scholarly journals Hematopoietic Stem and Progenitor Cells Improve Survival from Sepsis By Boosting Immunomodulatory Cells

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3261-3261
Author(s):  
Daniel Enrique Morales-Mantilla ◽  
Bailee Nicole Kain ◽  
Duy Le ◽  
Anthony R Flores ◽  
Silke Paust ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Immune Cells ◽  
Bacterial Load ◽  
Myeloid Cells ◽  
Lineage Tracing ◽  
Hematopoietic Stem ◽  
Pathogen Load ◽  
Cytokine Levels ◽  
Stem And Progenitor Cells ◽  
The Impact

Abstract Sepsis is a dysregulated inflammatory syndrome that accounts for as many as 20% of deaths worldwide. Elevated production of pro-inflammatory cytokines during sepsis, such as IL-1, IL-6, interferons (IFNs), and tumor necrosis factor contribute to the development of fever, vasodilation, and multiorgan failure. Novel therapies to treat sepsis are urgently needed. Hematopoietic stem and progenitor cells (HSPC) are responsible for the day-to-day production of blood and immune cells. Recent work from our group and others indicates that during emergency hematopoiesis, inflammatory signals including cytokines, chemokines, and pathogen-derived molecules direct HSPCs to differentiate into effector immune cells. While these signals are essential for a proper immune response, excessive signaling in HSPCs can be detrimental and lead to their depletion. Thus, the interactions between HSPCs and their inflammatory environment may play a deterministic role in immune responses and sepsis. We used a mouse model of Group A Streptococcus (GAS) infection to examine the role of HSPCs in pathogenic infection and sepsis. GAS is a common pathogen that can cause a plethora of diseases from mild skin infections to life-threatening necrotizing fasciitis. We infected mice with 10 6 cfu GAS by intramuscular injection, which typically results in sepsis and death within 7 days, and examined the impact of this infection on peripheral blood (PB) and bone marrow (BM) populations. In just 24 hrs after GAS infection, BM myeloid and HSPC populations are significantly depleted, with myeloid cells being heavily trafficked into circulation following increased levels of monocyte chemoattractant protein-1 (MCP-1). Lineage tracing experiments using KRT18-CreERT2:Rosa26-lox-STOP-lox-TdTomato demonstrated that endogenous HSPCs differentiate toward the myeloid lineage after GAS infection. Based on these data, we hypothesized that the inflammatory environment of GAS infection drives rapid HSPC differentiation resulting in a depletion that could be rescued by the infusion of new HSPCs. To test this hypothesis, we infused GAS-infected mice with 10 4 naïve HSPCs (1.7x10 7 cells per m 2) and evaluated pathogen load and overall survival. This number of HSPCs infused is very low in comparison to the current granulocyte therapies that use ~10 10 cells per m 2 cells per infusion. BM and PB analysis showed that HSPC infusion restored HSPC levels and significantly increased myeloid progenitors and circulating myeloid cells. Strikingly, HSPC infusion in GAS-infected mice significantly increased survival, with 50-75% of mice surviving as opposed to 0-10% of controls. Despite the restoration of hematopoietic populations, surprisingly, GAS-infected mice infused with HSPCs did not show a reduction in pathogen load. Given that HSPC infusion significantly increased survival without impacting pathogen clearance, we sought to determine whether infused HSPCs served an immunomodulatory role. Analysis of BM and PB did not show any changes in lymphocyte populations, suggesting that Tregs and Bregs were not strongly affected. However, BM and PB MDSC populations were severely depleted during GAS sepsis, and HSPC infusion led to a dramatic restoration of these MDSC populations. Interestingly and in accordance with MDSC numbers, the overall cytokine levels of GAS-infected mice are lower after HSPC infusion. Notably, serum levels of cytokines known to drive the symptoms of sepsis, like TNF, IL-12, MIP-1a, IL-6, and IL-1b were dampened in HSPC-rescued mice. In conclusion, while HSPC infusion did not reduce bacterial load, it conferred a significant survival advantage to GAS-infected mice. Our data showing restoration of MDSCs and lower cytokine levels after HSPC infusion suggest that HSPC infusion supports the development of immunomodulatory cells that can prevent sepsis-related hyperinflammation and death. Current work is directed at defining specific HSPC subpopulations that mediate this effect. Importantly, the rescue potential of such low numbers of infused HSPCs highlights the feasibility of this technique and its potential applications. Overall, the information gained in this project may contribute to a new therapeutic strategy to use HSPCs to fight bacterial infections and sepsis where granulocyte infusions have so far produced only mixed results. Disclosures No relevant conflicts of interest to declare.

scholarly journals Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3197-3207 ◽  
Author(s):  
Kirsteen J. Campbell ◽  
Mary L. Bath ◽  
Marian L. Turner ◽  
Cassandra J. Vandenberg ◽  
Philippe Bouillet ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Fetal Liver ◽  
Cytotoxic Agents ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Fetal Liver Cells ◽  
Follicular Lymphomas ◽  
The Impact

Abstract Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eμ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eμ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.

scholarly journals TLR2 and Dectin-1 Signaling in Mouse Hematopoietic Stem and Progenitor Cells Impacts the Ability of the Antigen Presenting Cells They Produce to Activate CD4 T Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1317 ◽  
Author(s):  
Alba Martínez ◽  
Cristina Bono ◽  
Daniel Gozalbo ◽  
Helen S. Goodridge ◽  
M. Luisa Gil ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Antigen Presenting Cells ◽  
Proinflammatory Cytokine Production ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Antigen Presenting ◽  
The Impact

Microbial recognition by pattern recognition receptors (PRRs) expressed on hematopoietic stem and progenitor cells (HSPCs) not only activates myelopoiesis but also programs the function of the monocytes and macrophages they produce. For instance, changes in HSPC programming modify the ability of macrophages derived from them to produce inflammatory cytokines. While HSPCs exposed to a TLR2 agonist give rise to tolerized macrophages (lower proinflammatory cytokine production), HSPCs treated with Dectin-1 ligands produce trained macrophages (higher proinflammatory cytokine production). However, nothing is known about the impact of HSPC exposure to microbes on the function of antigen presenting cells (APCs). In this study we evaluated whether treatment of murine bone marrow HSPCs with a TLR2 or Dectin-1 ligand impacts the antigen presenting capacity of APCs derived from them in vitro. Following activation with microbial ligands or Candida albicans yeasts, APCs derived from TLR2/Dectin-1-programed HSPCs exhibit altered expression of MHCII (signal 1), co-stimulatory molecules (CD40, CD80 and CD86; signal 2) and cytokines (TNF-α, IL-6, IL-12 p40 and IL-2; signal 3). Moreover, APCs derived from TLR2/Dectin-1-programed HSPCs prime enhanced Th1 and Th17 responses, which are important for antifungal defense, in CD4 T cell cocultures. Overall, these results demonstrate for the first time that microbial detection by bone marrow HSPCs can modulate the adaptive immune response by inducing the production of APCs with an altered phenotype.

scholarly journals Inflammation as a Driver of Clonal Evolution in Myeloproliferative Neoplasm

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Angela G. Fleischman
Keyword(s):  
Inflammatory Response ◽  
Characteristic Feature ◽  
Progenitor Cells ◽  
Clonal Evolution ◽  
Myeloproliferative Neoplasm ◽  
Clonal Expansion ◽  
Selective Advantage ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
The Impact

Our understanding of inflammation’s role in the pathogenesis of myeloproliferative neoplasm (MPN) is evolving. The impact of chronic inflammation, a characteristic feature of MPN, likely goes far beyond its role as a driver of constitutional symptoms. An inflammatory response to the neoplastic clone may be responsible for some pathologic aspects of MPN. Moreover,JAK2V617Fmutated hematopoietic stem and progenitor cells are resistant to inflammation, and this gives the neoplastic clone a selective advantage allowing for its clonal expansion. Because inflammation plays a central role in MPN inflammation is a logical therapeutic target in MPN.

scholarly journals Kinetics of normal hematopoietic stem and progenitor cells in a Notch1-induced leukemia model

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3783-3792 ◽  
Author(s):  
Xiaoxia Hu ◽  
Hongmei Shen ◽  
Chen Tian ◽  
Hui Yu ◽  
Guoguang Zheng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Quiescent State ◽  
Hematopoietic Stem ◽  
Definitive Evidence ◽  
Accelerated Proliferation ◽  
Stem And Progenitor Cells ◽  
Underlying Mechanisms ◽  
The Impact

Abstract The predominant outgrowth of malignant cells over their normal counterparts in a given tissue is a shared feature for all types of cancer. However, the impact of a cancer environment on normal tissue stem and progenitor cells has not been thoroughly investigated. We began to address this important issue by studying the kinetics and functions of hematopoietic stem and progenitor cells in mice with Notch1-induced leukemia. Although hematopoiesis was progressively suppressed during leukemia development, the leukemic environment imposed distinct effects on hematopoietic stem and progenitor cells, thereby resulting in different outcomes. The normal hematopoietic stem cells in leukemic mice were kept in a more quiescent state but remained highly functional on transplantation to nonleukemic recipients. In contrast, the normal hematopoietic progenitor cells in leukemic mice demonstrated accelerated proliferation and exhaustion. Subsequent analyses on multiple cell-cycle parameters and known regulators (such as p21, p27, and p18) further support this paradigm. Therefore, our current study provides definitive evidence and plausible underlying mechanisms for hematopoietic disruption but reversible inhibition of normal hematopoietic stem cells in a leukemic environment. It may also have important implications for cancer prevention and treatment in general.

Gabp Transcription Factor Is Required for Self-Renew and Proliferation of Hematopoietic Stem and Progenitor Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1284-1284
Author(s):  
Zhongfa Yang ◽  
Karen Drumea ◽  
James Cormier ◽  
Junling Wang ◽  
Xuejun Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Myeloid Cells ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Stem And Progenitor Cells ◽  
Ets Domain

Abstract Abstract 1284 GABP is an ets transcription factor that regulates genes which are required for normal hematopoietic development. In myeloid cells, GABP is an essential component of a retinoic acid-inducible enhanceosome that mediates granulocytic gene expression and, in lymphoid cells, GABP regulates expression of IL7-R and the essential transcription factor, Pax5. GABP is a tetrameric complex that includes GABPa, which binds DNA via its ets domain, and GABPb, which contains the transcription activation domain. Genetic disruption of mouse Gabpa caused early embryonic lethality. We created mice in which loxP recombination sites flank exons that encode the Gabpa ets domain, and bred them to mice that bear the Mx1Cre recombinase; injection with pIC induced Cre expression and efficiently deleted Gabpa in hematopoietic cells. One half of the Gabpa knock-out (KO) mice died within two weeks of pIC injection in association with widespread visceral hemorrhage. Gabpa KO mice exhibited a rapid loss of mature granulocytes, and residual myeloid cells exhibited myelodysplasia due, in part, to regulation by Gabp of the transcriptional repressor, Gfi-1. We used bone marrow transplantation to demonstrate that the defect in Gabpa null myeloid cells is cell intrinsic. Although hematopoietic progenitor cells in Gabpa KO bone marrow were decreased more than 100-fold compared to pIC treated control mice, there was not a statistically significant difference in the numbers of Lin−c-kit+Sca-1− hematopoietic stem cells (HSCs) between KO and control mice. Genetic disruption of Gfi-1 disruption in HSCs caused increased cell cycle activity – an effect that is diametrically opposite of the effect of Gabpa KO; this suggests that the effect of Gabpa on HSCs is not due to its control of Gfi-1. In contrast, Gabpa KO HSCs exhibited a marked decrease in cell cycle activity, but did not demonstrate increased apoptosis. The defects in S phase entry of Gabpa null HSCs are reminiscent of the cell cycle defects in Gabpa null fibroblasts, in which expression of Skp2 E3 ubiquitin ligase, which controls degradation of the cyclin dependent kinase inhibitors (CDKIs) p21 and p27, was markedly reduced following Gabpa disruption. We showed that Gabpa KO cells express reduced levels of Skp2. We propose that GABP controls self-renewal and proliferation of mouse bone marrow stem and progenitor cells, in part, through its regulation of Skp2. Thus, Gabpa is a key regulator of myeloid differentiation through its control of Gfi-1, but it is required for cell cycle activity of HSCs, by a distinct effect that may be due to its control of Skp2 and CDKIs. Disclosures: No relevant conflicts of interest to declare.

Latent Cardiogenic Potential in Endocardium and Hemogenic Endothelium Revealed in the Absence of Scl/tal1

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2362-2362
Author(s):  
Amelie Montel-Hagen ◽  
Ben Van Handel ◽  
Roberto Ferrari ◽  
Rajkumar Sasidharan ◽  
Tonis Org ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Lineage Tracing ◽  
Bhlh Transcription Factor ◽  
Wild Type ◽  
Transcriptional Program ◽  
Hemogenic Endothelium ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Abstract Abstract 2362 The endothelium in embryonic and extraembryonic hematopoietic tissues has the capacity to generate hematopoietic stem and progenitor cells (HS/PC). However, it is unknown how this unique endothelium is specified. Microarray analysis of endothelial cells from hematopoietic tissues of embryos deficient for the bHLH transcription factor Scl/tal1 revealed that Scl establishes a robust hematopoietic transcriptional program in the endothelium. Surprisingly, lack of Scl also induced an unexpected fate switching of the prospective hemogenic endothelium to the cardiac lineage. Scl deficient embryos displayed a dramatic upregulation of cardiac transcription factors and structural proteins within the yolk sac vasculature, resulting in the generation of spontaneously beating cardiomyocytes. Ectopic cardiac potential in Scl deficient embryos arose from endothelial-derived CD31+Pdgfrα+ cardiogenic progenitor cells (CPCs), which were present in all sites of HS/PC generation. Analysis of Runx1-deficient embryos revealed, that although Runx1 acts downstream of Scl during the emergence of definitive HS/PCs, it is not required for the suppression of the cardiac fate in the endothelium. The only wild type tissue that contained CD31+Pdgfrα+ putative CPCs was the heart, and this population was greatly expanded in Scl deficient embryos. Strikingly, endocardium in Scl−/− hearts also activated a robust cardiomyogenic transcriptional program and generated Troponin T+ cardiomyocytes both in vivo and in vitro. Although CD31+Pdgfrα+ CPCs from wild type hearts did not generate readily beating cells in culture, they produced cells expressing endothelial, smooth muscle and cardiomyocyte specific genes, implying multipotentiality of this novel CPC population. Furthermore, CD31+Pdgfrα+ CPCs were greatly reduced in Isl1−/− hearts, which fail to generate functional, multipotential CPCs. Lineage tracing using VE-cadherin Cre Rosa-YFP mouse strain demonstrated that, in addition to generating HS/PCs in hematopoietic tissues, endothelial cells are also the cell of origin for CD31+Pdgfrα+ CPCs in the heart. Together, these data suggest a broader role for embryonic endothelium as a potential source of tissue-specific stem and progenitor cells and implicate Scl/tal1 as an important regulator of endothelial fate choice. Disclosures: No relevant conflicts of interest to declare.

scholarly journals EBF1 As a Novel Regulator of Bone Marrow Mesenchymal Stromal Progenitors

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 96-96
Author(s):  
Marta Derecka ◽  
Senthilkumar Ramamoorthy ◽  
Pierre Cauchy ◽  
Josip Herman ◽  
Dominic Grun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloid Cells ◽  
Bone Marrow Niche ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Abstract Hematopoietic stem and progenitor cells (HSPC) are in daily demand worldwide because of their ability to replenish entire blood system. However, the in vitro expansion of HSPC is still a major challenge since the cues from bone marrow microenvironment remain largely elusive. Signals coming from the bone marrow niche, and specifically mesenchymal stem and progenitor cells (MSPC), orchestrate maintenance, trafficking and stage specific differentiation of HSPCs. Although, it is generally accepted that MSPCs are essential for hematopoietic homeostasis and generating multiple types of stromal cells, the exact transcriptional networks regulating MSPCs are not well established. Early B-cell factor 1 (Ebf1) has been discovered as lineage-specific transcription factor governing B lymphopoiesis. Additionally, it has been shown to play important role in differentiation of adipocytes, which are a niche component supporting hematopoietic regeneration. Thus, in this study we seek to examine if Ebf1 has an alternative function in non-hematopoietic compartment of bone marrow, specifically in mesenchymal stromal cells that maintain proper hematopoiesis. Here, we identified Ebf1 as new transcription regulator of MSPCs activity. Mesenchymal progenitors isolated from Ebf1-/- mice show diminished capacity to form fibroblasticcolonies (CFU-F) indicating reduced self-renewal. Moreover, cells expanded from these colonies display impaired in vitro differentiation towards osteoblasts, chondrocytes and adipocytes. In order to test how this defective MSPCs influence maintenance of HSPCs, we performed long-term culture-initiating cell assay (LTC-IC). After 5 weeks of co-culture of Ebf1-deficient stromal cells with wild type HSPCs we could observe significantly decreased number of cobblestone and CFU colonies formed by primitive HSPCs, in comparison to co-cultures with control stromal cells. Furthermore, in vivo adoptive transfers of wild type HSPCs to Ebf1+/- recipient mice showed a decrease in the absolute numbers of HSPCs in primary recipients and reduced donor chimerism within the HSCP compartment in competitive secondary transplant experiments. Additionally, Prx1-Cre-mediated deletion of Ebf1 specifically in MSPCs of mice leads to reduced frequency and numbers of HSPCs and myeloid cells in the bone marrow. These results confirm that mesenchymal stromal cells lacking Ebf1 render insufficient support for HSPCs to sustain proper hematopoiesis. Interestingly, we also observed a reduced ability of HSPCs sorted from Prx1CreEbf1fl/fl mice to form colonies in methylcellulose, suggesting not only impaired maintenance but also hindered function of these cells. Moreover, HSPCs exposed to Ebf1-deficient niche exhibit changes in chromatin accessibility with reduced occupancy of AP-1, ETS, Runx and IRF motifs, which is consistent with decreased myeloid output seen in Prx1CreEbf1fl/fl mice. These results support the hypothesis that defective niche can cause epigenetic reprograming of HSPCs. Finally, single cell and bulk transcriptome analysis of MSPCs lacking Ebf1 revealed differences in the niche composition and decreased expression of lineage-instructive signals for myeloid cells. Thus, our study establishes Ebf1 as a novel regulator of MSPCs playing a crucial role in the maintenance and differentiation of HSPCs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Conversion of Danger Signals into Cytokine Signals By Hematopoietic Stem and Progenitor Cells for Regulation of Stress-Induced Hematopoiesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2916-2916
Author(s):  
Jimmy L. Zhao ◽  
Chao Ma ◽  
Ryan O'Connell ◽  
Arnav Mehta ◽  
Jun Wang ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Conflicts Of Interest ◽  
Myeloid Cell ◽  
Cell Recovery ◽  
Hematopoietic Stem ◽  
Danger Signals ◽  
Multipotent Progenitor Cells ◽  
Stem And Progenitor Cells

Abstract Mammals respond to infection by rapid production of innate immune cells. Hematopoietic stem and progenitor cells (HSPCs) have the ability to respond to pathogens directly through toll-like receptors. However, how the pathogen sensing ability of HSPCs may contribute to immune cell output remains unknown. Using a novel single-cell proteomic platform and mouse genetic models, we have shown that in response to toll-like receptor stimulation, short-term HSCs and multipotent progenitor cells produce copious amounts of diverse cytokines through NF-κB signaling. Interestingly, the cytokine production ability of HSPCs trumps mature immune cells in both magnitude and breadth. Among cytokines produced by HSPCs, IL-6 is a particularly important regulator of myeloid differentiation and HSPC proliferation. This is especially important in mediating rapid early myeloid cell recovery during neutropenia after chemotherapy or HSC transplant. This study has uncovered an important property of HSPCs that enables them to convert danger signals into versatile cytokine signals for the regulation of stress-induced hematopoiesis. To translate these findings into human hematopoietic system, we have recently developed a human cytokine chip and our preliminary analysis suggests that purified human bone marrow HSCs also have the capacity to secrete cytokines. Disclosures No relevant conflicts of interest to declare.

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