https://orcid.org/0000-0002-6224-2334
Key Points
A comprehensive transcriptome analysis of aged murine HSC identifies an aging signature.
The HSC aging signature is highly enriched for cell membrane–related transcripts and identifies age-associated heterogeneity.
Subjects:
Hematopoiesis and Stem Cells
Abstract
We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists.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.
Subjects:
Hematopoiesis and Stem Cells
REFERENCES
1.
de Haan
G
, Nijhof
W
, Van Zant
G
. Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity
. Blood.
1997
;89
(5
):1543
-1550
.2.
Dykstra
B
, Olthof
S
, Schreuder
J
, Ritsema
M
, de Haan
G
. Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells
. J Exp Med.
2011
;208
(13
):2691
-2703
.3.
Morrison
SJ
, Wandycz
AM
, Akashi
K
, Globerson
A
, Weissman
IL
. The aging of hematopoietic stem cells
. Nat Med.
1996
;2
(9
):1011
-1016
.4.
Rossi
DJ
, Jamieson
CHM
, Weissman
IL
. Stems cells and the pathways to aging and cancer
. Cell.
2008
;132
(4
):681
-696
.5.
Sudo
K
, Ema
H
, Morita
Y
, Nakauchi
H
. Age-associated characteristics of murine hematopoietic stem cells
. J Exp Med.
2000
;192
(9
):1273
-1280
.6.
Verovskaya
E
, Broekhuis
MJC
, Zwart
E
, et al. Asymmetry in skeletal distribution of mouse hematopoietic stem cell clones and their equilibration by mobilizing cytokines
. J Exp Med.
2014
;211
(3
):487
-497
.7.
Verovskaya
E
, Broekhuis
MJC
, Zwart
E
, et al. Heterogeneity of young and aged murine hematopoietic stem cells revealed by quantitative clonal analysis using cellular barcoding
. Blood.
2013
;122
(4
):523
-532
.8.
López-Otín
C
, Blasco
MA
, Partridge
L
, Serrano
M
, Kroemer
G
. The hallmarks of aging
. Cell.
2013
;153
(6
):1194
-1217
.9.
Singh
PP
, Demmitt
BA
, Nath
RD
, Brunet
A
. The genetics of aging: a vertebrate perspective
. Cell.
2019
;177
(1
):200
-220
.10.
Beerman
I
, Rossi
DJ
. Epigenetic control of stem cell potential during homeostasis, aging, and disease
. Cell Stem Cell.
2015
;16
(6
):613
-625
.11.
Bersenev
A
, Rozenova
K
, Balcerek
J
, Jiang
J
, Wu
C
, Tong
W
. Lnk deficiency partially mitigates hematopoietic stem cell aging
. Aging Cell.
2012
;11
(6
):949
-959
.12.
Chambers
SM
, Shaw
CA
, Gatza
C
, Fisk
CJ
, Donehower
LA
, Goodell
MA
. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation
. PLoS Biol.
2007
;5
(8
):e201
.13.
Flach
J
, Bakker
ST
, Mohrin
M
, et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells
. Nature.
2014
;512
(7513
):198
-202
.14.
Grover
A
, Sanjuan-Pla
A
, Thongjuea
S
, et al. Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells
. Nat Commun.
2016
;7
(1
):11075
.15.
Kirschner
K
, Chandra
T
, Kiselev
V
, et al. Proliferation drives aging-related functional decline in a subpopulation of the hematopoietic stem cell compartment
. Cell Rep.
2017
;19
(8
):1503
-1511
.16.
Kowalczyk
MS
, Tirosh
I
, Heckl
D
, et al. Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells
. Genome Res.
2015
;25
(12
):1860
-1872
.17.
Mann
M
, Mehta
A
, de Boer
CG
, et al. Heterogeneous responses of hematopoietic stem cells to inflammatory stimuli are altered with age
. Cell Rep.
2018
;25
(11
): 2992
-3005
.18.
Maryanovich
M
, Zahalka
AH
, Pierce
H
, et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche [published correction appears in Nat Med. 2019;25:701]
. Nat Med.
2018
;24
(6
):782
-791
.19.
Noda
S
, Ichikawa
H
, Miyoshi
H
. Hematopoietic stem cell aging is associated with functional decline and delayed cell cycle progression
. Biochem Biophys Res Commun.
2009
;383
(2
):210
-215
.20.
Norddahl
GL
, Pronk
CJ
, Wahlestedt
M
, et al. Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging
. Cell Stem Cell.
2011
;8
(5
):499
-510
.21.
Quéré
R
, Saint-Paul
L
, Carmignac
V
, et al. Tif1γ regulates the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells
. Proc Natl Acad Sci USA.
2014
;111
(29
):10592
-10597
.22.
Rossi
DJ
, Bryder
D
, Zahn
JM
, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging
. Proc Natl Acad Sci USA.
2005
;102
(26
):9194
-9199
.23.
Sun
D
, Luo
M
, Jeong
M
, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal
. Cell Stem Cell.
2014
;14
(5
):673
-688
.24.
Wahlestedt
M
, Norddahl
GL
, Sten
G
, et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state
. Blood.
2013
;121
(21
):4257
-4264
.25.
Beerman
I
, Bock
C
, Garrison
BS
, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging
. Cell Stem Cell.
2013
;12
(4
):413
-425
.26.
Renders
S
, Svendsen
AF
, Panten
J
, et al. Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1
. Nat Commun.
2021
;12
(1
):608
.27.
Buenrostro
JD
, Giresi
PG
, Zaba
LC
, Chang
HY
, Greenleaf
WJ
. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position
. Nat Methods.
2013
;10
(12
):1213
-1218
.28.
Hidalgo
I
, Herrera-Merchan
A
, Ligos
JM
, et al. Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest
. Cell Stem Cell.
2012
;11
(5
):649
-662
.29.
Challen
GA
, Sun
D
, Mayle
A
, et al. Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells
. Cell Stem Cell.
2014
;15
(3
):350
-364
.30.
Wong
DJ
, Liu
H
, Ridky
TW
, Cassarino
D
, Segal
E
, Chang
HY
. Module map of stem cell genes guides creation of epithelial cancer stem cells
. Cell Stem Cell.
2008
;2
(4
):333
-344
.31.
de Magalhães
JP
, Curado
J
, Church
GM
. Meta-analysis of age-related gene expression profiles identifies common signatures of aging
. Bioinformatics.
2009
;25
(7
):875
-881
.32.
Blank
U
, Karlsson
S
. TGF-β signaling in the control of hematopoietic stem cells
. Blood.
2015
;125
(23
):3542
-3550
.33.
Subramanian
A
, Tamayo
P
, Mootha
VK
, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles
. Proc Natl Acad Sci USA.
2005
;102
(43
):15545
-15550
.34.
Liberzon
A
, Birger
C
, Thorvaldsdóttir
H
, Ghandi
M
, Mesirov
JP
, Tamayo
P
. The Molecular Signatures Database (MSigDB) hallmark gene set collection
. Cell Syst.
2015
;1
(6
):417
-425
.35.
Hamey
FK
, Göttgens
B
. Machine learning predicts putative hematopoietic stem cells within large single-cell transcriptomics data sets
. Exp Hematol.
2019
;78
:11
-20
.36.
Fidanza
A
, Kingdom
U
, Stumpf
P
, et al. Single-cell analyses and machine learning define hematopoietic progenitor and HSC-like cells derived from human PSCs
. Blood.
2020
; 136
(25
):2893
-2904
.37.
Keenan
CR
, Iannarella
N
, Naselli
G
, et al. Extreme disruption of heterochromatin is required for accelerated hematopoietic aging
. Blood.
2020
;135
(23
):2049
-2058
.38.
Sullivan
C
, Chen
Y
, Shan
Y
, et al. Functional ramifications for the loss of P-selectin expression on hematopoietic and leukemic stem cells
. PLoS One.
2011
;6
(10
):e26246
.39.
Rapisarda
V
, Borghesan
M
, Miguela
V
, et al. Integrin beta 3 regulates cellular senescence by activating the TGF-β pathway
. Cell Rep.
2017
;18
(10
):2480
-2493
.40.
Sanjuan-Pla
A
, Macaulay
IC
, Jensen
CT
, et al. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy
. Nature.
2013
;502
(7470
):232
-236
.41.
Pinho
S
, Marchand
T
, Yang
E
, Wei
Q
, Nerlov
C
, Frenette
PS
. Lineage-biased hematopoietic stem cells are regulated by distinct niches
. Dev Cell.
2018
;44
(5
):634
-641.e4
.42.
Gulati
GS
, Zukowska
M
, Noh
JJ
, et al. Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5+ mouse long-term hematopoietic stem cells
. Proc Natl Acad Sci USA.
2019
;116
(50
):25115
-25125
.43.
Jeannet
R
, Cai
Q
, Liu
H
, Vu
H
, Kuo
Y-H
. Alcam regulates long-term hematopoietic stem cell engraftment and self-renewal
. Stem Cells.
2013
;31
(3
):560
-571
.44.
Shimazu
T
, Iida
R
, Zhang
Q
, et al. CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential
. Blood.
2012
;119
(21
):4889
-4897
.45.
Thalheimer
FB
, Wingert
S
, De Giacomo
P
, et al. Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells
. Stem Cell Reports.
2014
;3
(1
):34
-43
.46.
Satoh
Y
, Yokota
T
, Sudo
T
, et al. The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages
. Immunity.
2013
;38
(6
):1105
-1115
.47.
Taiwo
O
, Wilson
GA
, Emmett
W
, et al. DNA methylation analysis of murine hematopoietic side population cells during aging
. Epigenetics.
2013
;8
(10
):1114
-1122
.48.
Oguro
H
, Ding
L
, Morrison
SJ
. SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors
. Cell Stem Cell.
2013
;13
(1
):102
-116
.49.
Beerman
I
, Bhattacharya
D
, Zandi
S
, et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion
. Proc Natl Acad Sci USA.
2010
;107
(12
):5465
-5470
.50.
Tadokoro
Y
, Ema
H
, Okano
M
, Li
E
, Nakauchi
H
. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells
. J Exp Med.
2007
;204
(4
):715
-722
.51.
Challen
GA
, Mayle
A
, Sun
D
, et al. Dnmt3b has few specific functions in adult hematopoietic stem cells but shows abnormal activity in the absence of Dnmt3a
. Blood.
2013
;122
(21
):734
.© 2021 by The American Society of Hematology
2021
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