Most hematopoietic stem cells (HSCs) are quiescent and rarely enter the cell cycle to self-renew or differentiate to maintain hematopoiesis under homeostasis [1,2]. Recent data suggest that HSCs undergo a limited number of self-renewing divisions (roughly four divisions in mice) before losing regenerative potential . Although some HSCs differentiate during these divisions to maintain oligopotent hematopoiesis the net result is an increase in HSCs as animals age [4,5,6▪]. However, aged HSCs show decreased self-renewal potential, donor reconstitution, bone marrow homing potential, and increased myeloid repopulation in comparison to young HSCs [7,8]. Decreased function of aged HSCs is due, in part, to normal cellular proliferation, which results in the production of reactive oxygen species (ROS) and other metabolites that damage cellular DNA, RNA, proteins, and lipids [9–11]. Although HSCs acquire DNA damage during the normal aging process, stress-induced proliferation contributes to DNA damage and accelerates HSC functional decline. For example, bone marrow transplantation (BMT) promotes HSC replication stress that leads to functional decline and HSCs exhaust during serial BMT. Further, mice treated with chemotherapeutic agents including 5 Fluorouracil (5-FU), which is toxic to cycling cells, promotes quiescent HSC proliferation and DNA damage that resembles aging [12,13]. Another driver of HSC proliferation is inflammation initiated by bacterial and viral infections and tissue injury. HSCs proliferate in response to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) released by injured cells through Toll-like receptors (TLRs) expressed on HSCs, or in response to proinflammatory cytokines through receptors expressed on HSCs [14,15]. Acute stress promotes HSC proliferation and differentiation that is quickly resolved, whereas prolonged or chronic stress can lead to HSC exhaustion (BMT, chronic infection/inflammation, chemotherapy). HSCs that lack Id1 show a blunted proliferative response to proinflammatory cytokines, are more quiescent and protected from exhaustion in conditions of chronic genotoxic and inflammatory stress, BMT, and aging [16▪]. Thus, Id1 has emerged as an important target to improve HSC survival and function during BMT, aging, and chronic stress. In this review, we highlight recent studies that discuss how chronic stress promotes HSC exhaustion and aging, and methods to mitigate HSC loss.
AGING, DNA DAMAGE, AND REACTIVE OXYGEN SPECIES
The DNA damage response is elicited during normal cellular proliferation, cell senescence, and cell growth [17,18]. HSCs show increased DNA damage and DNA damage response during normal self-renewing and differentiation divisions as they age, and when subjected to proliferative or inflammatory stress [19–22]. Aged human CD34+ HSCs display increased DNA damage and double-stranded breaks compared with young HSCs . DNA damage response-deficient HSCs show decreased self-renewal potential, HSC exhaustion, and limited donor reconstitution potential [9,10,11]. Collectively, the accumulation of DNA damage decreases the function and maintenance of HSCs as they age.
DNA damage is alleviated by recruitment of the kinase's Ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR) . Loss of ATM in HSCs resulted in increased levels of ROS and bone marrow failure . ROS accumulation and increased mitochondrial activity during the cell cycle promote DNA damage and depletion of HSCs [26,27,28▪]. HSCs reside in the hypoxic bone marrow microenvironment and are largely quiescent under low metabolic demands; thus, HSCs are protected from ROS and other metabolites that damage DNA. However, aged and stressed HSCs show increased levels of ROS [16▪,29]. Increased ROS in HSCs promotes increased proliferation, differentiation, and loss of HSC function and exhaustion [25,30,31]. Decreasing ROS in HSCs using N-acetyl cysteine (NAC) results in increased HSC maintenance and reconstitution capacity following bone marrow transplantation ([26,32], Unpublished Data). Similarly, we found that Id1−/− HSCs show decreased mitochondrial activation, ROS levels, and decreased H2A histone family member X (γH2AX) phosphorylation (DNA damage), decreased cycling, and increased quiescence and are protected from exhaustion during chronic proliferative stress including BMT [16▪]. Thus, inhibitors of Inhibitor of DNA binding (ID1) expression (Cannabidiol) and function could protect HSCs from proliferative stress and exhaustion (Fig. 1).
Several cell-signaling pathways are activated by increased levels of ROS, including the p38 Mitogen-activated protein kinase (MAPK) and Protein kinase B (AKT) signaling [25,33]. Forkhead box proteins (FOXO1 and FOXO3a) are negatively regulated by AKT signaling. FOXOs promote quiescence in HSCs by decreasing ROS in HSCs through the upregulation of superoxide dismutase and catalase, which convert free radical superoxide into peroxide then into water [34,35]. Thus, inhibiting or diminishing signaling through the Phosphoinositide 3-kinase-Protein kinase B pathway (PI3K-AKT) pathway could promote HSC quiescence. ROS is also elevated when HSCs use cellular respiration over glycolysis. Loss of hypoxia-inducible factor (HIF-1α) in HSCs, a master regulator of glycolysis, leads to increased cellular respiration and increased ROS production, which results in loss of HSC number and function during stress and as mice age [36,37▪,38]. Chemical stabilization of HIF-1α using DMOG and FG-4497 promotes engraftment and reconstitution in bone marrow transplants [39,40]. Taken together, high levels of ROS induce HSC proliferation and differentiation; therefore, targeting molecular pathways that reduce ROS in HSCs may represent viable therapeutic options to promote HSC quiescence and limit HSC loss during chronic stress (Fig. 1) .
INFECTION AND INFLAMMATION INDUCED STRESS
The hematopoietic system can quickly respond to conditions of infection and inflammation by increasing the production of myeloid and immune cells. For example, HSCs can exit quiescence and enter a proliferative state in response to infection and inflammatory stimuli [42▪]. HSCs can directly respond to inflammatory signals via TLRs and by proinflammatory cytokines including interleukins (ILs) IL-1, IL-3, and IL-6, interferons (IFN), transforming growth factor beta (TGFβ), tumor necrosis factor α (TNFα) and chemokines through cytokine receptors expressed on HSCs. These factors promote HSC proliferation and differentiation into multipotent progenitors which supply the increased demand for myeloid cells to the organism [14,15,43,44]. Acute stress is mediated, in part, by the innate immune response that is resolved with limited impact to HSCs, whereas chronic stress results in a prolonged sustained exposure to stress signals that can lead to HSC exhaustion . Inflammatory cytokines are known to induce the division of HSPCs by the process of emergency granulopoiesis , and if this process persists, it can lead to HSC exhaustion over time . Therefore, it is important for HSCs to balance proliferation/differentiation with quiescence during stress to sustain hematopoiesis for the long-term survival of the host. IFN-α (type I) regulates the balance between HSC quiescence and cell-cycle entry. IFN-α can directly promote HSC proliferation, and if chronically exposed to IFN stimulation, HSCs show decreased repopulation potential and loss of function . Furthermore, mice that lack interferon response factor-2 (IRF2), a negative regulator of type I interferon signaling, show chronic HSPC proliferation with defective repopulation ability under homeostasis, whereas blocking IFN signaling in these mice restores their repopulation ability in vivo, indicating that IRF2 can protect HSCs from chronic IFN-dependent exhaustion . Mechanistically, IFN-α and IFN-β affect proliferative stress by inhibiting key regulators of HSC quiescence including components of Notch and TGFβ-signaling pathway and, the transcription factor FOXO3a, and the CDKi, p57 . Significantly, patients with bone marrow failure syndromes and myelodysplastic syndrome (MDS) show increased production of proinflammatory signals including IFN and increased proliferation of CD34+ cells . IFN-γ is produced during infection and promotes the proliferation of quiescent HSCs, and sustained exposure to IFN-γ during chronic stress induces HSC exhaustion . A study by Alvarado et al.[52▪] found that IFN-γ-mediated HSPC depletion in human models of bone marrow failure syndrome was due to the perturbation of Thrombopoietin-induced signaling pathways, an important regulator of HSC maintenance and survival. Finally, prolonged exposure to other proinflammatory regulators including IL-1 , TNF , and LPS  promote chronic HSC proliferative stress, which results in impaired HSC function and exhaustion in vivo. Therefore, targeting proinflammatory cytokines or their receptors, PAMPs/DAMPs and TLRs could be therapeutically beneficial to protect HSCs from chronic proliferative stress and exhaustion (Fig.1).
Janus Kinases (JAK1) is an intracellular tyrosine kinase signaling molecule required for HSCs to respond to stress cytokines including IFN-α/β/γ and IL-3 . Jak1-deficient HSCs exhibited increased quiescence, inability to enter cell cycle, reduced response to type I interferons and IL-3, and impaired ability to reconstitute hematopoiesis during BMT and stress. Interestingly, we found that ID1 proteins are induced by IL-3 in normal HSPCs and cell lines and that Jak1/2 inhibitors block IL-3-induced ID1 expression, suggesting that the increased quiescence of Jak1−/− HSCs during stress may be mediated, in part, by reduced expression of ID1. Furthermore, these data suggest that Jak1 kinase inhibitors could protect HSCs from chronic proliferative stress. In support of this hypothesis, we have shown that administering pan-JAK and STAT inhibitors partially block ID1 induction in HSCs after BMT, suggesting that these inhibitors could be used to prevent HSCs from exhaustion during chronic stress [16▪]. Thus, we speculate that small molecule inhibitors of Jak signaling including ruxolitinib could be used to inhibit proinflammatory cytokines that signal through JAK kinases to reduce HSC exhaustion during BMT and chronic proliferative stress.
A histamine-dependent negative feedback mechanism has been proposed to restore HSC quiescence after acute inflammatory stress and infection. Specifically, myeloid-biased HSCs and their progeny express the histamine producing enzyme, histidine decarboxylase (Hdc), that produce histamine, which promotes quiescence in HSPCs by signaling through H2 receptors. Hdc knockout mice show increased HSC depletion following LPS-induced inflammatory stress and chemotherapy, which could be rescued by administration of a histamine mimetic . Thus, histamine could be used to promote HSPC cell quiescence and protect HSCs from depletion under chronic stress. In this regard, we demonstrated that loss of Id1 protects HSCs from stress-induced exhaustion and aging by promoting quiescence. Specifically, Id1−/− HSCs show reduced cycling, mitochondrial activation, and ROS levels, and a quiescent molecular signature compared with Id1+/+ HSCs after chronic stress and aging [16▪]. Thus, mechanism(s) that promote HSC quiescence during stress can be targeted to prevent HSC exhaustion.
BONE MARROW TRANSPLANTATION INDUCED STRESS
BMT is widely used to treat patients with hematopoietic malignancies and metabolic disorders. However, γ-Irradiation (IR) and other BMT conditioning regimens promote short and long-term damage to the hematopoietic microenvironment, which promotes acute and chronic inflammation. As a result, transplanted HSCs are under chronic proliferative stress for several months after BMT, after which, hematopoiesis returns to steady state [57–59]. Cytokines and proinflammatory stimuli released as a consequence of tissue injury during γ-IR and chemotherapy promote HSC proliferation and differentiation, suggesting that HSC exhaustion may be mediated, in part, by the proinflammatory hematopoietic microenvironment after BMT. Therefore, targeting the pathways involved in proinflammatory cytokine signaling during BMT could prevent HSC exhaustion. We found that Id genes are induced in HSPCs by proinflammatory cytokines including IL-3 and Granulocyte-macrophage colony-stimulating factor, and overexpression of Id1 in HSPC promotes HSPC proliferation suggesting a role for Id genes in regulating proliferation during hematopoietic stress [60,61]. In addition, HSCs that lack Id1 show reduced cell cycling, reduced DNA damage, decreased mitochondrial biogenesis and metabolic activity and are more quiescent than Id1+/+ HSCs after BMT. As Id1−/− HSCs are protected from exhaustion during serial transplantation, we hypothesized that inhibiting Id1 expression during BMT could prevent HSC exhaustion during BMT or other conditions of chronic stress [16▪]. Mechanistically, we showed that ID1 regulates HSC proliferation by restraining E protein function in HSCs (Id1-E2A-CDKi pathway). Id1 depleted HSCs showed reduced proliferation because of increased p16 and p27 expression in vitro, which was rescued by shRNA-mediated knockdown of E2A and p16. Id1 depleted HSCs showed increased p21 and p27 expression post-BMT supporting the notion that ID proteins regulate HSC proliferation by regulating CDKi expression [16▪]. In other experiments, the E protein (E47)/CDKi (p21) pathway was shown to be important in preventing HSC exhaustion during BMT and 5-FU mediated stress. Specifically, E47hetp21het HSCs exhibit decreased ability to self-renewal in serial BMT when compared with control mice, demonstrating that loss of E and Cdki expression in HSCs promotes cycling and exhaustion during stress .
HSCs undergo apoptosis when removed from microenvironmental signals that promote survival. Kollek et al. have shown that transient inhibition of apoptosis by blocking the proapoptotic proteins Bcl-2 interacting mediator (BIM) and Bcl-2 modifying factor (BMF) increases donor HSPC viability, reduces graft failure, and increases hematopoietic reconstitution during BMT. Thus, an efficient method to improve HSC survival during BMT may be to transiently inhibit apoptosis and/or senescence of the donor cells.
p38 mitogen-activated protein kinase (p38MAPK) is upregulated in HSCs during BMT and other hematopoietic stress. Elevated ROS levels induce phosphorylation and activation of p38MAPK in HSCs during BMT and stress. Karigane et al. have identified p38MAPK family isoform p38α as a cell cycle and metabolic regulator of HSPCs during hematological stress in vitro and in vivo during BMT. Inhibition of p38MAPK expression and activity protects HSCs from stressed induced proliferation and exhaustion during serial BMT and aging, suggesting that p38MAPK is a critical regulator of HSC exhaustion during chronic proliferative stress [65,13].
HSPCs can directly sense pathogens, PAMPs, and danger signals, DAMPs or alarmins, and proinflammatory cytokines produced during the inflammatory response after tissue damage or infection. TLRs and cytokine receptors expressed on HSCs and other immune cells promote HSC proliferation and differentiation . Bone Marrow cells (BMCs) that lack TLR4 or TLR9 have enhanced BMT reconstitution potential, suggesting that HSCs that lack TLR receptors are protected from stress-induced proliferation . HSCs that lack TLR4 proliferate in response to LPS treatment in vivo suggesting that proinflammatory cytokines including IL-6 produced by other cells including nonhematopoietic cells can indirectly regulate HSC proliferation [68,69]. Thus, blocking TLRs and IL-6 receptors might be important to prevent HSC exhaustion during chronic stress (Fig. 1).
The role of TNFα in HSC regulation is complex, Yamashita et al.[70▪] have shown that TNFα produced during inflammatory and genotoxic stress promotes HSC cycling and PU.1 expression that primes HSCs for myeloid differentiation. TNFα maintains NF-kB activity during inflammatory conditions after LPS and 5-FU treatment, which protects HSCs from necroptosis-mediated elimination and promotes myeloid regeneration. In other studies, TNFα released after total γ-IR and inflammatory stresses induce ROS formation through an NADPH oxidase-dependent manner in donor HSCs, which impairs their bone marrow reconstitution ability. Thus, short-term incubation with the antioxidant NAC or a specific inhibitor of TNFα or TNF receptor signaling could suppress ROS production and protect HSCs from chronic proliferative stress-induced depletion or exhaustion during BMT [26,32]. In this regard, BMCs that lack TNFR-p55 and TNFR-p75 show enhanced serial BMT ability . Therefore, examining additional small molecule inhibitors of TLRs, TNFRs, and other signal transduction pathways to prevent HSCs exhaustion during chronic proliferative stress will be important .
Most HSCs reside in a quiescent state during steady-state hematopoiesis and are protected from ROS and other metabolites that damage DNA, proteins, and lipids. Infection, blood loss, aging, BMT and genotoxic stress push quiescent HSCs into the cell cycle and promote differentiation to provide the host with progenitors for the increased demand for mature blood cells. Under acute stress, hematopoietic cells return to their quiescent state with minimal damage and loss of function; however, if the stress is chronic, HSCs are exposed to sustained proliferative signals, which results in decreased HSC function and exhaustion. Protecting HSCs from chronic proliferative stress has the potential to improve graft function during BMT, protect HSCs from chemotherapy-induced depletion, and reduce HSC loss during chronic inflammation, and aging. In addition, reducing chronic proliferative stress during hematopoietic malignancies and bone marrow failure could improve the outcome of these diseases. Therefore, understanding the cellular and molecular processes that protect HSCs from chronic proliferative stress could lead to therapeutic opportunities. These include inhibiting cytokine (IL-6/IL-1/TNF/IFN) and other proinflammatory stimuli and their receptors on HSCs and nonhematopoietic cells, inhibiting signaling pathways downstream of receptors (Jak/Stat), preventing apoptosis (BIM, BMF), inhibiting target genes (Id1) and pathways (HIF) that regulate proliferation and ROS production.
This project has been funded in part with Federal funds from the Frederick National Laboratory for Cancer Research, NIH, under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsements by the US Government.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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