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Neonatal Hepatic Myeloid Progenitors Expand and Propagate Liver Injury in Mice
Anas Alkhani1,2, Cathrine Korsholm1,2,3, Claire S Levy1,2
1Department of Surgery, University of California, San Francisco, CA 94143, USA.
Insights
Hematopoietic stem and progenitor cells (HSPCs) drive liver injury in newborns. Depleting HSPCs significantly improved survival in a mouse model of neonatal liver inflammation, suggesting a therapeutic target for biliary atresia.
Area of Science:
- Hepatology
- Immunology
- Developmental Biology
Background:
- Biliary atresia (BA) is a pediatric liver disease leading to cirrhosis and transplant necessity.
- Perinatal hepatic environment factors are crucial for disease progression.
- Hematopoietic stem and progenitor cells (HSPCs) are key inflammatory hubs in the fetal liver.
Purpose of the Study:
- To investigate the role of HSPCs in propagating perinatal liver injury (PLI).
- To determine if targeting HSPCs can mitigate liver damage in neonatal models.
Main Methods:
- Neonatal mice were infected with rhesus rotavirus (RRV) to induce PLI.
- HSPCs were depleted using anti-CD47 and anti-CD117 antibodies.
- Liver histology and flow cytometry were used for analysis.
Main Results:
- PLI increased common myeloid progenitors and CD34+ hematopoietic progenitors.
- Antibody-mediated HSPC depletion significantly increased survival rates (77.8% vs. 36.4%).
- HSPC depletion rescued animals from PLI.
Conclusions:
- HSPCs expand during RRV infection and propagate PLI.
- Targeting HSPCs shows potential for treating neonatal liver inflammatory diseases like BA.
Background:
Biliary atresia (BA) is a progressive pediatric inflammatory disease of the liver that leads to cirrhosis and necessitates liver transplantation. The rapid progression from liver injury to liver failure in children with BA suggests that factors specific to the perinatal hepatic environment are important for disease propagation. Hematopoietic stem and progenitor cells (HSPCs) reside in the fetal liver and are known to serve as central hubs of inflammation. We hypothesized that HSPCs are critical for the propagation of perinatal liver injury (PLI).
Methods:
Newborn BALB/c mice were injected with rhesus rotavirus (RRV) to induce PLI or with PBS as control. Livers were compared using histology and flow cytometry. To determine the effects of HSPCs on PLI, RRV-infected neonatal mice were administered anti-CD47 and anti-CD117 to deplete HSPCs.
Results:
PLI significantly increased the number of common myeloid progenitors and the number of CD34+ hematopoietic progenitors. Elimination of HSPCs through antibody-mediated myeloablation rescued animals from PLI and significantly increased survival (RRV+isotype control 36.4% vs. RRV+myeloablation 77.8%, Chi-test = 0.003).
Conclusions:
HSPCs expand as a result of RRV infection and propagate PLI. Targeting of HSPCs may be useful in preventing and treating neonatal inflammatory diseases of the liver such as BA.
