TY - JOUR
T1 - Aged murine hematopoietic stem cells drive aging-associated immune remodeling
AU - Leins, Hanna
AU - Mulaw, Medhanie
AU - Eiwen, Karina
AU - Sakk, Vadim
AU - Liang, Ying
AU - Denkinger, Michael
AU - Geiger, Hartmut
AU - Schirmbeck, Reinhold
N1 - Publisher Copyright:
© 2018 by The American Society of Hematology.
PY - 2018/8/9
Y1 - 2018/8/9
N2 - Aging-associated remodeling of the immune system impairs its functional integrity and contributes to increased morbidity and mortality in the elderly. Aging of hematopoietic stem cells (HSCs), from which all cells of the adaptive immune system ultimately originate, might play a crucial role in the remodeling of the aged immune system. We recently reported that aging of HSCs is, in part, driven by elevated activity of the small RhoGTPase Cdc42 and that aged HSCs can be rejuvenated in vitro by inhibition of the elevated Cdc42 activity in aged HSCs with the pharmacological compound CASIN. To study the quality of immune systems stemming selectively from young or aged HSCs, we established a HSC transplantation model in T- and B-cell-deficient young RAG12/2 hosts. We report that both phenotypic and functional changes in the immune system on aging are primarily a consequence of changes in the function of HSCs on aging and, to a large extent, independent of the thymus, as young and aged HSCs reconstituted distinct T- and B-cell subsets in RAG12/2 hosts that mirrored young and aged immune systems. Importantly, aged HSCs treated with CASIN reestablished an immune system similar to that of young animals, and thus capable of mounting a strong immune response to vaccination. Our studies further imply that epigenetic signatures already imprinted in aged HSCs determine the transcriptional profile and function of HSC-derived T and B cells.
AB - Aging-associated remodeling of the immune system impairs its functional integrity and contributes to increased morbidity and mortality in the elderly. Aging of hematopoietic stem cells (HSCs), from which all cells of the adaptive immune system ultimately originate, might play a crucial role in the remodeling of the aged immune system. We recently reported that aging of HSCs is, in part, driven by elevated activity of the small RhoGTPase Cdc42 and that aged HSCs can be rejuvenated in vitro by inhibition of the elevated Cdc42 activity in aged HSCs with the pharmacological compound CASIN. To study the quality of immune systems stemming selectively from young or aged HSCs, we established a HSC transplantation model in T- and B-cell-deficient young RAG12/2 hosts. We report that both phenotypic and functional changes in the immune system on aging are primarily a consequence of changes in the function of HSCs on aging and, to a large extent, independent of the thymus, as young and aged HSCs reconstituted distinct T- and B-cell subsets in RAG12/2 hosts that mirrored young and aged immune systems. Importantly, aged HSCs treated with CASIN reestablished an immune system similar to that of young animals, and thus capable of mounting a strong immune response to vaccination. Our studies further imply that epigenetic signatures already imprinted in aged HSCs determine the transcriptional profile and function of HSC-derived T and B cells.
UR - http://www.scopus.com/inward/record.url?scp=85051367819&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051367819&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-02-831065
DO - 10.1182/blood-2018-02-831065
M3 - Article
C2 - 29891535
AN - SCOPUS:85051367819
SN - 0006-4971
VL - 132
SP - 565
EP - 576
JO - Blood
JF - Blood
IS - 6
ER -