TY - JOUR
T1 - A comprehensive transcriptome signature of murine hematopoietic stem cell aging
AU - Flohr Svendsen, Arthur
AU - Yang, Daozheng
AU - Kim, KyungMok
AU - Lazare, Seka
AU - Skinder, Natalia
AU - Zwart, Erik
AU - Mura-Meszaros, Anna
AU - Ausema, Albertina
AU - von Eyss, Björn
AU - de Haan, Gerald
AU - Bystrykh, Leonid
N1 - Funding Information: The authors thank T. Bijma, G. Mesander, and J. Teunis from University Medical Center Groningen (UMCG) Flowcytometry Unit facilities for their assistance on cell sorting; Klaas Sjollema from UMCG Microscopy and Imaging Center for assistance with confocal microscopy; and B. Bakker, M. Gerritsen, E. Verovskaya, and all members of the Ageing Biology and Stem Cells Laboratory for discussions. This work was supported by the Netherlands Organization for Scientific Research/Mouse Clinic for Cancer and Aging, the Landsteiner Foundation for Blood Transfusion Research (LSBR1703), a China Student Council Fellowship (D.Y.), Marriage, a EU FP7 Marie Curie Initial Training Network (contract 316964), and ARCH (a European Union's Horizon 2020 Research and Innovation Program) under Marie Sk?odowska-Curie grant agreement 813091. B.v.E. was supported by grants from the Deutsche Forschungsgemeinschaft (EY 120/1-1), Else Kr?ner-Fresenius Foundation (2016_A58), and the German Cancer Aid (Deutsche Krebshilfe, 70113138). The Fritz Lipmann Institute is a member of the Leibniz Association and is financially supported by the Federal Government of Germany and the State of Thuringia. Funding Information: This work was supported by the Netherlands Organization for Scientific Research/Mouse Clinic for Cancer and Aging, the Landsteiner Foundation for Blood Transfusion Research (LSBR1703), a China Student Council Fellowship (D.Y.), Marriage, a EU FP7 Marie Curie Initial Training Network (contract 316964), and ARCH (a European Union's Horizon 2020 Research and Innovation Program) under Marie Skłodowska-Curie grant agreement 813091. B.v.E. was supported by grants from the Deutsche Forschungsgemeinschaft (EY 120/1-1), Else Kröner-Fresenius Foundation (2016_A58), and the German Cancer Aid (Deutsche Krebshilfe, 70113138). The Fritz Lipmann Institute is a member of the Leibniz Association and is financially supported by the Federal Government of Germany and the State of Thuringia. Publisher Copyright: © 2021 American Society of Hematology
PY - 2021/8/12
Y1 - 2021/8/12
N2 - We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists. Despite substantial heterogeneity between individual studies, we uncovered a core and robust HSC aging signature. We detected increased transcriptional activation in aged HSCs, further confirmed by chromatin accessibility analysis. Unexpectedly, using 2 independent computational approaches, we established that deregulated aging genes consist largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We show that Selp (P-selectin), the most consistent deregulated gene, is not merely a marker for aged HSCs but is associated with HSC functional decline. Additionally, single-cell transcriptomics analysis revealed increased heterogeneity of the aged HSC pool. We identify the presence of transcriptionally “young-like” HSCs in aged bone marrow. We share our results as an online resource and demonstrate its utility by confirming that exposure to sympathomimetics or deletion of Dnmt3a/b molecularly resembles HSC rejuvenation or aging, respectively.
AB - We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists. Despite substantial heterogeneity between individual studies, we uncovered a core and robust HSC aging signature. We detected increased transcriptional activation in aged HSCs, further confirmed by chromatin accessibility analysis. Unexpectedly, using 2 independent computational approaches, we established that deregulated aging genes consist largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We show that Selp (P-selectin), the most consistent deregulated gene, is not merely a marker for aged HSCs but is associated with HSC functional decline. Additionally, single-cell transcriptomics analysis revealed increased heterogeneity of the aged HSC pool. We identify the presence of transcriptionally “young-like” HSCs in aged bone marrow. We share our results as an online resource and demonstrate its utility by confirming that exposure to sympathomimetics or deletion of Dnmt3a/b molecularly resembles HSC rejuvenation or aging, respectively.
UR - http://www.scopus.com/inward/record.url?scp=85112381790&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood.2020009729
DO - https://doi.org/10.1182/blood.2020009729
M3 - Article
C2 - 33876187
SN - 0006-4971
VL - 138
SP - 439
EP - 451
JO - Blood
JF - Blood
IS - 6
ER -