Neonatal hepatic myeloid progenitors expand and propagate liver inflammation in mice

Abstract

Background and AimsBiliary atresia is a rapidly progressive pediatric inflammatory disease of the liver that leads to cirrhosis and necessitates liver transplantation. The rapid progression from liver injury to fulminant liver failure in children with biliary atresia suggests that factors specific to the perinatal hepatic environment are important for disease propagation. Hematopoietic stem and progenitor cells (HSPCs) serve as central hubs of inflammation and rely on inflammatory signals for their emigration from the liver to the bone marrow in neonatal mice. We hypothesized that HSPCs are critical for the propagation of perinatal liver inflammation (PLI). MethodsNewborn BALB/c mice were injected intraperitoneally with 1.5x106 focus forming units of Rhesus Rotavirus (RRV) to induce PLI or with PBS as control. Livers from RRV- and PBS-injected mice were compared using histology and flow cytometry. To determine the effects of HSPCs on perinatal inflammation, RRV-infected neonatal mice were injected with anti-CD47 and anti-CD117 to deplete HSPCs. ResultsRRV-induced PLI led to a significant increase in the number of common myeloid progenitors (Flt3+ CMPs: PBS=4426{+/-}247.2 vs RRV=9856{+/-}2009, p=0.0316; Flt3- CMPs: PBS=3063{+/-}254.9 vs RRV=9743{+/-}1539, p=0.0012). We corroborated these findings by observing a significant increase in CD34+ hematopoietic progenitors/cm2 in histological sections of RRV-infected livers (PBS=4.977{+/-}2.573 vs RRV=27.09{+/-}12.49, p=0.0075). Elimination of progenitors through antibody-mediated myeloablation rescued animals from PLI and significantly increased survival (RRV+isotype control 55.56% vs RRV+myeloablation 94.12%, Chi-test=0.01). ConclusionsThese data demonstrate that RRV causes expansion of HSPCs and propagates PLI. Targeting of HSPCs may be useful in preventing and treating neonatal inflammatory diseases of the liver like biliary atresia. SYNOPSISHematopoietic progenitors reside in juvenile mouse livers even after the main site of hematopoiesis has shifted to the bone marrow. These progenitors are critical for the pathogenesis of perinatal liver inflammation as myeloablation rescues animals from disease.