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Transplantation of patient-specific bile duct bioengineered with chemically reprogrammed and microtopographically differentiated cells

ABSTRACT: Cholangiopathy is a diverse spectrum of chronic progressive bile duct disorders with limited treatment options and dismal outcome. Scaffold- and stem cell-based tissue engineering technologies hold great promise for the reconstructive surgery and tissue repair. Here, we report a combined application of 3D scaffold fabrication and direct reprogramming of the patient-specific human hepatocytes to a population of pluripotent stem cells to fabricate implantable artificial tissues that imitate mechanical and biological properties of the native bile ducts. The chemically derived hepatic progenitor cells (hCdHs) were generated using two small molecules A8301 and CHIR99021 and seeded inside the tubular scaffold engineered as synergistic combination of two layers. The inner electrospun fibrous layer was made of nanoscale-macroscale polycaprolactone fibers acting to promote the hCdHs attachment, alignment, and differentiation, while the outer microporous acellular foam layer served to increase mechanical stability. The two layers of fiber and foam were fused robustly together thus creating a coordinated mechanical flexibility to exclude any possible breaking or tear during surgery. The gene expression profiling and histochemical assessment confirmed that hCdHs acquired the biliary epithelial phenotype and filled the entire volume surface of fibrous matrix after two weeks of growth in cholangiocyte differentiation medium in vitro. The fabricated construct replaced the macroscopic part of the common bile duct (CBD) and re-stored the bile flow in a rabbit model of acute CBD injury. Animals which received the acellular scaffolds did not survive the replacement surgery. Thus, the artificial bile duct constructs populated with the patient-specific hepatic progenitor cells could provide a scalable and compatible platform for treating bile duct diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152809 | GEO | 2021/06/18

REPOSITORIES: GEO

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Project description:Liver dysfunction and cirrhosis affect vasculature in several organ systems and cause impairment of organ functions, thereby increasing morbidity and mortality. If a mouse model of hepatopulmonary syndrome (HPS) could be established, greater insight into the genetic basis of the disease would be gained. Our objectives were to establish a mouse model of lung injury after common bile duct ligation (CBDL) and to investigate pulmonary pathogenesis for application in future therapeutic approaches. Balb/c mice were subjected to CBDL. Immunohistochemical analyses and real-time quantitative reverse transcriptional polymerase chain reaction were performed on pulmonary tissues. The presence of HPS markers were detected by western blot and microarray analyses. We observed extensive proliferation of CD31-positive pulmonary vascular endothelial cells 2 weeks after CBDL, and identified 11 up-regulated and 8 down-regulated proteins that were associated with angiogenesis. MMP-9 protein was highly expressed at 3 weeks after CBDL, and less expressed in lungs of the control group. Contrary to our expectation, lung pathology in our mouse model exhibited differences from that of rat models, and the mechanisms responsible for these differences are unknown. This phenomenon may be explained by contrasting processes related to TNF induction of angiogenic signaling pathways in the inflammatory phase; thus, we suggest that our mouse model can be applied to pulmonary pathological analyses in the inflammatory phase, i.e., to systemic inflammatory response syndrome, acute lung injury, and MOD syndrome. After induction of anesthesia, a median abdominal incision was made and the common bile duct was identified. The duct was dissected carefully under a microscope, and doubly ligated with 7-0 Prolene and transected. In the sham operation (control) group, the duct was dissected without common bile duct ligation. Mice were sacrificed at 2 and 3 weeks after surgery. CD31-positive cells were assembled from three mice in each group.

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Transplantation of patient-specific bile duct bioengineered with chemically reprogrammed and microtopographically differentiated cells

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