cells

Review
Inflammation, Aging and Hematopoiesis: A Complex
Relationship
Pavlos Bousounis 1,2 , Veronica Bergo 1,2,3 and Eirini Trompouki 1,4, *

1 Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics,
79108 Freiburg, Germany; bousounis@ie-freiburg.mpg.de (P.B.); bergo@ie-freiburg.mpg.de (V.B.)
2 Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
3 International Max Planck Research School for Immunobiology, Epigenetics and Metabolism (IMPRS-IEM),
79108 Freiburg, Germany
4 Centre for Integrative Biological Signaling Studies (CIBSS), University of Freiburg, 79104 Freiburg, Germany
* Correspondence: trompouki@ie-freiburg.mpg.de; Tel.: +49-761-5108-550

Abstract: All vertebrate blood cells descend from multipotent hematopoietic stem cells (HSCs),
whose activity and differentiation depend on a complex and incompletely understood relationship
with inflammatory signals. Although homeostatic levels of inflammatory signaling play an intricate
role in HSC maintenance, activation, proliferation, and differentiation, acute or chronic exposure
to inflammation can have deleterious effects on HSC function and self-renewal capacity, and bias
their differentiation program. Increased levels of inflammatory signaling are observed during aging,
affecting HSCs either directly or indirectly via the bone marrow niche and contributing to their
loss of self-renewal capacity, diminished overall functionality, and myeloid differentiation skewing.
These changes can have significant pathological consequences. Here, we provide an overview of





 the current literature on the complex interplay between HSCs and inflammatory signaling, and
how this relationship contributes to age-related phenotypes. Understanding the mechanisms and
Citation: Bousounis, P.; Bergo, V.;
Trompouki, E. Inflammation, Aging
outcomes of this interaction during different life stages will have significant implications in the
and Hematopoiesis: A Complex modulation and restoration of the hematopoietic system in human disease, recovery from cancer and
Relationship. Cells 2021, 10, 1386. chemotherapeutic treatments, stem cell transplantation, and aging.
https://doi.org/10.3390/cells
10061386 Keywords: hematopoiesis; hematopoietic stem cells; bone marrow niche; regeneration; aging; in-
flammatory signaling; myeloid bias; myelodysplasia
Academic Editors: Katherine
C. MacNamara and Martijn A. Nolte

Received: 30 April 2021 1. Introduction

Accepted: 1 June 2021
The establishment and maintenance of the lifelong supply of blood cells relies on a rare
Published: 4 June 2021
population of multipotent and self-renewing hematopoietic stem cells (HSCs), which reside
in specialized niches within the bone marrow (BM) [1]. The hematopoietic process, from
Publisher’s Note: MDPI stays neutral
development to adulthood, as well as the genetic programs regulating HSC biology are
with regard to jurisdictional claims in
published maps and institutional affil-
well conserved among vertebrates [1–3]. Embryonic hematopoietic development proceeds
iations.
via distinct waves. The first or “primitive” wave is HSC-independent and gives rise to
hematopoietic cells required for the immediate needs of the developing embryo, such as
erythrocytes, megakaryocytes, myeloid cells, and macrophages. The intermediate wave
gives rise to transient erythro-myeloid precursors. During the third “definitive” wave,
HSCs emerge from the aorta-gonad-mesonephros (AGM) region of the developing embryo,
Copyright: © 2021 by the authors.
specifically from hemogenic endothelial cells located in the dorsal aorta, via an endothelial-
Licensee MDPI, Basel, Switzerland.
to-hematopoietic transition (EHT). The newly generated HSCs then migrate to the fetal liver,
This article is an open access article
distributed under the terms and
where they expand before reaching the BM, the site of adult hematopoiesis. Once HSCs
conditions of the Creative Commons
localize to the BM, the vast majority remain quiescent within specialized niches [1,4–6].
Attribution (CC BY) license (https://
The maintenance of HSCs in a non-cycling, quiescent state keeps energy requirements
creativecommons.org/licenses/by/ low, prevents oxidative damage, and ensures lifelong availability of a stable pool of viable
4.0/). HSCs that can be activated as needed to maintain and restore the hematopoietic system [7].

Cells 2021, 10, 1386. https://doi.org/10.3390/cells10061386 https://www.mdpi.com/journal/cells

Cells 2021, 10, 1386 2 of 15

HSC quiescence, self-renewal, and differentiation are controlled by cell-intrinsic mech-

anisms, mainly involving transcriptional, epigenetic and metabolic alterations, but also
cell cycle regulators [8], as well as cell-extrinsic signals from the cells and extracellular
matrix (EM) of the BM niche [9–11]. The self-renewal capacity of HSCs progressively di-
minishes as long-term-HSCs (LT-HSCs) differentiate into short-term-HSCs (ST-HSCs), and
eventually multipotent progenitors (MPPs), but is also affected by “stress” signals such as
infections, pathological conditions or physiological stress such as aging [12–14]. It is critical
to understand how HSC homeostasis is preserved under steady-state conditions and how
it is affected by stress conditions, as its deregulation may result in the development of
hematological malignancies.
Inflammation has evolved as an adaptive response against infection, tissue injury, and
other “stress” signals, used to induce regeneration and restore tissue homeostasis via the
removal of damaged cells and stem cell activation. The relationship between inflammation
and HSCs has been the focus of many recent studies [9,15,16]. Inflammatory signaling
is a critical regulator of HSC development [17–23] and maintenance during adulthood.
In fact, adult, quiescent HSCs are rapidly activated in response to inflammatory signals,
which affect not only their proliferation rate, but also their commitment towards specific
lineages [24–29]. Systemic, low-grade chronic inflammation has been shown to affect HSC
functionality, numbers, and differentiation, but is also one of the hallmarks of the aged
hematopoietic system [30–32]. Excessive exposure to these signals can also be a harbinger of
HSC exhaustion and functional impairment [33]. Moreover, it has been accepted that HSC
aging entails increased numbers of functionally impaired HSCs with reduced self-renewal,
and a bias towards myeloid differentiation [7,30,31,34,35].
In this review, we outline the known effects of inflammation on HSCs and their
niche during adulthood and upon aging. Understanding how inflammation affects HSC
homeostasis and cell fate decisions can lead to the development of clinical interventions and
therapies for maintaining a healthy hematopoietic system after insults, cancer treatments,
and aging.

2. Inflammatory Signaling as a Key Regulator of HSC Homeostasis

HSC quiescence and activation are thoroughly modulated by a complex interplay
between cell-intrinsic and cell-extrinsic factors. Over the past years, many studies have in-
vestigated the role of inflammatory signaling in HSC homeostasis, proposing inflammation
as a key regulator of HSC fate.
Interferons (IFNs) are a potent family of autocrine and paracrine cytokines that include
Type I IFNs: IFN-α, IFN-β and others, or Type II IFNs: IFN-γ. They are fundamental for
the mediation and resolution of infections [36]. HSCs are able to sense and respond to
IFNs, as they express a plethora of different IFN receptors on their cellular surface. While
low steady-state levels of IFNs may be required for HSC homeostasis, acute or chronic
IFN exposure can have deleterious effects on the HSC compartment, as hyperstimulation
by IFNs leads to HSC overactivation and eventually exhaustion [37]. Exposure to IFN-
α forces HSCs to exit quiescence in a STAT1-dependent manner, ultimately leading to
self-renewal defects [25]. HSCs need to return to a quiescent state in order to prevent
exhaustion, and they appear to employ not fully characterized “braking” mechanisms. For
example, exposure to Type I IFNs transiently induces HSC activation in vivo, followed by
re-entry into quiescence if IFN exposure persists chronically [26], a mechanism that has
been suggested to be c-MYC-dependent [38]. In this context, the cell cycle machinery is not
affected by IFNs. Instead, IFNs trigger a brief, but broad transcriptional downregulation
of many quiescence-enforcing genes, such as Foxo3a, Foxo1, and Pten, as well as Notch
and TGF-β associated genes, to a level that allows HSC proliferation. Other cell-intrinsic
mechanisms can modulate the activation of IFN response as well. For example, IRGM1
and the RNA-editing enzyme ADAR1 have been identified as critical feedback inhibitors,
which balance and prevent the deleterious effects of prolonged IFN exposure. IRGM1
deficient HSCs exhibit elevated IFN signaling accompanied by hyperproliferation, self-
Cells 2021, 10, 1386 3 of 15

renewal and autophagy defects which are normalized in the absence of IFN receptors
or STAT1 [39]. ADAR1 is an essential regulator of the IFN response in HSCs, as its
deficiency leads to a widespread upregulation of transcripts associated with Type I and
Type II interferon responses, triggering HSC pool exhaustion [40]. The effects of IFNs on
HSCs, however, appear to be context-specific. IFN-γ, for instance, can either stimulate or
suppress HSC proliferation and reconstitution capacity. IFN-γ produced during bacterial
infections transiently activates HSCs to exit dormancy and differentiate, yet prolonged
IFN-γ exposure in chronic infections appears to negatively affect the maintenance of mouse
HSCs, decreasing the number of self-renewing divisions favoring asymmetric divisions,
reducing engraftment, and leading to HSC exhaustion. HSC cell-cycle entry, proliferation,
differentiation, and apoptosis, however, were not impeded, which is consistent with the
activation-to-exhaustion effects of other pro-inflammatory cytokines [24,41–43]. Interferons
produced in response to infection also induce megakaryopoiesis. It was shown by Haas et al.
that a lineage-primed population of HSCs designated stem-like megakaryocyte-committed
progenitors (SL-MkPs) rapidly restores platelets after infection [44].
Tumor necrosis factor α (TNFα) acts as a pro-inflammatory cytokine in a variety of
processes, from fever stimulation to the regulation of tissue homeostasis, by influencing cell
proliferation and differentiation [45–48]. Like with interferons, the contribution of TNFα
signaling to HSC homeostasis depends on the dose and duration of the exposure, and
could be influenced by the local environment within the BM [49]. TNFα exposure in vitro
has been reported to negatively regulate the maintenance of cycling HSCs by promoting
differentiation at the cost of self-renewing divisions [50,51]. In addition, HSCs exposed
to TNFα were not able to sustain multi-lineage differentiation upon transplantation into
NOD-SCID mice, and exhibited skewing towards myeloid differentiation [50]. However, it
has also been demonstrated that in vitro TNFα production by CD8+ T-cells strengthens
HSC function and supports hematopoietic reconstitution upon transplantation, as HSCs
showed a better engraftment capacity [52]. In vivo experiments have also proven that
TNFα overexpression restricts the activity of HSCs by a mechanism that depends on
TNFRS1a and TNFRS1b receptors. This effect seems to affect mainly cycling rather than
quiescent HSCs, and it can change with age [53]. At the molecular level, TNFα activates a
NF-κB-dependent transcriptional program that promotes HSC survival and poises them for
myeloid differentiation [54] through the upregulation of PU.1, a myeloid lineage-instructing
transcription factor [55].
Studying the effects of interleukins (ILs) on HSC homeostasis is complicated, as they
have often redundant functions. Interleukins play a plethora of essential roles within the
immune system, such as sustaining proliferation, maturation and migration. Moreover,
they have both pro- and anti-inflammatory properties, according to the microenviron-
ment and the cell types they act on [56]. The effects of interleukins on adult HSCs are
still unclear. Acute IL-1 exposure is known to act as a “pro-inflammatory” signal dur-
ing infection, promoting cell division and priming HSCs towards myeloid differentiation
through the activation of the transcription factor PU.1 [27]. Chronic exposure strongly
impairs HSC self-renewal capacity, as they fail to replenish the hematopoietic system
upon transplantation [27]. However, these results have been proven to be transient. Re-
cent results from the same group showed that the exposure of LT-HSCs to IL-1 activates
PU.1 that directly binds and represses genes related to cycling and protein synthesis, thus
safeguarding HSC functionality [57]. In addition, IL-27 has been shown to induce the
expansion of the hematopoietic stem and progenitor cell (LSK) compartment during emer-
gency hematopoiesis, promoting myeloid differentiation [58]. Among the others, IL-33 has
been studied in the context of total body irradiation, showing that it enhances HSC sur-
vival, preventing the activation of apoptosis by repressing the TP53-PUMA pathway [59].
Additionally, IL-12 has been shown to support HSC self-renewal in vitro by controlling the
division rate through the activation of the JAK/STAT pathway [60]. Finally, IL-6 produced
after the stimulation of Toll-like receptors (TLRs) is important for myeloid differentiation
and hematopoietic stem and progenitor cell (HSPC) proliferation [61].
Cells 2021, 10, 1386 4 of 15

The function of TLRs is also important for HSCs. Agonists against TLR7/8 induce the
expansion and mobilization of HSPCs [62], while germline or mosaic activation of TLR8
leads to immunodeficiency and bone marrow failure [63]. The function of the granulocyte
colony-stimulating factor (G-CSF) in HSCs is also mediated, at least partly, by TLR2/4 [64],
while pathogen-induced TLR4 signaling leads to HSC cycling, but at a loss of self-renewal
capacity [65].
In conclusion, inflammation plays a pivotal role in “jump-starting” dormant HSCs
in response to infection or hematological insults or when “emergency hematopoiesis” is
needed. Inflammatory signals skew HSC differentiation towards first-responder cells of
the myeloid lineage. If the inflammatory response is not resolved and chronically persists,
the overall effect on HSCs can lead to their exhaustion.

3. Inflammation Affects HSC Homeostasis via the BM Niche

The BM niche has emerged in the last few years as an important regulator of HSCs
even though the exact localization of HSCs in the BM niche is still under debate. The
structure of the BM niche is complex and involves multiple cell types that regulate not only
HSCs but also distinct progenitor populations. The BM mesenchymal stromal cells (MSCs)
are rare perivascular cells important for HSC maintenance together with other cells such as
osteoblasts, endothelial cells, and neuronal cells, but also some hematopoietic cells such as
megakaryocytes and macrophages [66–68].
Inflammation influences HSCs in a cell-extrinsic manner by altering their BM niche,
as shown by a growing number of studies [67,69,70]. BM niche cells respond to peripheral
inflammation or infection by releasing factors that promote myelopoiesis [71,72]. For
example, peripheral inflammation drives the secretion of G-CSF, mainly from endothelial
cells, which then plays a central role in the differentiation of hematopoietic progenitors
towards mature granulocytes [71,73]. Inflammation also affects the proximity of HSCs to
quiescence-promoting BM niche cells, which is also an important factor affecting HSC func-
tions. Under homeostatic conditions, CXCR4 expressed by HSCs interacts with CXCL12 on
CXCL12-abundant reticular (CAR) cells residing in the HSC niche [74,75]. The stimulation
of HSCs with IFN-γ in culture causes their displacement from quiescence-promoting CAR
cells. This displacement was shown to occur via upregulation of the expression of the
glycoprotein BST2 on the HSC surface [28]. Additionally, it was shown that IFN-γ secreted
by cytotoxic CD8+ T cells in a model of lymphocytic choriomeningitis virus infection
stimulates MSCs to secrete IL-6, which in turn enhances myelopoiesis [76]. Integrin sig-
naling synergizes with IFN-γ to modulate HSCs. Indeed, integrin β3 signaling enhances
STAT-1 mediated signaling upon IFN-γ treatment and thus intensifies the effect of IFN-γ
on HSCs [77]. Type-I IFNs influence HSCs by affecting the BM niche as well. Prednergast
et al. demonstrated that the BM of IFN-α or poly(I:C)-treated mice exhibited increased vas-
cularity, expansion, and activation of endothelial cells. Mechanistically, these changes were
mediated by vascular endothelial growth factor (VEGF) signaling crosstalk between ECs
and other BM cells, including HSCs. This facilitated BM remodeling and suggests a role for
HSCs themselves in the regulation of their niche [78]. Moreover, BM granulocytes secrete
TNFα, which acts on ECs and promotes vessel and hematopoietic regeneration [79]. This
effect was lost in mice deficient for TNF receptors, and transplantation experiments proved
the direct function of TNFα on HSCs. Recently, single cell expression analysis showed that
poly(I:C) or lipopolysaccharide (LPS) administration induces abundant cytokine expression
from CAR cells (IL6, IL1b, CXCL2 and CXCL5) and sinusoidal endothelial cells concomitant
to the downregulation of factors that contribute to HSC retention and lymphopoiesis, thus
providing a mechanistic explanation for the observed myeloid skewing [72].
These studies show that inflammation can affect HSC activity via niche-dependent
interactions. However, how inflammation directly affects specific populations in the BM
niche and how they consequently affect HSCs need further investigation.
 to HSC retention and lymphopoiesis, thus providing a mechanistic explanation for the
observed myeloid skewing [72].
Cells 2021, 10, 1386 These studies show that inflammation can affect HSC activity via niche-dependent
5 of 15
interactions. However, how inflammation directly affects specific populations in the BM
niche and how they consequently affect HSCs need further investigation.

4. Inflammation and HSC Aging

Although the
Although the number
numberofofHSCsHSCsresiding
residingininthethe
BMBMis is generally
generally increased
increased in aged
in aged in-
individuals,
dividuals, aged
aged HSCsexhibit
HSCs exhibitimpaired
impairedlong-term
long-termrepopulation
repopulationcapacity
capacity[80][80](Figure
(Figure 1).
1).
One of the most prominent characteristics of aged HSCs is “inflamm-aging”,
One of the most prominent characteristics of aged HSCs is “inflamm-aging”, defined as a defined
as a sterile,
sterile, systemic,
systemic, low-grade
low-grade chronic
chronic inflammatory
inflammatory phenotype
phenotype [29]. An[29]. An increasing
increasing number
number of publications indicate that chronic inflammation influences
of publications indicate that chronic inflammation influences HSC functionality, HSC functionality,
differen-
differentiation,
tiation, and renewal
and renewal in agedinorganisms
aged organisms both directly
both directly and indirectly
and indirectly [29,81].
[29,81]. The
The exact
exact mechanisms
mechanisms of how of these
how these changes
changes occuroccur
in HSCsin HSCs androle
and the the of role of “inflamm-aging”
“inflamm-aging” in
in this
this process are still being elucidated.
process are still being elucidated.

Figure 1.
Figure 1. Hallmarks
Hallmarks of
ofHSC
HSCaging.
aging.Aged
AgedHSCs
HSCsexhibit
exhibit diminished
diminished self-renewal
self-renewal andand reconstitution
reconstitution capacity
capacity uponupon trans-
transplan-
plantation which contributes to HSC exhaustion despite their increased numbers in aged individuals. They are also char-
tation which contributes to HSC exhaustion despite their increased numbers in aged individuals. They are also characterized
acterized by myeloid skewing, DNA damage accumulation and decreased protein quality control. Inflammation, although
by myeloid skewing, DNA damage accumulation and decreased protein quality control. Inflammation, although essential
essential for HSC homeostasis, is increased during aging and exerts detrimental effects on aged HSCs. Indeed, inflamma-
for HSC homeostasis, is increased during aging and exerts detrimental effects on aged HSCs. Indeed, inflammation
tion accelerates the proliferation of mutated HSCs, thus contributing to clonal hematopoiesis. Created with BioRen-
accelerates the proliferation
der.com, accessed on 29 Mayof mutated HSCs, thus contributing to clonal hematopoiesis. Created with BioRender.com,
2021.
accessed on 29 May 2021.
Increased senescence accompanied by the secretion of pro-inflammatory cytokines
Increased senescence accompanied by the secretion of pro-inflammatory cytokines
such as IL-1, TNFα, and IL-6 and others, immune modulators, growth factors, and prote-
such as IL-1, TNFα, and IL-6 and others, immune modulators, growth factors, and
ases—termed the senescence-associated secretory phenotype (SASP)—accompanies and
proteases—termed the senescence-associated secretory phenotype (SASP)—accompanies
most likely plays a role in diminishing the functionality of aged HSCs [29,81–83]. A recent
and most likely plays a role in diminishing the functionality of aged HSCs [29,81–83].
study showed that age-related inflammation promotes HSC aging by inducing the surface
A recent study showed that age-related inflammation promotes HSC aging by inducing
expression of IL27Ra via TNFα-ERK-ETS1 signaling. The deletion of IL27Ra was shown
the surface expression of IL27Ra via TNFα-ERK-ETS1 signaling. The deletion of IL27Ra
was shown to rescue the functional decline and myeloid bias of HSCs by reversing the
effects of TNFα [81]. Likewise, endogenous activation of NF-κB signaling mediated by
RAD21/cohesin in aged mice led to increased responsiveness to inflammation, conse-
quently driving HSC differentiation and leading to the loss of their self-renewal capac-
ity [84]. As with TNFα, increased exposure to IL-1 also biases aged HSCs towards myeloid
Cells 2021, 10, 1386 6 of 15

differentiation via NF-κB-mediated activation of PU.1, likely signifying a common down-

stream response of HSCs to pro-inflammatory signals that become more active with age [29].
Results from another study showed that the P38a isozyme of P38-MAPK differentially
influences HSC differentiation bias and re-population capacity in young versus aged cells.
The activation of P38-MAPK signaling in response to stress, DNA damage, inflamma-
tory signaling, BM transplantation or loss of ATM induces reactive oxygen species (ROS),
leading to decreased HSC quiescence and exhaustion [85]. Mann et al. identified a CD61
positive population of LT-HSCs that responds to inflammatory challenges and is potentially
responsible for the myeloid bias observed in aged HSCs [86], in accordance with previous
studies showing that functionally distinct HSCs are responsible for the myeloid bias [87].
HSCs naturally accumulate DNA damage as they age, which significantly contributes
to age-related tissue degeneration and malignancies [88–90]. The extent of DNA damage is
directly associated with the replicative stress induced in HSCs as they enter the cell cycle in
response to external cues, and depends, at least in part, on the effects of IFN-α on LT-HSCs.
DNA damage in HSCs was shown, however, to most likely be a result of cell cycle entry
and not of an IFN-α-induced transcriptional program [89]. In addition, repeated activation
and re-entry into quiescence of HSCs in adult WT mice via serial activation of type-I IFN
response with poly(I:C) led to a progressive depletion of functional HSCs, with no sign of
later recovery due to the absence of self-renewal divisions [91]. High levels of replicative
stress during aging are associated with cell cycle defects and chromosomal abnormalities,
mainly due to decreased expression of MCM helicase components [88].
Dysfunction of the HSC epigenetic regulatory machinery has been shown to play
a prominent role in the chronically inflamed aged phenotype as well. A recent study
by Sera et al. [92] demonstrated the role of the epigenetic modifier ubiquitously tran-
scribed tetratricopeptide repeat gene, X chromosome (UTX/KDM6A) in maintaining HSC
“youthfulness”. UTX levels in HSCs are known to decrease with age, and HSPCs from
UTX-deficient mice displayed an aged gene expression program, including impaired DNA
repair mechanisms, ROS accumulation, and increased expression of the aging-associated
marker CD41. UTX-deficient mice further presented with trilineage dysplasia, a condition
similar to myelodysplastic syndrome (MDS) in humans, which becomes more common
with age [92]. It is possible that these aging effects on HSCs are caused by inflammation,
as UTX has been associated with deregulated inflammatory signaling in a UTX-deficient
mouse model of bladder cancer [93].
Of note, chaperone-mediated autophagy (CMA) has been shown to maintain adult
HSC function in mice by controlling protein quality and up-regulating fatty acid metabolism
in active HSCs. Quiescent HSCs from young mice had higher levels of CMA activity com-
pared to quiescent HSCs from older mice, and CMA activity was further increased in the
activated HSCs after 5-FU treatment [94]. Importantly, CMA has been shown to decrease
in response to inflammation, and reduced CMA activity contributes to the aged HSC
phenotype [81,94]. Reactivating CMA alleviated some of the phenotypes of aged HSCs [94].
In general, autophagy has been shown to be critical for maintaining the metabolism and
function of both young and old HSCs [95].
While several studies pinpoint a role of inflammatory signaling in hematopoietic
aging, it is still debatable whether we know the exact cytokine profile important for HSC
aging and the interplay between different sterile inflammatory signals.

5. Inflammation Alters the Aged HSC Niche

HSCs are influenced by age-related changes to the BM niche, and especially by the
elevated levels of pro-inflammatory cytokines expressed in the aged niche (Figure 2).
The inflammatory milieu in the aged bone marrow drives stromal and hematopoietic
remodeling. Specifically, osteogenic MSCs decrease in numbers at the endosteum while
pro-inflammatory perisinusoidal MSCs expand in the central marrow. Importantly, block-
ing IL-1 signaling improves the features of the aged hematopoietic system [96]. Ergen et al.
showed that the production of the cytokine CCL5 by BM niche cells is increased with age
 5. Inflammation Alters the Aged HSC Niche
HSCs are influenced by age-related changes to the BM niche, and especially by the el-
evated levels of pro-inflammatory cytokines expressed in the aged niche (Figure 2). The in-
Cells 2021, 10, 1386 flammatory milieu in the aged bone marrow drives stromal and hematopoietic remodeling. 7 of 15
Specifically, osteogenic MSCs decrease in numbers at the endosteum while pro-inflamma-
tory perisinusoidal MSCs expand in the central marrow. Importantly, blocking IL-1 signal-
ing improves the features of the aged hematopoietic system [96]. Ergen et al. showed that
andproduction
the is pivotal for
of the
the myeloid
cytokine skewing
CCL5 byobserved
BM nicheincells
aged is HSCs [97].with
increased The overexpression
age and is pivotalof
CCL5 in young mice mirrored the decrease in lymphoid and increase in myeloid
for the myeloid skewing observed in aged HSCs [97]. The overexpression of CCL5 in young lineage
production
mice observed
mirrored in agedinmice,
the decrease lymphoid Ccl5increase
while and knockout inHSCs exhibit
myeloid decreased
lineage myeloid
production ob-
bias [97]. Mature myeloid and megakaryocytic cells themselves are known sources of
served in aged mice, while Ccl5 knockout HSCs exhibit decreased myeloid bias [97]. Mature
inflammatory cytokines, which likely reinforce and perpetuate the myeloid skewing of
myeloid and megakaryocytic cells themselves are known sources of inflammatory cyto-
HSCs with age [98]. Indeed, increased inflammatory signals concomitant to decreased
kines, which likely reinforce and perpetuate the myeloid skewing of HSCs with age [98].
phagocytosis from macrophages instigate a platelet bias in the aged BM [99]. TNFα pro-
Indeed, increased inflammatory signals concomitant to decreased phagocytosis from mac-
duced by macrophages, lymphocytes, and endothelial cells regulates HSC gene expression
rophages instigate a platelet bias in the aged BM [99]. TNFα produced by macrophages,
via activation of the transcription factor NF-κB, and exerts diverse effects, especially during
lymphocytes, and endothelial cells regulates HSC gene expression via activation of the tran-
aging [54].
scription factor NF-κB, and exerts diverse effects, especially during aging [54].

Figure 2. Effects of inflammation and aging on the HSC niche. (A) Multiple bone marrow niche cells such as mesenchymal
Figure 2. Effects of inflammation and aging on the HSC niche. (A) Multiple bone marrow niche cells such as mesenchymal
stromal cells (MSCs) and specifically CXCL12-abundant reticular (CAR) cells, endothelial cells, but also hematopoietic cells
stromal cells (MSCs) and specifically CXCL12-abundant reticular (CAR) cells, endothelial cells, but also hematopoietic
such as megakaryocytes, T-cells and macrophages affect HSC quiescence through diverse molecular mechanisms, including
cells suchsecretion
cytokine as megakaryocytes, T-cells
as depicted. (B) and aging,
During macrophages affect HSC but
HSC accumulation quiescence through
with increased diversefrom
distance molecular mechanisms,
arterioles, sinusoids
including cytokine secretion
and megakaryocytes as depicted.
is accompanied (B) During aging,
by inflammatory HSCand
signaling accumulation but withfrom
cytokine secretion increased distance
various from arterioles,
bone marrow popula-
sinusoids and megakaryocytes
tions including CAR cells and is accompanied
senescent by inflammatory
fibroblasts signaling and cytokine
(SASP: Senescence-associated secretion
secretory from various
phenotype). Agedbone
MSCsmarrow
turn
populations
primarily intoincluding CAR
adipocytes cells
and and senescent
adrenergic fibroblasts
signaling (SASP:
is disturbed. Senescence-associated
Created secretory
with BioRender.com, phenotype).
accessed on 3 JuneAged
2021.MSCs
turn primarily into adipocytes and adrenergic signaling is disturbed. Created with BioRender.com, accessed on 3 June 2021.

Single-cell transcriptome analysis of the mouse BM niche after treatment with 5-

fluorouracil, a myeloablative chemotherapeutic agent, showed significant transcriptional
remodeling within the BM populations. These changes include the expansion of the
perivascular population, and the downregulation of the Notch delta-like ligands Dll1
and Dll4, which promote a myeloid-differentiation transcriptional program in HSCs [83].
Cells 2021, 10, 1386 8 of 15

Furthermore, aging induces the gradual replacement of BM cells, such as stromal and
perivascular cells, with adipocytes, which are a source of regulatory cytokines. When
MSCs differentiate into adipocytes, they cease to produce and secrete factors important for
hematopoiesis and HSC maintenance, such as CXCL-12, IGF-1, and c-KIT ligand. These
alterations mirror chronically inflamed, aged hematopoietic systems [37]. Adrenergic
signaling is also important for aged HSCs [100]. Increased sympathetic adrenergic activity
has been previously described during aging [101]. Recently, it has been shown that aging
remodels the HSC niche by expanding non-endosteal neurovascular niches at the expense
of endosteal niches. In addition, increased β2-adrenergic signaling during aging promotes
IL-6 dependent myeloid differentiation [102].
These studies show that sterile inflammation is important for the remodeling of the
aged bone marrow niche, which in turn affects HSCs.

6. Inflammation, Aging and Hematological Disorders

Inflammation is an acute response to various stress conditions and often leads to
restoration of tissue homeostasis. However, failure in resolving inflammatory cues may
impair tissue function. Given the role of inflammation in HSC homeostasis, it is not
surprising that the deregulation of this interaction affects the emergence, progression, and
outcome of various hematological disorders. Indeed, the connection between deregulated
inflammatory signaling and bone marrow dysfunction has been extensively described.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological dis-
orders, characterized by defective hematopoiesis, blood dysplasia, and the tendency to
progress to leukemia [103]. In the past years, further evidence supporting the role of
inflammatory signaling dysregulation in MDS has been presented [104,105], demonstrating
that the BM microenvironment also plays a critical role in disease emergence and progres-
sion [106]. For example, MDS patients show increased levels of IFN-γ and TFNα in the
bone marrow [107], which is associated with higher apoptosis rates in MDS BM cells [108].
Multiple components of the TLR signaling pathway, such as receptors and downstream
mediators, were found to be overexpressed or altered in MDS [109]. For instance, increased
expression of TLR2, TLR4 and TLR9 has been correlated with higher levels of TFNα, which
decreases upon leukemic transformation [110,111]. MDS progression leads to the develop-
ment of leukemia, a broad group of either acute or chronic hematological malignancies. In
particular, the progression of MDS to acute myeloid leukemia (AML) is observed in one
third of the patients [112].
Over the past years, inflammation has been directly linked to myeloid malignan-
cies and proposed as one of the drivers of pathogenesis, while also influencing disease
progression and burden [113,114]. The NF-κB pathway plays an important role in HSC
proliferation and differentiation, and as expected it was shown to be constitutively active
in AML cells [115]. IFN-γ and TFNα have been shown to promote differentiation and
suppress clonal growth in AML blasts [116]. A recent study has also described a crucial
contribution of the microenvironment to AML. Indeed, inflammatory cytokines, such as
IL-6 and IL-1β, released by mesenchymal and progenitor cells are sensed by AML cells,
activating JAK/STAT signaling to boost AML progression [117]. Elevated cytokines levels
are also observed in patients with myeloproliferative neoplasms (MPN) [118] and chronic
myeloid leukemia (CML) [119].
Inflammation also contributes to clonal hematopoiesis (CH). As HSCs age, they are
more likely to accumulate DNA damage and mutations as a consequence of both time and
impaired DNA repair mechanisms, leading ultimately to hematological disorders. If an
HSC gains at least one mutation that grants it a selective advantage, it may give rise to
a population of mutated clones. CH occurs when this altered HSC population ends up
significantly contributing to the total number of mature blood cells. Clonal hematopoiesis
of indeterminate potential (CHIP) describes the progression of CH to a level where at least
4% of all nucleated blood cells harbor a cancer-associated mutation, and this condition
can progress to leukemia [120]. For example, mutations in genes encoding for epigenetic
Cells 2021, 10, 1386 9 of 15

regulators such as Dnmt3a, Tet2, and Asxl1 confer an advantage in terms of self-renewal and
inhibit differentiation [121]. In vitro exposure of TET2-deficient human and murine HSCs
to TNFα leads to a strong proliferative advantage [122], while mouse TET2-deficient HSCs
resist apoptosis under inflammatory stress and increase their repopulation capacity [123].
Recently, it has been shown that inflammation could drive the expansion of Dnmt3a
knockout cells, thus mimicking clonal hematopoiesis [124]. Additional studies need to be
performed, as new insights on clonal hematopoiesis can enhance our understanding on
preleukemic development and cancer evolution. Moreover, understanding the features of
CH will also help predict and prevent the progression of this condition to hematological
malignancies.
Inflammation also plays a role in genetically inherited conditions. Fanconi anemia
(FA) is characterized by genomic instability, bone marrow failure, short stature and a high
relative risk of myeloid leukemia. FA stem cells are especially vulnerable to a variety of
inflammatory stress signals [89,125]. FA has been associated with increased bone marrow
levels of IFN-γ and TFNα [126], and another study showed that although acute TNFα ex-
posure profoundly inhibited the growth of Fancc−/− stem cells, chronic exposure promoted
leukemic clonal evolution within the HSC compartment [127].
The interplay between inflammation and hematological disorders is evident. Future
studies will help to better dissect the contribution of inflammatory signaling in disease
progression.

7. Discussion
Inflammation appears to act as a multi-edged sword in the context of hematopoiesis.
Although certain levels of inflammation are required for proper HSC development, mainte-
nance, activation, and differentiation, sustained chronic or excessive levels of inflammatory
signaling negatively affect the function and self-renewal of HSCs, and bias their differentia-
tion program. In addition to the cell-intrinsic effects of inflammatory signaling of HSCs,
there is a growing body of evidence that inflammatory signals from the BM microenvi-
ronment also contribute to HSC aging. Understanding the mechanisms of inflammation
during adulthood and upon aging will have important clinical implications in regenerative
therapies, stem cell transplantation and the treatment of leukemias. Pinpointing which
pathways to modulate in aged stem cells could improve cancer treatment outcomes at
all ages and make the transplantation and engraftment of HSCs from older individuals
feasible, thereby significantly expanding the pool of potential donors.

Author Contributions: P.B. and V.B. wrote the review. P.B. designed and drew the figures. E.T.
provided the critical revision of the manuscript. All authors have read and agreed to the published
version of the manuscript.
Funding: E.T. was supported by the Max Planck Society and The Fritz Thyssen Stiftung (Az
10.17.1.026MN). E.T. received funds from the Deutsche Forschungsgemeinschaft, Research Training
Group GRK2344 “MeInBio –BioInMe” and the German Research Foundation (DFG) under Germany’s
Excellence Strategy (CIBSS-EXC-2189-Project ID 390939984 to ET).
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

AGM Aorta-Gonad-Mesonephros
AML Acute Myeloid Leukemia
BM Bone Marrow
CH Clonal Hematopoiesis
CHIP Clonal Hematopoiesis of Indeterminate Potential
CMA Chaperone-Mediated Autophagy
Cells 2021, 10, 1386 10 of 15

CML Chronic Myeloid Leukemia

FA Fanconi Anemia
G-CSF Granulocyte Colony-Stimulating Factor
HSC Hematopoietic Stem Cell
HSPC Hematopoietic Stem and Progenitor Cell
IFN Interferon
IL Interleukin
LPS Lipopolysaccharide
LT-HSC Long Term Hematopoietic Stem Cell
MDS Myelodysplastic Syndromes
MPN Myeloproliferative Neoplasms
MPP Multi-Potent Progenitor
MSC Mesenchymal Stem Cell
SASP Senescence-Associated Secretory Phenotype
ST-HSC Short Term Hematopoietic Stem Cell
TLR Toll-like Receptor
TNFα Tumor Necrosis Factor α
VEGF Vascular endothelial growth factor

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