Improved HSC reconstitution and protection from inflammatory stress and chemotherapy in mice lacking granzyme B

Carnevalli, Larissa S.; Scognamiglio, Roberta; Cabezas-Wallscheid, Nina; Rahmig, Susann; Laurenti, Elisa; Masuda, Kohei; Jöckel, Lars; Kuck, Andrea; Sujer, Stefanie; Polykratis, Apostolos; Erlacher, Miriam; Pasparakis, Manolis; Essers, Marieke; Trumpp, Andreas

doi:10.1084/jem.20131072

Cited by 20 publications

(16 citation statements)

References 65 publications

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“…In addition, the increased expression of Gzmb may also contribute to HSPC damage, as Gzmb is induced by lipopolysaccharide and associated with increased cell death of HSPCs (Fig. C) .…”

Section: Resultsmentioning

confidence: 99%

Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure

Xiu

Xue²,

Lambertz

et al. 2016

Stem Cells

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Previously we have shown that loss of non-canonical NF-κB signaling impairs self-renewal of hematopoietic stem/progenitor cells (HSPCs). This prompted us to investigate whether persistent activation of the non-canonical NF-κB signaling will have supportive effects on HSPC self-renewal. NF-κB-inducing kinase (NIK) is an important kinase that mainly activates the non-canonical pathway through directly phosphorylating IKKα. In contrast to our expectations, constitutive activation of NIK in the hematopoietic system leads to bone marrow failure and postnatal lethality due to intrinsic impairment of HSPC self-renewal and extrinsic disruption of bone marrow microenvironment through enhancing osteoclastogenesis. The impaired HSPC function is associated with reduced cell proliferation and increased apoptosis and inflammatory cytokine responses. RNAseq analysis of control and NIK-activated HSPCs reveals that these effects are through non-canonical NF-κB signaling without significant changes in the canonical pathway. Gene set expression analysis of RNAseq data reveals globally decreased stem cell signature, increased maturation signature, and increased inflammatory responses. Many genes (Mpl, Tifab, Emcn, Flt3, Bcl2, and others) that regulate HSPC self-renewal, lineage commitment, and apoptosis are significantly downregulated—and those genes that regulate inflammatory responses and cell cycle inhibition (Cdkn2a and Cdkn2b) are significantly upregulated—by activation of NIK. Importantly, our data demonstrate that activation of NIK-non-canonical signaling has distinct phenotypes – smaller spleen size, decreased white blood cell counts, and reduced HSPC proliferation – compared to activation of canonical signaling. Collectively, these data indicate that the balanced non-canonical NF-κB signaling is essential for maintaining normal hematopoiesis and NIK-non-canonical signaling contributes to the development of bone marrow failure.

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“…In addition, the increased expression of Gzmb may also contribute to HSPC damage, as Gzmb is induced by lipopolysaccharide and associated with increased cell death of HSPCs (Fig. C) .…”

Section: Resultsmentioning

confidence: 99%

Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure

Xiu

Xue²,

Lambertz

et al. 2016

Stem Cells

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“…A significant IFN response was also obtained in the S11C). Note that the level of granzyme B expressed in the CD34 + cell population was 3 ± 1.2-fold higher in transplantations with unpurified UCB than with enriched CD34 + cells, suggesting that HSPCs experienced more stress (35) when mature immune cells were cotransplanted ( fig. S11D).…”

Section: Donor-derived Memory T Cells Secrete Tnfmentioning

confidence: 99%

Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell–mediated TNFα signaling

et al. 2017

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Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but the large number of HSCs required limits its widespread use. Host conditioning and donor cell composition are known to affect HSCT outcomes. However, the specific role that the posttransplantation signaling environment plays in donor HSC fate is poorly understood. To mimic clinical HSCT, we injected human umbilical cord blood (UCB) cells at different doses and compositions into immunodeficient NOD/SCID/IL-2Rgc-null (NSG) mice. Surprisingly, higher UCB cell doses inversely correlated with stem and progenitor cell engraftment. This observation was attributable to increased donor cell-derived inflammatory signals. Donor T cell-derived tumor necrosis factor-α (TNFα) was specifically found to directly impair the survival and division of transplanted HSCs and progenitor cells. Neutralizing donor T cell-derived TNFα in vivo increased short-term stem and progenitor cell engraftment, accelerated hematopoietic recovery, and altered donor immune cell compositions. This direct effect of TNFα on transplanted cells could be decoupled from the indirect effect of alleviating graft-versus-host disease (GVHD) by interleukin-6 (IL-6) blockade. Our study demonstrates that donor immune cell-derived inflammatory signals directly influence HSC fate, and provides new clinically relevant strategies to improve engraftment efficiency during HSCT.

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“…Interestingly, a recent study showed that LPS induced granyzme B expression in LT-HSCs through the TLR4-TRIF-p65 NF-κB axis and granzyme B caused cell-autonomous apoptosis in HSCs [27*]. On the other hand, LPS induced cytokine production in ST-HSCs and MPPs through the TLR-p50 NF-κB pathway, leading to cytokine production and autocrine/paracrine signaling [11*].…”

Section: Regulation Of Stress-induced Hematopoiesis By Tlr Signalingmentioning

confidence: 99%

Regulation of stress-induced hematopoiesis

Zhao

Baltimore²

2015

Current Opinion in Hematology

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Purpose of review Hematopoietic stem cells (HSCs) can self-renew and also give rise to the entire repertoire of hematopoietic cells. During acute infectious and inflammatory stresses, the hematopoietic system can quickly adapt to demand by increasing output of innate immune cells many-fold, often at the expense of lymphopoiesis and erythropoiesis. We review recent advances in understanding the regulation of stress-induced hematopoiesis with a specific focus on the direct effects of inflammatory signaling on hematopoietic stem and progenitor cells (HSPCs). Recent findings Recent studies have highlighted several areas of exciting new developments in the field, including the complex interaction and crosstalk within HSPCs and between bone marrow mesenchymal stem cells and endothelial cells needed to achieve regulated myelopoiesis, identification of increased number of inflammatory and infectious molecules with direct effects on HSPCs, the critical role of inflammatory signaling on embryonic specification of HSCs, and the ability of cytokines to instruct lineage choice at the HSPC level. Summary These exciting new findings will shape our fundamental understanding of how inflammatory signaling regulates hematopoiesis in health and disease, and facilitate the development of potential interventions to treat hematologic diseases associated with altered inflammatory signaling.

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Improved HSC reconstitution and protection from inflammatory stress and chemotherapy in mice lacking granzyme B

Abstract: Granzyme B is expressed by hematopoietic stem cells (HSCs) and stromal cells in response to bacterial products or chemotherapy agents and limits HSC reconstitution potential.

Cited by 20 publications

References 65 publications

Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure

Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure

Enhanced human hematopoietic stem and progenitor cell engraftment by blocking donor T cell–mediated TNFα signaling

Regulation of stress-induced hematopoiesis

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