Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity of self-renewal, homing, and low immunogenicity. These distinct biological characteristics have already shown immense potential in regenerative medicine. MSCs also possess immunomodulatory properties that can maintain immune homeostasis when the immune response is over-activated or under-activated. The secretome of MSCs consists of cytokines, chemokines, signaling molecules, and growth factors, which effectively contribute to the regulation of immune and inflammatory responses. The immunomodulatory effects of MSCs can also be achieved through direct cell contact with microenvironmental factors and immune cells. Furthermore, preconditioned and engineered MSCs can specifically improve the immunomodulation effects in diverse clinical applications. These multifunctional properties of MSCs enable them to be used as a prospective therapeutic strategy to treat immune disorders, including autoimmune diseases and incurable inflammatory diseases. Here we review the recent exploration of immunomodulatory mechanisms of MSCs and briefly discuss the promotion of the genetically engineered MSCs. Additionally, we review the potential clinical applications of MSC-mediated immunomodulation in four types of immune diseases, including systemic lupus erythematosus, Crohn’s disease, graft-versus-host disease, and COVID-19.

Biliary Atresia is a devastating pediatric cholangiopathy affecting the bile ducts of the liver. In this review, we describe recent progress in the understanding of liver development with a focus on cholangiocyte differentiation and how use of technical platforms, including rodent, zebrafish and organoid models, advances our understanding of Biliary Atresia. This is followed by a description of potential pathomechanisms, such as autoimmune responses, inflammation, disturbed apical-basal cell polarity, primary cilia dysfunction as well as beta-amyloid accumulation. Finally, we describe current and emerging diagnostic opportunities and recent translation breakthroughs for Biliary Atresia in the area of emerging therapy development, including immunomodulation and organoid-based systems for liver and bile duct repair.

Recent developments in paediatric gastrointestinal surgery have focused on minimally invasive surgery, the accumulation of high-quality clinical evidence, and scientific research. The benefits of minimally invasive surgery for common disorders like appendicitis and hypertrophic pyloric stenosis are all supported by good clinical evidence. Although minimally invasive surgery has been extended to neonatal surgery, it is difficult to establish its role for neonatal disorders such as oesophageal atresia and biliary atresia through clinical trials because of the rarity of these disorders. Advances in treatments for biliary atresia and necrotising enterocolitis have been achieved through specialisation, multidisciplinary management, and multicentre collaboration in research; similarly robust clinical evidence for other rare gastrointestinal disorders is needed. As more neonates with gastrointestinal diseases survive into adulthood, their long-term sequelae will also need evidence-based multidisciplinary care. Identifying cures for long-term problems of a complex developmental anomaly such as Hirschsprung's disease will rely on unravelling its pathogenesis through genetics and the development of stem-cell therapy.

Biliary atresia (BA) is a poorly understood deadly liver disease, often diagnosed late, is incurable and frequently requires liver transplantation. In this study, we aim to investigate the underlying pathomechanisms and molecular signatures associated with BA. We combine organoid and transcriptomic analysis to gain new insights into BA pathobiology. Liver organoids from BA patients and a BA mouse model, Rhesus rotavirus A-infected mice, exhibited aberrant morphology and disturbed apical-basal organization. Transcriptomic analysis of BA organoids revealed a shift from cholangiocyte to hepatocyte transcriptional signatures and altered beta-amyloid-related gene expression. Beta-amyloid accumulation was observed around the bile ducts in BA livers and exposure to beta-amyloid induced the aberrant morphology in control organoids. Beta-amyloid deposition represents a novel finding with pathobiological implications, a new diagnostic feature and uncovers a previously unsuspected disease mechanism for BA. Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns, often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse 'liver mini-organs in the dish', we unexpectedly identified beta-amyloid deposition, the main pathological feature of Alzheimer's disease and Cerebral Amyloid Angiopathy, around BA bile ducts. This finding reveals a novel pathomechanism for BA important for future diagnosis and treatment considerations.

We have previously reported on the potential pathogenic role of neutrophils in biliary atresia (BA). Herein, we aimed to delineate the role of CD177+ neutrophils in the pathogenesis of BA. Immune cells from the livers of mice with rhesus rotavirus-induced BA were analysed. Single-cell RNA-sequencing was performed to specifically analyse Gr-1⁺ (Ly6C/Ly6G⁺) cells in the liver. Gene expression profiles of CD177⁺ cells were analysed using the Smart-Seq RNA-sequencing method, and the pathogenesis of BA was examined in Cd177^-/- mice. Neutrophil extracellular trap (NET) inhibitors were used to determine the role of CD177⁺ cell-derived NETs in BA-associated bile duct damage, and a pilot clinical study evaluated the potential effects of N-acetylcysteine on NET release in BA. Increased levels of Gr-1⁺ cells were observed in the livers of mice with rhesus rotavirus-induced BA. RNA-sequencing analysis revealed that CD177⁺ cells were the main population of Gr-1⁺ cells and expressed elevated levels of both interferon-stimulated and neutrophil degranulation genes. Cd177^-/- BALB/c mice exhibited delayed disease onset and reduced morbidity and mortality. High numbers of mitochondria were detected in CD177⁺ cells derived from mice with BA; these cells were associated with increased levels of reactive oxygen species and increased NET formation, which induced the apoptosis of biliary epithelial cells in cocultures. In a pilot clinical study, the administration of N-acetylcysteine to patients with BA reduced CD177⁺ cell numbers and reactive oxygen species levels, indicating a potential beneficial effect. Our data indicate that CD177⁺ cells play an important role in the initiation of BA pathogenesis via NET formation. The pilot study of N-acetylcysteine treatment in patients with BA was registered on the Chinese Clinical Trial Registry (ChiCTR2000040505). Neutrophils (a type of innate immune cell, i.e. an immune cell that doesn't target a specific antigen) are thought to play a role in the development of biliary atresia (a rare but potentially lethal condition of the bile ducts that occurs in infants). Herein, we found that neutrophils expressing a particular protein (CD177) played an important role in bile duct damage by releasing a special structure (NET) that can trap and kill pathogens but that can also cause severe tissue damage. A pilot study in patients with biliary atresia showed that inhibiting NETs could have a beneficial effect.