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Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury.

ABSTRACT: Damage to hepatic sinusoidal endothelial cells (SECs) initiates sinusoidal obstruction syndrome (SOS), which is most commonly a consequence of myeloablative chemoirradiation or ingestion of pyrrolizidine alkaloids such as monocrotaline (Mct). This study examines whether SECs are of bone marrow origin, whether bone marrow repair can be a determinant of severity of liver injury, and whether treatment with progenitor cells is beneficial.Mct-treated female rats received infusion of male whole bone marrow or CD133(+) cells at the peak of sinusoidal injury. The Y chromosome was identified in isolated SECs by fluorescent in situ hybridization. Bone marrow suppression was induced by irradiation of both lower extremities with shielding of the abdomen.SECs in uninjured liver have both hematopoietic (CD45, CD33) and endothelial (CD31) markers. After Mct-induced SOS, infusion of bone marrow-derived CD133(+) progenitor cells replaces more than one quarter of SECs. All CD133(+) cells recovered from the SEC fraction after injury are CD45(+). CD133(+)/CD45(+) progenitors also repaired central vein endothelium. Mct suppresses CD133(+)/CD45(+) progenitors in bone marrow by 50% and in the circulation by 97%. Irradiation-induced bone marrow suppression elicited SOS from a subtoxic dose of Mct, whereas infusion of bone marrow during the necrotic phase of SOS nearly eradicates histologic features of SOS.SECs have both hematopoietic and endothelial markers. Bone marrow-derived CD133(+)/CD45(+) progenitors replace SECs and central vein endothelial cells after injury. Toxicity to bone marrow progenitors impairs repair and contributes to the pathogenesis of SOS, whereas timely infusion of bone marrow has therapeutic benefit.

SUBMITTER: Harb R

PROVIDER: S-EPMC2747805 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury.

Harb Rula R Xie Guanhua G Lutzko Carolyn C Guo Yumei Y Wang Xiangdong X Hill Colin K CK Kanel Gary C GC DeLeve Laurie D LD

Gastroenterology 20090515 2

<h4>Background & aims</h4>Damage to hepatic sinusoidal endothelial cells (SECs) initiates sinusoidal obstruction syndrome (SOS), which is most commonly a consequence of myeloablative chemoirradiation or ingestion of pyrrolizidine alkaloids such as monocrotaline (Mct). This study examines whether SECs are of bone marrow origin, whether bone marrow repair can be a determinant of severity of liver injury, and whether treatment with progenitor cells is beneficial.<h4>Methods</h4>Mct-treated female r ...[more]

PMID: 19447108

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Project description:BackgroundBased on the gut-liver axis theory, a leaky gut can aggravate liver injury. However, clinical studies suggest that although gut mucosa damage is commonly observed in inflammatory bowel disease (IBD), it seldom leads to severe liver injury. We hypothesize that there is a hepatic barrier in the gut-liver axis, which protects the liver against gut-derived invasive factors.MethodsColitis was induced by dextran sulfate sodium (DSS) in eight different liver injury models in Sprague-Dawley rats. Liver sinusoidal endothelial cell (LSEC) injury was evaluated by a scanning and transmission electron microscope. Neutrophils were depleted by injection of anti-rat polymorphonuclear serum. Two pneumonia models were also induced to investigate the mechanism of neutrophil recruitment and activation. LSECs isolated from rat liver were used to investigate the effect on neutrophil recruitment and activation.ResultsAmong eight liver injury models, DSS colitis had no effect on liver injury in three models with normal LSECs. In the other five models with LSEC rupture, liver injury was significantly exacerbated by colitis, and increased hepatic neutrophil accumulation was observed. When neutrophils were depleted, colitis-induced liver injury was significantly attenuated. In pneumonia, liver injury, and colitis models, the level of CXCL1 correlated with the recruitment of neutrophils in different tissues, while DSS colitis and LSEC injury synergistically contributed to increased CXCL1 expression in the liver. In colitis-induced liver injury, neutrophils were activated in the liver. Injured LSECs showed both structural and functional changes, with significantly increased expression of CXCL1 and TNF-α under the stimulation of lipopolysaccharide (LPS). The combination of gut-derived LPS and LSEC-derived TNF-α led to the activation of neutrophils, characterized by enhanced production of reactive oxygen species, pro-inflammatory cytokines, and the formation of neutrophil extracellular traps.ConclusionLSECs constitute a vitally important barrier in the gut-liver axis, defending the liver against colitis-induced injury. When LSECs are damaged, they can turn into a pro-inflammatory pattern under the stimulation of LPS. LSEC injury and colitis-derived LPS synergistically contribute to the recruitment and activation of hepatic neutrophils. Neutrophils play a pivotal role as a downstream effector in colitis-induced liver injury.

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Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury.

Publications

Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury.

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