Alkhani Anas, Korsholm Cathrine, Levy Claire S, Mohamedaly Sarah, Duwaerts Caroline C, Pietras Eric M, Nijagal Amar
Department of Surgery, University of California, San Francisco, CA 94143, USA.
The Liver Center, University of California, San Francisco, CA 94143, USA.
J Clin Med. 2023 Jan 1;12(1):337. doi: 10.3390/jcm12010337.
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).
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.
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).
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.
胆道闭锁（BA）是一种进行性儿童肝脏炎性疾病，可导致肝硬化并需要进行肝移植。BA患儿从肝损伤迅速进展至肝衰竭，这表明围生期肝脏环境特有的因素对疾病传播至关重要。造血干细胞和祖细胞（HSPCs）存在于胎儿肝脏中，已知其为炎症的中心枢纽。我们推测HSPCs对围生期肝损伤（PLI）的传播至关重要。
给新生BALB/c小鼠注射恒河猴轮状病毒（RRV）以诱导PLI，或注射PBS作为对照。使用组织学和流式细胞术对肝脏进行比较。为了确定HSPCs对PLI的影响，给感染RRV的新生小鼠注射抗CD47和抗CD117以清除HSPCs。
PLI显著增加了普通髓系祖细胞的数量和CD34造血祖细胞的数量。通过抗体介导的骨髓消融消除HSPCs可使动物从PLI中获救并显著提高生存率（RRV + 同型对照36.4% vs. RRV + 骨髓消融77.8%，卡方检验 = 0.003）。
HSPCs因RRV感染而扩增并传播PLI。靶向HSPCs可能有助于预防和治疗新生儿肝脏炎性疾病，如BA。
