TY - JOUR
T1 - TNFAIP3 Plays a Role in Aging of the Hematopoietic System
AU - Smith, Molly A.
AU - Culver-Cochran, Ashley E.
AU - Adelman, Emmalee R.
AU - Rhyasen, Garrett W.
AU - Ma, Averil
AU - Figueroa, Maria E.
AU - Starczynowski, Daniel T.
N1 - Funding Information:
We thank the DNA Sequencing, Flow Cytometry, and Genotyping Cores at CCHMC for their assistance. We thank Jeff Bailey and Victoria Summey for assistance with transplantations (Comprehensive Mouse and Cancer Core at CCHMC). We also thank the members of the Starczynowski and Figueroa labs and Jordan Althoff for helpful suggestions.
Funding Information:
This work was supported in parts by the National Institutes of Health (R35HL135787, R01DK102759, R01DK113639 to DS and R01HL126947 to MF), Leukemia and Lymphomas Society (DS), and Cincinnati Children’s Hospital Research Foundation (DS). MS was supported by a National Institute of Health Research Training and Career Development Grant (F31HL132420). AC-C is supported by a National Institutes of Health Research Training and Career Development Grant (F32CA232402) and EA is supported by a T32CA217835 training award from the National Institutes of Health. DS and MF are Leukemia and Lymphoma Society Scholars.
Publisher Copyright:
© Copyright © 2020 Smith, Culver-Cochran, Adelman, Rhyasen, Ma, Figueroa and Starczynowski.
PY - 2020/11/3
Y1 - 2020/11/3
N2 - Hematopoietic stem and progenitor cells (HSPC) experience a functional decline in response to chronic inflammation or aging. Haploinsufficiency of A20, or TNFAIP3, an innate immune regulator, is associated with a variety of autoimmune, inflammatory, and hematologic malignancies. Based on a prior analysis of epigenomic and transcriptomic changes during normal human aging, we find that the expression of A20 is significantly reduced in aged HSPC as compared to young HSPC. Here, we show that the partial reduction of A20 expression in young HSPC results in characteristic features of aging. Specifically, heterozygous deletion of A20 in hematopoietic cells resulted in expansion of the HSPC pool, reduced HSPC fitness, and myeloid-biased hematopoiesis. These findings suggest that altered expression of A20 in HSPC contributes to an aging-like phenotype, and that there may be a common underlying mechanism for diminished HSPC function between inflammatory states and aging.
AB - Hematopoietic stem and progenitor cells (HSPC) experience a functional decline in response to chronic inflammation or aging. Haploinsufficiency of A20, or TNFAIP3, an innate immune regulator, is associated with a variety of autoimmune, inflammatory, and hematologic malignancies. Based on a prior analysis of epigenomic and transcriptomic changes during normal human aging, we find that the expression of A20 is significantly reduced in aged HSPC as compared to young HSPC. Here, we show that the partial reduction of A20 expression in young HSPC results in characteristic features of aging. Specifically, heterozygous deletion of A20 in hematopoietic cells resulted in expansion of the HSPC pool, reduced HSPC fitness, and myeloid-biased hematopoiesis. These findings suggest that altered expression of A20 in HSPC contributes to an aging-like phenotype, and that there may be a common underlying mechanism for diminished HSPC function between inflammatory states and aging.
KW - A20 (TNFAIP3)
KW - aging
KW - hematopoiesis
KW - hematopoietic (stem) cells
KW - inflammation
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U2 - 10.3389/fimmu.2020.536442
DO - 10.3389/fimmu.2020.536442
M3 - Article
C2 - 33224133
AN - SCOPUS:85096178566
VL - 11
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 536442
ER -