Dataset Information

Modulation of Human Neutrophil Peptides on P. aeruginosa Killing, Epithelial Cell Inflammation and Mesenchymal Stromal Cell Secretome Profiles.

ABSTRACT: Objective:Neutrophil infiltration and release of the abundant human neutrophil peptides (HNP) are a common clinical feature in critically ill patients. We tested a hypothesis that different cell types respond to HNP differently in lung microenvironment that may influence the host responses. Methods:Plasma concentrations of HNP were measured in healthy volunteers and patients with sepsis. Cells including the bacteria P. aeruginosa, human lung epithelial cells and mesenchymal stromal cells (MSCs) were exposed to various concentrations of HNP. Bacterial killing, epithelial cell inflammation, MSC adhesion and behaviours were examined after HNP stimulation. Results:Incubation of P. aeruginosa or stimulation of human lung epithelial cells with HNP resulted in bacterial killing or IL-8 production at a dose of 50 ?g/mL, while MSC adhesion and alternations of secretome profiles took place after HNP stimulation at a dose of 10 ?g/mL. The secretome profile changes were characterized by increased release of the IL-6 family members such as C-reactive protein (CRP), leukemia inhibitory factor (LIF) and interleukin (IL-11), and first apoptosis signal (FAS) and platelet-derived growth factor-AA as compared to a vehicle control group. Conclusion:Stimulation of MSCs with HNP resulted in changes of secretome profiles at 5-fold lower concentration than that required for bacterial killing and lung epithelial inflammation. This undisclosed risk factor of HNP in lung environment should be taken into consideration when MSCs are applied as cell therapy in inflammatory lung diseases.

SUBMITTER: Dai Q

PROVIDER: S-EPMC6927223 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Modulation of Human Neutrophil Peptides on <i>P. aeruginosa</i> Killing, Epithelial Cell Inflammation and Mesenchymal Stromal Cell Secretome Profiles.

Dai Qingqing Q Morita Yasumasa Y Huang Yongbo Y Liaw Patricia C PC Wu Jianfeng J Khang Julie J Islam Diana D Yu Kaijiang K Li Yimin Y Zhang Haibo H

Journal of inflammation research 20191218

<h4>Objective</h4>Neutrophil infiltration and release of the abundant human neutrophil peptides (HNP) are a common clinical feature in critically ill patients. We tested a hypothesis that different cell types respond to HNP differently in lung microenvironment that may influence the host responses.<h4>Methods</h4>Plasma concentrations of HNP were measured in healthy volunteers and patients with sepsis. Cells including the bacteria <i>P. aeruginosa</i>, human lung epithelial cells and mesenchymal ...[more]

PMID: 31908518

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Project description:BackgroundEfficient and sustained hematopoietic recovery after hematopoietic stem cell or bone marrow transplantation is supported by paracrine signaling from specific subpopulations of mesenchymal stromal cells (MSCs). Here, we considered whether in vitro mechanopriming of human MSCs could be administered to predictively and significantly improve in vivo hematopoietic recovery after irradiation injury.MethodsFirst, we implemented regression modeling to identify eight MSC-secreted proteins that correlated strongly with improved rescue from radiation damage, including hematopoietic recovery, in a murine model of hematopoietic failure. Using these partial least squares regression (PLSR) model parameters, we then predicted recovery potential of MSC populations that were culture expanded on substrata of varying mechanical stiffness. Lastly, we experimentally validated these predictions using an in vitro co-culture model of hematopoiesis and using new in vivo experiments for the same irradiation injury model used to generate survival predictions.ResultsMSCs grown on the least stiff (elastic moduli ~ 1 kPa) of these polydimethylsiloxane (PDMS) substrata secreted high concentrations of key proteins identified in regression modeling, at concentrations comparable to those secreted by minor subpopulations of MSCs shown previously to be effective in supporting such radiation rescue. We confirmed that these MSCs expanded on PDMS could promote hematopoiesis in an in vitro co-culture model with hematopoietic stem and progenitor cells (HSPCs). Further, MSCs cultured on PDMS of highest stiffness (elastic moduli ~ 100 kPa) promoted expression of CD123+ HSPCs, indicative of myeloid differentiation. Systemic administration of mechanoprimed MSCs resulted in improved mouse survival and weight recovery after bone marrow ablation, as compared with both standard MSC expansion on stiffer materials and with biophysically sorted MSC subpopulations. Additionally, we observed recovery of white blood cells, platelets, and red blood cells, indicative of complete recovery of all hematopoietic lineages.ConclusionsThese results demonstrate that computational techniques to identify MSC biomarkers can be leveraged to predict and engineer therapeutically effective MSC phenotypes defined by mechanoprimed secreted factors, for translational applications including hematopoietic recovery.

Project description:ObjectivesSepsis results in organ dysfunction caused by a dysregulated host response, in part related to the immune response of a severe infection. Mesenchymal stromal cells are known to modulate the immune response, and expression of stromal cell-derived factor-1 regulates mobilization of neutrophils from the bone marrow. We are investigating the importance of stromal cell-derived factor-1 in mesenchymal stromal cells and its role in promoting neutrophil function after the onset of cecal ligation and puncture-induced sepsis. Stromal cell-derived factor-1 expression was silenced in mesenchymal stromal cells, compared with the control scrambled construct mesenchymal stromal cells.DesignAnimal study and cell culture.SettingLaboratory investigation.SubjectsBALB/c mice.InterventionsPolymicrobial sepsis was induced by cecal ligation and puncture. shSCR mesenchymal stromal cells and shSDF-1 mesenchymal stromal cells were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils.Measurements and main resultsInjection of shSCR mesenchymal stromal cells after the onset of sepsis led to an increase in mouse survival (70%) at 7 days, whereas survival of mice receiving shSDF-1 mesenchymal stromal cells was significantly diminished (33%). The loss of survival benefit in mice receiving shSDF-1 mesenchymal stromal cells was associated with less efficient bacterial clearance compared with shSCR mesenchymal stromal cells. Although shSCR mesenchymal stromal cells, or their conditioned medium, were able to increase neutrophil phagocytosis of bacteria, this effect was significantly blunted with shSDF-1 mesenchymal stromal cells. Assessment of peritoneal inflammation revealed that neutrophils were significantly increased and more immature in septic mice receiving shSDF-1 mesenchymal stromal cells. This response was associated with hypocellularity and increased neutrophil death in the bone marrow of mice receiving shSDF-1 mesenchymal stromal cells.ConclusionsExpression of stromal cell-derived factor-1 in mesenchymal stromal cells enhances neutrophil function with increased phagocytosis, more efficient clearance of bacteria, and bone marrow protection from depletion of cellular reserves during sepsis.

Dataset Information

Modulation of Human Neutrophil Peptides on P. aeruginosa Killing, Epithelial Cell Inflammation and Mesenchymal Stromal Cell Secretome Profiles.

Publications

Modulation of Human Neutrophil Peptides on <i>P. aeruginosa</i> Killing, Epithelial Cell Inflammation and Mesenchymal Stromal Cell Secretome Profiles.

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