Matthias
AU - McKinney Freeman, Shannon
AU - Florian, Maria Carolina
AU - King, Katherine Y.
AU - Frenette, Paul S.
AU - Rieger, Michael A.
AU - Milsom, Michael D.
N1 - Funding Information:
We thank members of the Division of Experimental Hematology for supporting the experimental work described in this manuscript; and Steven Lane, Thordur Oskarsson, Martin Sprick, and Leonard Zon for critical proofreading of this work. We also thank the Center for Preclinical Research DKFZ core facility; the Flow Cytometry DKFZ core facility; the Single Cell Open Lab DKFZ Core Facility; the Genomics and Proteomics DKFZ Core Facility; the Omics IT and Data Management DKFZ Core Facility; and Damir Krunic from the Light Microscopy DKFZ core facility. This work was supported by funding from the German Research Foundation (DFG) SFB873 (M.D.M. and M.A.G.E.), FOR2674 (M.D.M., D.B.L., B.B., K.R., and J.-P.M.) and SFB834 (M.A.R. and M.F.); the Deutsche Jose Carreras Leukämiestiftung (grant R15/09 to M.D.M. and 10R/2017 to M.A.R.); the Fritz Thyssen Stiftung (grant 10.16.1.023MN to M.D.M.); the Helmholtz Zukunftsthema Aging and Metabolic Programming (AMPro) ZT-0026 (M.D.M. and D.B.L.); the DKFZ-MOST German-Israel Cooperative Research Program (M.D.M.); the Cancer Transitional Research and Exchange Program (Cancer-TRAX) within the German-Israeli Helmholtz International Research School (S.S.); the National Institutes of Health RO1 DK056638 (P.S.F.), R01 DK112976 (P.S.F.), F31HL154661 (D.L.), R35HL155672 (K.Y.K.); the Wilhelm-Sander Foundation (grant 2018-116.1 to M.A.R.); and the Dietmar Hopp Stiftung (M.D.M. and M.A.G.E.). Graphical abstract was created with BioRender.com . This manuscript is dedicated to the memory of Dr. Paul Frenette, a truly outstanding scientist, colleague, and friend.
Funding Information:
We thank members of the Division of Experimental Hematology for supporting the experimental work described in this manuscript; and Steven Lane, Thordur Oskarsson, Martin Sprick, and Leonard Zon for critical proofreading of this work. We also thank the Center for Preclinical Research DKFZ core facility; the Flow Cytometry DKFZ core facility; the Single Cell Open Lab DKFZ Core Facility; the Genomics and Proteomics DKFZ Core Facility; the Omics IT and Data Management DKFZ Core Facility; and Damir Krunic from the Light Microscopy DKFZ core facility. This work was supported by funding from the German Research Foundation (DFG) SFB873 (M.D.M. and M.A.G.E.), FOR2674 (M.D.M. D.B.L. B.B. K.R. and J.-P.M.) and SFB834 (M.A.R. and M.F.); the Deutsche Jose Carreras Leukämiestiftung (grant R15/09 to M.D.M. and 10R/2017 to M.A.R.); the Fritz Thyssen Stiftung (grant 10.16.1.023MN to M.D.M.); the Helmholtz Zukunftsthema Aging and Metabolic Programming (AMPro) ZT-0026 (M.D.M. and D.B.L.); the DKFZ-MOST German-Israel Cooperative Research Program (M.D.M.); the Cancer Transitional Research and Exchange Program (Cancer-TRAX) within the German-Israeli Helmholtz International Research School (S.S.); the National Institutes of Health RO1 DK056638 (P.S.F.), R01 DK112976 (P.S.F.), F31HL154661 (D.L.), R35HL155672 (K.Y.K.); the Wilhelm-Sander Foundation (grant 2018-116.1 to M.A.R.); and the Dietmar Hopp Stiftung (M.D.M. and M.A.G.E.). Graphical abstract was created with BioRender.com. This manuscript is dedicated to the memory of Dr. Paul Frenette, a truly outstanding scientist, colleague, and friend. R.B. B.B. S.H. D.B.L. K.Y.K. S.M.F. M.C.F. M.A.G.E. K.R. P.S.F. M.A.R. and M.D.M. designed and directed the experimental scheme of work; R.B. P.K. M.F. A.-M.M. M.B.-S. S.V.P. N.A. M.B. J.K. S.S. D.W. A.P. D.L. M.G. A.V. E.R.C. M.J.C.-G. V. Wagner, and J.-P.M. performed experiments; R.B. P.K. M.F. F.F. F.B. S.S. B.B. S.H. D.B.L. M.A.G.E. T.H.-L. J.-P.M. M.G. K.Y.K. M.S. S.K. S.M.F. K.R. P.S.F. M.A.R. and M.D.M. carried out data analysis and/or interpretation of experimental data; V. Weru, T.H.-L. M.G. and R.B. performed statistical analysis of the data; R.B. M.F. N.A. F.F. F.B. P.S.F. M.A.R. and M.D.M. wrote the manuscript. The authors declare no competing interests.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/8/4
Y1 - 2022/8/4
N2 - Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration.
AB - Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration.
KW - accelerated aging
KW - aging
KW - clonal hematopoiesis
KW - hematopoietic stem cells
KW - HSCs
KW - inflammaging
KW - inflammation
KW - self-renewal
KW - stem cell exhaustion
KW - stress hematopoiesis
UR - http://www.scopus.com/inward/record.url?scp=85135390419&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135390419&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2022.06.012
DO - 10.1016/j.stem.2022.06.012
M3 - Article
C2 - 35858618
AN - SCOPUS:85135390419
SN - 1934-5909
VL - 29
SP - 1273-1284.e8
JO - Cell stem cell
JF - Cell stem cell
IS - 8
ER -