An Obligatory Role of NF-κB in Mediating Bone Marrow Derived Endothelial Progenitor Cell Recruitment and Proliferation Following Endotoxemic Multiple Organ Injury in Mice

Abstract

BackgroundRecruitment of bone marrow derived endothelial progenitor cells (BMDEPCs) alleviates multiple organ injury (MOI) and improves outcomes. However, mechanisms mediating BMDEPC recruitment following septic MOI remain largely unknown. This study characterized the kinetics of BMDEPC recruitment and proliferation and defined the role of NF-κB in regulating BMDEPC recruitment and proliferation.Methods and Main FindingsChimeric mice with an intact or disrupted NF-κB p50 gene and BMDEPC-restricted expression of green fluorescent protein were created and injected with LPS (2 mg/kg, i.p.). BMDEPC recruitment and proliferation in multiple organs were quantified. BMDEPC recruitment and proliferation are highly organ-dependent. Lungs had the highest number of BMDEPC recruitment, whereas heart, liver and kidney had only a small fraction of the number of BMDEPCs in lungs. Number of proliferating BMDEPCs was several-fold higher in lungs than in other 3 organs. Kinetically, BMDEPC recruitment into different organs showed different time course profiles. NF-κB plays obligatory roles in mediating BMDEPC recruitment and proliferation. Universal deletion of NF-κB p50 gene inhibited LPS-induced BMDEPC recruitment and proliferation by 95% and 69% in heart. However, the contribution of NF-κB to these regulations varies significantly between organs. In liver, universal p50 gene deletion reduced LPS-induced BMDEPC recruitment and proliferation only by 49% and 35%. NF-κB activities in different tissue compartments play distinct roles. Selective p50 gene deletion either in stromal/parenchymal cells or in BM/blood cells inhibited BMDEPC recruitment by a similar extent. However, selective p50 gene deletion in BM/blood cells inhibited, but in stromal/parenchymal cells augmented BMDEPC proliferation.ConclusionsBMDEPC recruitment and proliferation display different kinetics in different organs following endotoxemic MOI. NF-κB plays obligatory and organ-dependent roles in regulating BMDEPC recruitment and proliferation. NF-κB activities in different tissue compartments play distinct roles in regulating BMDEPC proliferation.

Exacerbation of Chikungunya Virus Rheumatic Immunopathology by a High Fiber Diet and Butyrate

“…CHIKV infects endothelial cells in vivo (37, 169) and edema is a well-known symptom of CHIKV infection (47, 82). Endothelial barrier repair requires NF-κB activation (170, 171) and a NF-κB to AP-1 transition (172). Herein we provide evidence that butyrate promoted certain AP-1 activities and markedly inhibited canonical NF-κB pathways, consistent with previous studies on butyrate (31–34, 142).…”

Neglected No More: Emerging Cellular Therapies in Traumatic Injury

“…Systemic mobilization of EPCs into the peripheral blood increases in the setting of either local or systemic organ dysfunction, prompting interest in their use as a potential biomarker for various disease processes [ 107 ]. Additionally, increased EPC recruitment to various organs, including the lung, liver, and kidney has shown physiologic benefit [ 112 ]. However, despite these correlations, their actual contribution to organ repair remains an area of contention.…”

“…Their role in vasculogenesis-previously thought to occur only via migration of existing endothelial cells or through induction of hematopoietic stem cells-has been wellestablished [107]. Several studies have shown a correlation between the presence of EPCs in blood to various disease processes, including neurologic and cardiovascular disease, sepsis, malignancy, and severe trauma, among others [108][109][110][111][112]. Given their ubiquitous nature and the importance of endothelial maintenance and neovascularization to wound healing, EPCs are an encouraging option for future trauma therapies.…”

Controversial Role of Toll-like Receptor 4 in Adult Stem Cells

“…Interestingly, there are data, both in mice and humans, indicating that LPS/endotoxemia can mobilize bone marrow-derived EPCs to assist lung repair after bacterial pneumonia [98]. NF-κB has been shown to play a fundamental, yet organ-specific role in the mobilization, recruitment and proliferation process [99].…”