Abstract 328: Viral Anti-Atherogenic Proteins Alter Monocyte and Neutrophil Invasion in Mice and Bag3 Gene Expression

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Jennifer Davids ◽  
Sami Saikaly ◽  
Alexandra Lucas
Keyword(s):  
Gene Expression ◽  
Knockout Mice ◽  
Granzyme B ◽  
Nod Mice ◽  
Response To Treatment ◽  
Mouse Strains ◽  
Human Monocytes ◽  
Caspase 1 ◽  
Apoptotic Pathways

Aim Atherosclerosis is characterized by chronic inflammation and cell death (apoptosis). Serine protease inhibitors, or serpins, regulate inflammatory, thrombotic and apoptotic pathways. Poxviruses encode cross-class serpins that prevent host cell apoptosis. Serp-2, from Myxoma, reduces plaque, inflammation and apoptosis in animal models; CrmA, from Vaccinia, does not. Both serpins target Caspase 1 and Granzyme B, but the reasons for the differing effects in vivo are unknown. In prior research three Myxoma viral proteins, including Serp-2, reduced monocyte invasion, plaque growth, and aneurysm formation in ApoE-/- mice after angioplasty. These same proteins alter expression of a shared cohort of 48 apoptosis-related genes in human monocytes treated with camptothecin. This study assesses the effects of Serp-2 and CrmA on apoptotic gene expression in a mouse peritoneal inflammation model. Methods Mouse strains deficient for Granzyme B (GzmB, N=13) and Caspase 1 (Casp1, N=15) were compared to their respective background mice (C57Bl/6 and Nod, N=15 each) 18 hours after treatment with PMA and either Serp-2 or CrmA. RNA was isolated and analyzed by RT-PCR and normalized to GAPDH, then to the PMA-only treated control. Results Compared to human monocytes, mouse peritoneal exudates from knockout mice displayed differential alteration of BCL2-associated athanogene 3 (BAG3) in response to treatment with Serp-2 or CrmA. Serp-2 treatment reduced expression levels compared to CrmA treatment in GzmB (p=0.0267) and C57Bl/6 mice (p=0.0280). Casp1-/- mice treated with Serp-2 downregulate BAG3, expressing 9.7-fold less than Nod mice (p=0.0006), but CrmA had no significant effect in either strain. An associated differential migration of Ly6Chi and Ly6Ghi cells was also discovered in knockout mice with serpin treatments. Discussion One candidate gene found in human monocytes, BAG3, has reduced gene expression after Serp-2 treatment in mouse peritoneal exudates but increased by CrmA. BAG3 is known to alter cell migration and apoptosis, important to atherosclerotic progression. BAG3 is regulated by 3 myxomaviral proteins in human and mouse cells, underscoring a potential role as a lynchpin in viral protein anti-inflammatory and anti-apoptotic pathways.

Abstract 268: Strain-specific Cardiac Fibroblast Response to Isoproterenol-induced Cardiac Fibrosis

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Shuin Park ◽  
Sara Ranjbarvaziri ◽  
Fides Lay ◽  
Peng Zhao ◽  
Aldons J Lusis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Expression Profiles ◽  
Inbred Mouse ◽  
Gene Expression Profiles ◽  
Mouse Strains ◽  
Sequencing Analysis ◽  
Different Strains

Fibroblasts are a heterogeneous population of cells that function within the injury response mechanisms across various tissues. Despite their importance in pathophysiology, the effects of different genetic backgrounds on fibroblast contribution to the development of disease has yet to be addressed. It has previously been shown that mice in the Hybrid Mouse Diversity Panel, which consists of 110 inbred mouse strains, display a spectrum in severity of cardiac fibrosis in response to chronic treatment of isoproterenol (ISO). Here, we characterized cardiac fibroblasts (CFbs) from three different mouse strains (C57BL/6J, C3H/HeJ, and KK/HIJ) which exhibited varying degrees of fibrosis after ISO treatment. The select strains of mice underwent sham or ISO treatment via intraperitoneally-implanted osmotic pumps for 21 days. Masson’s Trichrome staining showed significant differences in fibrosis in response to ISO, with KK/HIJ mice demonstrating the highest levels, C3H/HeJ exhibiting milder levels, and C57BL/6J demonstrating little to no fibrosis. When CFbs were isolated and cultured from each strain, the cells demonstrated similar traits at the basal level but responded to ISO stimuli in a strain-specific manner. Likewise, CFbs demonstrated differential behavior and gene expression in vivo in response to ISO. ISO treatment caused CFbs to proliferate similarly across all strains, however, immunofluorescence staining showed differential levels of CFb activation. Additionally, RNA-sequencing analysis revealed unique gene expression profiles of all three strains upon ISO treatment. Our study depicts the phenotypic heterogeneity of CFbs across different strains of mice and our results suggest that ISO-induced cardiac fibrosis is a complex process that is independent of fibroblast proliferation and is mainly driven by the activation/inhibition of genes involved in pro-fibrotic pathways.

A Novel Role of Coagulation Proteases on Viral-Based Gene Transfer Efficacy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 691-691
Author(s):  
Joerg Schuettrumpf ◽  
Jianxiang Zou ◽  
Shin Jen Tai ◽  
Alexander Schlachterman ◽  
Kian Tian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Transfer ◽  
Knockout Mice ◽  
Viral Vectors ◽  
Hemophilia B ◽  
Gene Copy ◽  
Dependent Manner ◽  
Deficient Mice

Abstract Coagulation proteases are crucial for hemostasis and have also been implicated in inflammatory responses, blood vessel formation, and tumor cell metastasis. Cellular responses triggered by proteases are mediated by protease-activated receptors (PAR). Adeno-associated virus (AAV)-2 vectors hold promise for the treatment of several diseases and were already tested in Phase I studies for hemophilia B following intramuscular or hepatic artery deliveries. Previously, we determined an unexpected inhibitory effect (60–70% downregulation) on AAV-2 and adenovirus mediated gene transfer by thrombin- or FXa inhibitors. These results were independent of mouse strain, transgene product, or vector promoter, and gene expression by vectors of alternate serotypes AAV-5 or -8, which do not share cellular receptors with AAV-2, were not affected by any drug. Here we present in vivo evidence of a novel role of coagulation proteases and PARs in modulating gene transfer by viral vectors. We tested AAV-2 gene transfer efficacy in (a) animal models for proteases deficiency [FX and FIX deficient animals], (b) PAR-1 or PAR-2 deficient mice, (c) and following in vivo activation of PARs. FX knockout mice with residual activity of only 1–3% of normal (n=9) were injected with AAV-2-human(h)FIX vector and compared to littermates with FX levels of 50% (n=4). FIX expression levels were 2-fold lower among FX-deficient mice compared to controls (p<0.03). The second model, FIX deficient mice, received AAV expressing α1-antitrypsin (AAT-1). Severe hemophilia B models due to large-gene deletion (n=5) or missense mutation (R180T) in the FIX gene (n=3, <1% FIX) were compared to littermate controls with normal FIX levels (n=6). The results showed that AAT-1 levels among hemophilia B mice were 2-fold lower than in controls (24 vs 48 ng/ml, p<0.05, respectively). Because PAR activation by thrombin enhances αVβ5 (co-receptor for AAV-2 and adenovirus)-dependent cellular function (JBC 276:10952) we hypothesized that PAR modulates AAV-2 gene transfer. Homozygous (−/−) or heterozygous deficient (+/−) PAR-1 (n=24) or PAR-2 (n=25) mice received AAV-2-hF.IX and were compared to littermate controls (+/+). FIX levels among PAR-1 controls (1.9 μg/ml) were comparable to levels obtained among heterozygotes but higher than in homozygotes (1.1 μg/ml, p<0.02). Similarly, PAR-2 deficient mice presented 2-fold lower FIX levels than controls (0.7 vs 1.3 μg/ml, p<0.02) whereas heterozygous mice presented intermediate levels. To further confirm the role of PARs in AAV-2 gene transfer we activated PARs prior to AAV-2 injection. C57BL/6 mice received specific peptide agonists at doses ranging from 10 to 60 μM/kg (n=4 per dose and per peptide) and were compared to controls receiving scramble peptide. FIX levels increased 1.5 to 5-fold in a dose-dependent manner and the activation of PAR-1 and -2 simultaneously was superior to single peptide. Gene copy monitoring revealed low vector uptake by livers of PAR knockout mice while activation of PARs increased uptake. In conclusion, these data demonstrated a novel in vivo role of coagulation proteases and PARs on viral vectors (AAV-2 and adenovirus)-mediated gene expression and provide an alternative target to modulate gene therapy strategies.

scholarly journals Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Mar Gacias ◽  
Sevasti Gaspari ◽  
Patricia-Mae G Santos ◽  
Sabrina Tamburini ◽  
Monica Andrade ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Social Behavior ◽  
Gut Microbiota ◽  
Nod Mice ◽  
Mouse Strains ◽  
Social Avoidance ◽  
Nonobese Diabetic ◽  
Gene Environment ◽  
Transcriptional Changes

Gene-environment interactions impact the development of neuropsychiatric disorders, but the relative contributions are unclear. Here, we identify gut microbiota as sufficient to induce depressive-like behaviors in genetically distinct mouse strains. Daily gavage of vehicle (dH2O) in nonobese diabetic (NOD) mice induced a social avoidance behavior that was not observed in C57BL/6 mice. This was not observed in NOD animals with depleted microbiota via oral administration of antibiotics. Transfer of intestinal microbiota, including members of the Clostridiales, Lachnospiraceae and Ruminococcaceae, from vehicle-gavaged NOD donors to microbiota-depleted C57BL/6 recipients was sufficient to induce social avoidance and change gene expression and myelination in the prefrontal cortex. Metabolomic analysis identified increased cresol levels in these mice, and exposure of cultured oligodendrocytes to this metabolite prevented myelin gene expression and differentiation. Our results thus demonstrate that the gut microbiota modifies the synthesis of key metabolites affecting gene expression in the prefrontal cortex, thereby modulating social behavior.

scholarly journals Targeted Disruption of Mapk14 (p38MAPKα) in Granulosa Cells and Cumulus Cells Causes Cell-Specific Changes in Gene Expression Profiles that Rescue COC Expansion and Maintain Fertility

2010 ◽  
Vol 24 (9) ◽  
pp. 1794-1804 ◽  
Author(s):  
Zhilin Liu ◽  
Heng-Yu Fan ◽  
Yibin Wang ◽  
JoAnne S. Richards
Keyword(s):  
Gene Expression ◽  
Granulosa Cells ◽  
Knockout Mice ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Cumulus Cells ◽  
Mutant Mice ◽  
Prostaglandin E

Abstract MAPK14 (p38MAPKα) is critical for FSH and prostaglandin E (PGE)2 signaling cascades in granulosa cells (GCs) and cumulus cell-oocyte complexes (COCs) in culture, indicating that this kinase might impact follicular development and COC expansion in vivo. Because Mapk14 knockout mice are embryonic lethal, we generated GC specific Mapk14 knockout mice (Mapk14gc−/−) by mating Mapk14fl/fl and Cyp19-Cre mice. Unexpectedly, the Mapk14gc−/− female mice were fertile. Analyses of gene expression patterns showed that amphiregulin (Areg) and epiregulin (Ereg), two key regulators of ovulation and COC expansion, were up-regulated in the GCs but down-regulated in cumulus cells of the mutant mice in vivo. COCs from the mutant mice expanded and expressed matrix-related genes, if cultured with AREG, but not when cultured with forskolin or PGE2, the latter being a key factor regulating MAPK14 activity in cumulus cells. Conversely, when GCs from the Mapk14gc−/− mice were cultured with forskolin, they produced more Areg and Ereg mRNA than did wild-type GCs. These results indicate that disruption of Mapk14 selectively alters the expression of Areg and other genes in each cell type. Greater AREG and EREG produced by the GCs appears to by-pass and compensate for the critical need for MAPK14 signaling and induction of Areg/Ereg (and hence matrix genes) by PGE2 in cumulus cells of the mutant mice. In conclusion, although MAPK14 is not overtly essential for preovulatory follicle development or events associated with ovulation and luteinization in vivo, it does impact gene expression profiles.

HMGN proteins play roles in DNA repair and gene expression in mammalian cells

2004 ◽  
Vol 32 (6) ◽  
pp. 918-919 ◽  
Author(s):  
K.L. West
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Knockout Mice ◽  
Mammalian Cells ◽  
High Mobility ◽  
Genetically Engineered ◽  
Expression In Mammalian Cells ◽  
Transcription And Replication

HMGN (high-mobility-group N) family members are vertebrate proteins that unfold chromatin and promote transcription and replication of chromatin templates in vitro. However, their precise roles in vivo have been elusive until recently. This paper summarizes recent advances from studies of Hmgn1 knockout mice and genetically engineered cell lines that are beginning to reveal the diverse roles that HMGN proteins play in DNA repair and transcription within mammalian cells.

scholarly journals Strain-Dependent Migration of CD4 and CD8 Lymphocyte Subsets to Lymph Nodes in NOD (Nonobese Diabetic) and Control Mice

1994 ◽  
Vol 3 (4) ◽  
pp. 273-282
Author(s):  
Christelle Faveeuw ◽  
Marie-Claude Gagnerault ◽  
Françoise Lepault
Keyword(s):  
Nod Mice ◽  
Lymphoid Cells ◽  
The Other ◽  
T Cell Subsets ◽  
Mouse Strains ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Nonobese Diabetic ◽  
Other Hand

Subpopulations of lymphoid cells were compared with respect to their ability to migrate into peripheral lymphoid organs of nonobese diabetic (NOD) mice and various strains of control mice. In short-term,in vivohoming studies, no major differences in the pattern of homing of B and T cells were observed among all mouse strains studied. On the other hand, CD4 cells localized consistently more efficiently than CD8 cells in both PP and LN of adult NOD and BALB/c mice, whereas both populations migrated roughly equivalently in LN of adult DBA/2, CBA, and C57BL/6 mice. No age-dependent differences in the homing of CD4 and CD8 cells were observed in BALB/c mice. On the contrary, in 2-week-old NOD mice, CD4 and CD8 cells migrated equally well. The preferential entry of CD4 cells in adult NOD and BALB/c did not result from increased blood transit time of CD8 cells. On the other hand, the preferential migration of CD8 cells was observed in the liver, whereas the two T-cell subsets migrated equally well in the lungs. The differences in the homing characteristics of CD4 and CD8 cells among NOD, BALB/c, and C57BL/6 mice were not related to modifications in the level of expression of adhesion molecules such as MEL-14, LFA-1, and Pgp-1.

scholarly journals Presentation of Antigen by Endothelial Cells and Chemoattraction Are Required for Homing of Insulin-specific CD8+ T Cells

2003 ◽  
Vol 197 (5) ◽  
pp. 643-656 ◽  
Author(s):  
Alexei Y. Savinov ◽  
F. Susan Wong ◽  
Austin C. Stonebraker ◽  
Alexander V. Chervonsky
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cd8 T Cells ◽  
Chemokine Receptors ◽  
Nod Mice ◽  
Cell Receptor ◽  
Mouse Strains ◽  
Β Cells ◽  
Cd8 Cells

Activated insulin-specific CD8+ T cells (IS-CD8+ cells) home to the pancreas, destroy β cells, and cause rapid diabetes upon transfer into diabetes-prone NOD mice. Surprisingly, they also cause diabetes in mouse strains that are free of preexistent inflammation. Thus, we hypothesized that islet-specific homing may be in part dependent on IS-CD8+ cells' recognition of the cognate major histocompatibility complex (MHC)/peptide complexes presented by pancreatic endothelial cells, which acquire the antigen (insulin) from β cells. In fact, islet-specific homing was abrogated in mice that lack MHC class I expression, or presentation of the specific peptide, or have impaired insulin secretion. Moreover, we found that IS-CD8+ cells directly recognized pancreatic endothelial cells in islet organ cultures. Triggering of IS-CD8+ cells' T cell receptor (TCR) led to activation of integrins expressed by these cells. In addition, chemokines, particularly SLC (CCL21), were also required for IS-CD8+ cells' adhesion to endothelial monolayers and for successful homing in vivo. Thus, signaling through TCR and chemokine receptors work in concert to assure firm adhesion of T cells to the pancreatic endothelium. The antigen cross-presentation ability of endothelia may therefore contribute to the specificity of homing of activated T lymphocytes to the tissues where antigens are generated by other cell types.

scholarly journals Lessons from Tau-Deficient Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Yazi D. Ke ◽  
Alexandra K. Suchowerska ◽  
Julia van der Hoven ◽  
Dineeka M. De Silva ◽  
Christopher W. Wu ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Mouse Strains ◽  
Motor Deficits ◽  
Transgenic Mouse Models ◽  
The Past ◽  
Number Of Publications ◽  
The Brain ◽  
Deficient Mice

Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to the umbrella term “tauopathies” for these conditions, also emphasizing the central role of tau in AD and FTD. Generation of transgenic mouse models expressing human tau in the brain has contributed to the understanding of the pathomechanistic role of tau in disease. To reveal the physiological functions of tauin vivo, several knockout mouse strains with deletion of the tau-encodingMAPTgene have been established over the past decade, using different gene targeting constructs. Surprisingly, when initially introduced tau knockout mice presented with no overt phenotype or malformations. The number of publications using tau knockout mice has recently markedly increased, and both behavioural changes and motor deficits have been identified in aged mice of certain strains. Moreover, tau knockout mice have been instrumental in identifying novel functions of tau, both in cultured neurons andin vivo. Importantly, tau knockout mice have significantly contributed to the understanding of the pathophysiological interplay between Aβand tau in AD. Here, we review the literature that involves tau knockout mice to summarize what we have learned so far from depleting tauin vivo.

scholarly journals 716 NL-201 induces inflammation in a 'cold' tumor microenvironment through upregulation of MHC-I, expansion of the TCR repertoire, and potent antitumor activity when combined with PD-1 inhibition

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A745-A745
Author(s):  
Christie Mortales ◽  
Benjamin Dutzar ◽  
Jerry Chen ◽  
Alex Chen ◽  
Justin Huard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Gene Expression Analysis ◽  
Granzyme B ◽  
Mhc I ◽  
B16f10 Cells ◽  
Tcr Repertoire

BackgroundNL-201 is a potent, selective, and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors that is being developed as an immunotherapy for cancer. Downregulation of MHC class I (MHC-I) expression by tumors is a well-known mechanism of immune escape, and IFNγ is known to upregulate MHC-I. Here, we investigated whether NL-201 monotherapy can convert a 'cold' tumor microenvironment (TME) to an immunologically 'hot' TME through IFNγ-mediated MHC-I expression. This effect could expand the TCR repertoire for increased antitumor response and improve anti-PD-1 combination therapy.MethodsFor in vitro assays, mouse splenocytes were cultured with Neo-2/15 to assess effector cell function, as well as co-cultured with B16F10 cells to assess IFNγ-induced MHC-I and PD-L1 expression. B16F10 tumors were established in C57BL/6 mice and dosed with NL-201, anti-PD-1, or both to assess in vivo efficacy. B16F10 tumors were excised and dissociated for phenotyping of tumor-infiltrating lymphocytes (TILs) using flow cytometry. For gene expression analysis, RNA and genomic DNA were extracted from tumors and submitted for NanoString Pancancer Immune Profiling and Adaptive ImmunoSEQ analysis, respectively.ResultsIn vitro, Neo-2/15 induced greater CD8+ T cell and NK cell proliferation, as well as granzyme B production and IFNγ-dependent MHC-I upregulation on B16F10 tumor cells, compared to IL-2 or IL-15. In 'cold' B16F10 syngeneic tumors, NL-201 monotherapy reduced tumor growth and induced MHC-I, IFNγ, and granzyme B upregulation. Gene expression analysis of NL-201–treated tumors demonstrated increased TCR repertoire diversity and inflammatory signature at the tumor. In addition, PD-L1 was significantly upregulated on B16F10 cells. While the B16F10 tumors exhibited resistance to anti-PD-1 monotherapy, combination treatment with NL-201 significantly improved anti-PD-1 activity. This may explain the potent anti-tumor activity of NL-201 with anti-PD-1 combination therapy.ConclusionsNL-201 induces potent inflammatory effects on effector cells and is able to turn 'cold' TMEs 'hot'. We demonstrate that NL-201 strongly upregulated MHC-I expression in vitro and in vivo via an IFNγ-dependent pathway. Increased antigen presentation drives TCR diversity while augmenting the inflammatory signature at the tumor. This adaptive response also upregulates PD-L1 expression and results in impressive antitumor activity when NL-201 and PD-1 inhibitors are co-administered. The demonstration that NL-201 can convert 'cold' tumors to immunologically 'hot' tumors may provide a novel therapeutic option for patients unresponsive to current standard of care checkpoint inhibitors. A Phase 1 study of NL-201 in patients with advanced solid tumors is currently underway (NCT04659629).Ethics ApprovalAll experiments were approved by the Institutional Animal Care and Use Committee of Bloodworks Northwest and performed under protocol 5360-03.

scholarly journals Exosomes from primed MSCs can educate monocytes as a cellular therapy for hematopoietic acute radiation syndrome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Matthew H. Forsberg ◽  
John A. Kink ◽  
Anna S. Thickens ◽  
Bryson M. Lewis ◽  
Charlie J. Childs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Radiation ◽  
Prolonged Survival ◽  
Human Monocytes ◽  
Acute Radiation Syndrome ◽  
Nsg Mice ◽  
Human Cd34 ◽  
Hematopoietic Recovery ◽  
Lethal Irradiation

Abstract Background Acute radiation syndrome (ARS) is caused by acute exposure to ionizing radiation that damages multiple organ systems but especially the bone marrow (BM). We have previously shown that human macrophages educated with exosomes from human BM-derived mesenchymal stromal cells (MSCs) primed with lipopolysaccharide (LPS) prolonged survival in a xenogeneic lethal ARS model. The purpose of this study was to determine if exosomes from LPS-primed MSCs could directly educate human monocytes (LPS-EEMos) for the treatment of ARS. Methods Human monocytes were educated by exosomes from LPS-primed MSCs and compared to monocytes educated by unprimed MSCs (EEMos) and uneducated monocytes to assess survival and clinical improvement in a xenogeneic mouse model of ARS. Changes in surface molecule expression of exosomes and monocytes after education were determined by flow cytometry, while gene expression was determined by qPCR. Irradiated human CD34+ hematopoietic stem cells (HSCs) were co-cultured with LPS-EEMos, EEMos, or uneducated monocytes to assess effects on HSC survival and proliferation. Results LPS priming of MSCs led to the production of exosomes with increased expression of CD9, CD29, CD44, CD146, and MCSP. LPS-EEMos showed increases in gene expression of IL-6, IL-10, IL-15, IDO, and FGF-2 as compared to EEMos generated from unprimed MSCs. Generation of LPS-EEMos induced a lower percentage of CD14+ monocyte subsets that were CD16+, CD73+, CD86+, or CD206+ but a higher percentage of PD-L1+ cells. LPS-EEMos infused 4 h after lethal irradiation significantly prolonged survival, reducing clinical scores and weight loss as compared to controls. Complete blood counts from LPS-EEMo-treated mice showed enhanced hematopoietic recovery post-nadir. IL-6 receptor blockade completely abrogated the radioprotective survival benefit of LPS-EEMos in vivo in female NSG mice, but only loss of hematopoietic recovery was noted in male NSG mice. PD-1 blockade had no effect on survival. Furthermore, LPS-EEMos also showed benefits in vivo when administered 24 h, but not 48 h, after lethal irradiation. Co-culture of unprimed EEMos or LPS-EEMos with irradiated human CD34+ HSCs led to increased CD34+ proliferation and survival, suggesting hematopoietic recovery may be seen clinically. Conclusion LPS-EEMos are a potential counter-measure for hematopoietic ARS, with a reduced biomanufacturing time that facilitates hematopoiesis.

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