A model of hematopoietic bone marrow apoptosis during growth factor deprivation in combination with a cytokine.

BACKGROUND: The process by which blood cells are formed is referred to as hematopoiesis. This process involves a complex sequence of phases that blood cells must complete. During hematopoiesis, a small fraction of cells undergo cell death. Causes of cell death are dependent upon various factors; one such factor being growth factor deprivation. METHODS: In this paper, a mathematical model of hematopoiesis during growth factor deprivation is presented. The model consists of a set of three coupled differential delay equations. Phase plane and linear stability analysis are performed in order to locate and determine stability of fixed points. Numerical simulations of the governing equations are run and provide a visual display of the behavior of the stem cell population undergoing growth factor deprivation. In addition, the effect of cytokine administration is incorporated in the model in an effort to understand how cytokine administration can offset the negative effects of apoptosis caused by growth factor deprivation. CONCLUSIONS: The model produces qualitatively similar results to that observed during serum deprivation. The model captures apoptosis levels of cells at different time points. Additionally, it is shown that cytokine administration stabilizes the stem cell count.

A model of hematopoietic stem cell proliferation under the influence of a chemotherapeutic agent in combination with a hematopoietic inducing agent.

BACKGROUND: Hematopoiesis is a complex process that encompasses both pro-mitotic and anti-mitotic stimuli. Pharmacological agents used in chemotherapy have a prominent anti-mitotic effect. The approach of inhibiting cell proliferation is rational with respect to the rapidly dividing malignant cells. However, it poses a serious problem with respect to cell proliferation of cell types required for the 'house-keeping' operations of the human body. One such affected system is hematopoiesis. Chemotherapy induced anemia is an undesired side effect of chemotherapy that can lead to serious complications. Patients exhibiting anemia or leukopenia during chemotherapy are frequently administered a hematopoietic inducing agent that enhances hematopoiesis. METHODS: In previous work, we derived a mathematical model consisting of a set of delay differential equations that was dependent on the effect of a hematopoietic inducing agent. The aim of the current work was to formulate a mathematical model that captures both the effect of a chemotherapeutic agent in combination with a hematopoietic inducing agent. Steady state solutions and stability analysis of the system of equations is performed and numerical simulations of the stem cell population are provided. RESULTS: Numerical simulations confirm that our mathematical model captures the desired result which is that the use of hematopoietic agents in conjunction with chemotherapeutic agents can decrease the negative secondary effects often experienced by patients. CONCLUSIONS: The proposed model indicates that the introduction of hematopoietic inducing agents have clinical potential to offset the deleterious effects of chemotherapy treatment. Furthermore, the proposed model is relevant in that it enhances the understanding of stem cell dynamics and provides insight on the stem cell kinetics.

Oleic acid and peanut oil high in oleic acid reverse the inhibitory effect of insulin production of the inflammatory cytokine TNF-alpha both in vitro and in vivo systems.

BACKGROUND: Chronic inflammation is a key player in pathogenesis. The inflammatory cytokine, tumor necrosis factor-alpha is a well known inflammatory protein, and has been a therapeutic target for the treatment of diseases such as Rheumatoid Arthritis and Crohn's Disease. Obesity is a well known risk factor for developing non-insulin dependent diabetes melitus. Adipose tissue has been shown to produce tumor necrosis factor-alpha, which has the ability to reduce insulin secretion and induce insulin resistance. Based on these observations, we sought to investigate the impact of unsaturated fatty acids such as oleic acid in the presence of TNF-alpha in terms of insulin production, the molecular mechanisms involved and the in vivo effect of a diet high in oleic acid on a mouse model of type II diabetes, KKAy. METHODS: The rat pancreatic beta cell line INS-1 was used as a cell biological model since it exhibits glucose dependent insulin secretion. Insulin production assessment was carried out using enzyme linked immunosorbent assay and cAMP quantification with competitive ELISA. Viability of TNF-alpha and oleic acid treated cells was evaluated using flow cytometry. PPAR-gamma translocation was assessed using a PPRE based ELISA system. In vivo studies were carried out on adult male KKAy mice and glucose levels were measured with a glucometer. RESULTS: Oleic acid and peanut oil high in oleic acid were able to enhance insulin production in INS-1. TNF-alpha inhibited insulin production but pre-treatment with oleic acid reversed this inhibitory effect. The viability status of INS-1 cells treated with TNF-alpha and oleic acid was not affected. Translocation of the peroxisome proliferator- activated receptor transcription factor to the nucleus was elevated in oleic acid treated cells. Finally, type II diabetic mice that were administered a high oleic acid diet derived from peanut oil, had decreased glucose levels compared to animals administered a high fat diet with no oleic acid. CONCLUSION: Oleic acid was found to be effective in reversing the inhibitory effect in insulin production of the inflammatory cytokine TNF-alpha. This finding is consistent with the reported therapeutic characteristics of other monounsaturated and polyunsaturated fatty acids. Furthermore, a diet high in oleic acid, which can be easily achieved through consumption of peanuts and olive oil, can have a beneficial effect in type II diabetes and ultimately reverse the negative effects of inflammatory cytokines observed in obesity and non insulin dependent diabetes mellitus.

Hematopoietic stem cell proliferation modeling under the influence of hematopoietic-inducing agent.

The process by which hematopoietic stem cells (HSCs) residing in the bone marrow differentiate into blood cells is known as hematopoiesis. In the event of hemorrhagic shock, it is crucial for the HSC to rapidly differentiate into new committed erythroid progenitor cells that will give rise to erythrocytes. Growth factors and cytokines enhance the self-renewing process of HSC and are therefore crucial to restoring normal levels of blood cells in the body. Hematopoietic inducing agents (HIAs) such as the cytokine erythropoietin and granulocyte-colony-stimulating factor play a vital role in hematopoiesis because they are capable of inducing the proliferation of stem cells. The aim of the current study is to mathematically model the effect of HIA on the proliferation rate of hematopoietic stem cells at varying levels of oxygenation. The role of HIA was analyzed by constructing a set of coupled ordinary differential equations upon which mathematical analysis was performed. The model makes predictions of hematopoietic activity during low oxygen levels (ranging from 3% to 15%) similar to conditions ranging from acute blood loss to normal conditions.

Bone marrow-derived dendritic cells generated in the presence of resolvin E1 induce apoptosis of activated CD4+ T cells.

In contrast to the role of dendritic cells (DC) in immunity and tolerance, little is known about their possible role in the resolution of inflammatory processes. In addition to the reduction in the number of infiltrating immune cells, the elimination of effector T cells already present at the inflammatory site represents an essential step toward resolution. Recently, lipid mediators such as the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their metabolites, including resolvin E1 (RvE1), have been shown to accumulate in inflammatory foci during the resolution phase. RvE1 has been reported to reduce immune cell infiltration and proinflammatory cytokine production. In this study we report that DC exposed to RvE1, especially during differentiation, acquire the capacity to induce apoptosis of activated T cells through the induction and activity of indoleamine 2,3-dioxygenase. To our knowledge, this study is the first to report on an omega-3 fatty acid derivative inducing indoleamine 2,3-dioxygenase expression in DC. RvE1-exposed DC maintain an immature chemokine receptor expression pattern even following TLR stimulation, with high CCR5 and no CCR7 expression. This effect implies that DC exposed to RvE1 and pathogens remain at the inflammatory site, instead of migrating to lymph nodes, and induce apoptosis in effector T cells infiltrating the inflammatory site. To our knowledge, the DC described in this study represent a new functional DC subtype, whose essential function resides in the resolution of inflammation.