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Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals and ROS accumulation resulting in compromised stem cell function. Conversely, abrogation of the pro-inflammatory activity of UM171 through treatment with dexamethasone, cAMP elevating agents or NFkB inhibitors abolishes EPCR upregulation and HSC expansion. Together, these results show that UM171 stimulates ex vivo HSC expansion by establishing a critical balance between key pro- and anti-inflammatory mediators of self-renewal.
This article was published in the following journal.
Name: PloS one
Microglia transform from homeostatic to disease-associated-microglia (DAM) profiles in neurodegeneration. Within DAM, we recently identified distinct pro-inflammatory and anti-inflammatory sub-profile...
Esophagectomy for esophageal cancer is a very invasive surgery that induces an intense systemic inflammatory response. Postoperative infectious complications worsen survival after esophagectomy throug...
The inflammatory response was targeted by unsuccessful therapies but ignored pathogen. We hypothesized that the inflammatory response differs according to organism in human septic shock.
Staphylococcus aureus is a leading cause of skin and soft issue infection, but paradoxically, it also transiently, and often harmlessly, colonizes human skin. An obstacle to understanding this contrad...
Keratinocytes produce cytokines and nerve growth factor (NGF) as part of a repair response to injury, disease or stress, and express alpha-adrenoceptors (α-AR). The expression of these receptors is e...
This device-study includes a pilot, physiological investigation of normal human subjects. The aim is to determine how existing non-invasive neuromodulation devices affect brain circuitry a...
Cord blood (CB) transplants are an option for patients lacking an HLA identical donor but are hampered by low cell dose, prolonged aplasia and high transplant related mortality. UM171, a n...
Allogeneic hematopoietic stem cell transplantation is a life-saving procedure in patients with blood cancers. Cord blood (CB) represents an alternative source of stem cells, which is assoc...
Detoxification, in an inpatient or outpatient program, is the primary and essential step for managing alcohol dependence. The superiority of one or other method of detoxification has never...
The primary hypothesis that orthopaedic surgery induces a neuroinflammatory response within 48 hours after elective hip surgery and that there is an association between exaggerated CNS inf...
A member of the CXC chemokine family that plays a role in the regulation of the acute inflammatory response. It is secreted by variety of cell types and induces CHEMOTAXIS of NEUTROPHILS and other inflammatory cells.
A small cluster of chemoreceptive and supporting cells located near the bifurcation of the internal carotid artery. The carotid body, which is richly supplied with fenestrated capillaries, senses the pH, carbon dioxide, and oxygen concentrations in the blood and plays a crucial role in their homeostatic control.
A spectrum of inflammation involving the female upper genital tract and the supporting tissues. It is usually caused by an ascending infection of organisms from the endocervix. Infection may be confined to the uterus (ENDOMETRITIS), the FALLOPIAN TUBES; (SALPINGITIS); the ovaries (OOPHORITIS), the supporting ligaments (PARAMETRITIS), or may involve several of the above uterine appendages. Such inflammation can lead to functional impairment and infertility.
Exuberant inflammatory response towards previously undiagnosed or incubating opportunistic pathogens. It is frequently seen in AIDS patients following HAART.
An inflammatory process with loss of supporting bone in the tissues surrounding functioning DENTAL IMPLANTS.
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