Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging.
Declining immune function with age is associated with reduced lymphoid output of hematopoietic stem cells (HSCs). Currently, there is poor understanding of changes with age in the heterogeneous multipotent progenitor (MPP) cell compartment, which is long lived and responsible for dynamically regulating output of mature hematopoietic cells. In this study, we observe an early and progressive loss of lymphoid-primed MPP cells (LMPP/MPP4) with aging, concomitant with expansion of HSCs. Transcriptome and in vitro functional analyses at the single-cell level reveal a concurrent increase in cycling of aging LMPP/MPP4 with loss of lymphoid priming and differentiation potential. Impaired lymphoid differentiation potential of aged LMPP/MPP4 is not rescued by transplantation into a young bone marrow microenvironment, demonstrating cell-autonomous changes in the MPP compartment with aging. These results pinpoint an age and cellular compartment to focus further interrogation of the drivers of lymphoid cell loss with aging.
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609.
Kira
0000-0002-1598-9793
K
Young
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609.
Sneha
0000-0003-1723-9598
S
Borikar
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609.
Rebecca
R
Bell
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609.
Lauren
L
Kuffler
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609.
Vivek
0000-0001-5126-707X
V
Philip
The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609 jennifer.trowbridge@jax.org.
Jennifer J
0000-0002-7636-9504
JJ
Trowbridge
D000375:Aging / Q000502:physiology*; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology; D059010:Single-Cell Analysis; D059467:Transcriptome / Q000235:genetics