Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness

Takizawa, Hajime; Fritsch, Kristin; Kovtonyuk, Larisa V.; Saito, Yasuyuki; Yakkala, Chakradhar; Jacobs, Kurt; Ahuja, Akshay K.; Lopes, Massimo; Hausmann, Annika; Hardt, Wolf‐Dietrich; Gomariz, Álvaro; Nombela‐Arrieta, César; Manz, Markus G.

doi:10.1016/j.stem.2017.06.013

Cited by 221 publications

(270 citation statements)

References 60 publications

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“…Notably, such myeloid activation promoted Hdc hi MB-HSCs and progenitors to enter the cell cycle, mobilized them into the circulation, and induced extramedullary hematopoiesis (Figure 2). Given the high expression of TLR4 on Hdc-GFP hi HSCs and HSPCs, and their increased number following LPS treatment (Figure 2), our results support a recent study that LPS can directly active the proliferation of HSC via TLR4 (Takizawa et al, 2017). Although LPS stimulation also can enhance the role of histamine/H 2 R axis through expansion of Hdc-GFP hi myeloid cells to enforce the quiescence of MB-HSCs, the increased myeloid demand may over time overwhelm the inhibitory effects of the feedback loop, leading to the depletion of Hdc-GFP hi HSCs (Figure 2C).…”

Section: Discussionsupporting

confidence: 88%

“…Toll-like receptors (TLRs) expressed on myeloid cells are known to sense bacterial products, which lead to rapid myelopoiesis (Nagai et al, 2006; Takeuchi et al, 1999). Lipopolysaccharide (LPS) treatment recapitulates gram-negative bacterial infection and specifically activates TLR4 on myeloid cells (Takizawa et al, 2017). HSCs can be activated by LPS either directly through cell intrinsic TLR signaling or indirectly through upregulation of myeloid-derived inflammatory cytokines (Nagai et al, 2006; Rodriguez et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…Although LPS stimulation also can enhance the role of histamine/H 2 R axis through expansion of Hdc-GFP hi myeloid cells to enforce the quiescence of MB-HSCs, the increased myeloid demand may over time overwhelm the inhibitory effects of the feedback loop, leading to the depletion of Hdc-GFP hi HSCs (Figure 2C). Further studies are required to confirm whether this belongs to the indirect effects of LPS on the behaviors of HSC (Takizawa et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

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Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop

et al. 2017

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SUMMARY Myeloid-biased hematopoietic stem cells (MB-HSCs) play critical roles in recovery from injury, but little is known about how they are regulated within the bone marrow niche. Here, we describe an auto/paracrine physiologic circuit that controls quiescence of MB-HSCs and hematopoietic progenitors marked by histidine decarboxylase (Hdc). Committed Hdc+ myeloid cells lie in close anatomical proximity to MB-HSCs and produce histamine, which activates the H2 receptor on MB-HSCs to promote their quiescence and self-renewal. Depleting histamine-producing cells enforces cell cycle entry, induces loss of serial transplant capacity, and sensitizes animals to chemotherapeutic injury. Increasing demand for myeloid cells via LPS treatment specifically recruits MB-HSCs and progenitors into the cell cycle; cycling MB-HSCs fail to revert into quiescence in the absence of histamine feedback, leading to their depletion, while an H2 agonist protects MB-HSCs from depletion after sepsis. Thus, histamine couples lineage-specific physiological demands to intrinsically-primed MB-HSCs to enforce homeostasis.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop

et al. 2017

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“…Viral agents also trigger BM hypoplasia, drive monopoiesis and impair erythropoiesis and B lymphopoiesis (Nombela Arrieta and Isringhausen, 2017). A common hallmark of hematopoietic responses to inflammatory challenges is the rapid activation of HSC cycling, which increases their proliferative history and leads to functional deficits (Takizawa et al, 2017;Walter et al, 2015;Zhang et al, 2016). The existing similarities between aging and inflammation-related effects have inspired the inflammaging hypothesis, which associates age-induced degeneration to the progressive emergence of a low-grade, basal inflammatory condition at tissue wide and systemic levels .…”

Section: Introductionmentioning

confidence: 99%

Global transcriptomic profiling of the bone marrow stromal microenvironment during postnatal development, aging and inflammation

Helbling

Piñeiro-Yáñez

Gerosa

et al. 2019

Preprint

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Bone marrow (BM) stromal cells provide the structural and regulatory framework for hematopoiesis and contribute to developmental-stage specific niches, such as those preserving hematopoietic stem cell (HSCs). Despite recent advances in our understanding of stromal composition and function, little is known on the dynamic transcriptional remodeling that this compartment undergoes over time and during adaptation to stress. Similarly, how molecular changes in stroma are linked to age-related modulation of hematopoiesis is poorly understood. Using RNA-sequencing, we performed a longitudinal comparison of the transcriptional profile of four principal mesenchymal and endothelial stromal subsets, namely CXCL12-abundant reticular (CARc), PDGFR-α + Sca-1 + , sinusoidal (SECs) and arterial endothelial cells (AECs), isolated from early postnatal, adult and aged mice. Our data i) provide molecular fingerprints defining novel, cell-specific anatomical and functional features ii) reveal radical reprogramming of pro-hematopoietic, immune and matrisomic transcriptional programs during the narrow temporal transition from juvenile to adult stages iii) demonstrate that homeostatic aging is characterized by a progressive and pronounced upregulation of pro-inflammatory gene-expression and loss of stromal cell fitness. By profiling in vivo responses of stromal cells to infection-mimicking agents, we finally demonstrate that transcriptomic pathways elicited by sterile inflammation are largely recapitulated during aging, thereby supporting the inflammatory basis of aging-related adaptations of BM hematopoietic function. Transcriptomic profiling of BM stroma Helbling et al.

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“…Recent studies indicate that HSCs respond to inflammatory signals in case of acute and chronic infection and directly participate in the primary immune response [30]. In vivo injection of inflammatory mediators (including IFN-α/β, IFN-γ, IL-1, TNF-α or PAMPs) [40, 61, 41, 38, 39] and more physiological models mimicking bacterial and viral infections [40, 33, 62•] are invariably associated with HSC loss of quiescence, differentiation and mobilization toward the periphery. Recent reviews provide excellent summaries of these studies [63•–65].…”

Section: Introductionmentioning

confidence: 99%

Tuning of the Hematopoietic Stem Cell Compartment in its Inflammatory Environment

Govindarajah

Reynaud

2018

Curr Stem Cell Rep

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Purpose of review The hematopoietic stem cell (HSC) compartment is the cornerstone of a lifelong blood cell production but also contributes to the ability of the hematopoietic system to dynamically respond to environmental challenges. This review summarizes our knowledge about the interaction between HSCs and its inflammatory environment during life and questions how its disruption could affect the health of the hematopoietic system. Recent findings The latest research demonstrates the direct role of inflammatory signals in promoting the emergence of the HSCs during development and in setting their steady-state activity in adults. They indicate that inflammatory patho-physiological conditions or immunological history could shape the structure and biology of the HSC compartment, therefore altering its overall fitness. Summary Through instructive and/or selective mechanisms, the inflammatory environment seems to provide a key homeostatic signal for HSCs. Although the mechanistic basis of this complex interplay remains to be fully understood, its dysregulation has broad consequences on HSC physiology and the development of hematological diseases. As such, developing experimental models that fully recapitulate a normal basal inflammatory state could be essential to fully assess HSC biology in native conditions.

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Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness

Cited by 221 publications

References 60 publications

Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop

Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop

Global transcriptomic profiling of the bone marrow stromal microenvironment during postnatal development, aging and inflammation

Tuning of the Hematopoietic Stem Cell Compartment in its Inflammatory Environment

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