Functional Human and Murine Tissue-Engineered Liver Is Generated from Adult Stem/Progenitor Cells

Abstract

Liver disease affects large numbers of patients, yet there are limited treatments available to replace absent or ineffective cellular function of this crucial organ. Donor scarcity and the necessity for immunosuppression limit one effective therapy, orthotopic liver transplantation. But in some conditions such as inborn errors of metabolism or transient states of liver insufficiency, patients may be salvaged by providing partial quantities of functional liver tissue. After transplanting multicellular liver organoid units composed of a heterogeneous cellular population that includes adult stem and progenitor cells, both mouse and human tissue‐engineered liver (TELi) form in vivo. TELi contains normal liver components such as hepatocytes with albumin expression, CK19‐expressing bile ducts and vascular structures with α‐smooth muscle actin expression, desmin‐expressing stellate cells, and CD31‐expressing endothelial cells. At 4 weeks, TELi contains proliferating albumin‐expressing cells and identification of β2‐microglobulin‐expressing cells demonstrates that the majority of human TELi is composed of transplanted human cells. Human albumin is detected in the host mouse serum, indicating in vivo secretory function. Liquid chromatography/mass spectrometric analysis of mouse serum after debrisoquine administration is followed by a significant increase in the level of the human metabolite, 4‐OH‐debrisoquine, which supports the metabolic and xenobiotic capability of human TELi in vivo. Implanted TELi grew in a mouse model of inducible liver failure. Stem Cells Translational Medicine 2017;6:238–248

Hepatic Prominin-1 expression is associated with biliary fibrosis

“…The function of CD133 is unknown, although several studies indicate its role in maintaining the topology of the plasma membrane, in effect regulating the state of cellular differentiation [4] [5] [6]. Prom1 -expressing hepatic progenitor cells possess great regenerative and malignant potential [7] and may contribute to the populating of tissue-engineered liver constructs [8]. We have also previously demonstrated the expansion of a population of cells expressing PROM1 within periportal regions of evolving biliary fibrosis in both the rodent rotavirus model of BA as well as in infants with BA [9].…”

Engineering the Vasculature of Stem-Cell-Derived Liver Organoids

“…At the time of harvest, there were visible branched capillaries on the surface of TELi. Vascular structures similar to the native liver were demonstrated by the presence of α-SMA-expressing portal fibroblast cells and CD31− expressing ECs [41].…”

Liver cell therapy: is this the end of the beginning?

“…The cells have self-assembled into 3D organoids, resulting in improved hepatocyte differentiation [ 129 ]. Multicellular liver organoid units composed of heterogeneous cell populations that contain human adult stem and progenitor cells, hepatocytes, bile ducts and vascular structures, hepatic stellate cells, and endothelial cells have been transplanted under the abdominal skin in immunodeficient mice with a liver failure [ 147 ]. The transplanted organoids provided a functional support up to 4 weeks post-transplantation [ 147 ].…”

“…Multicellular liver organoid units composed of heterogeneous cell populations that contain human adult stem and progenitor cells, hepatocytes, bile ducts and vascular structures, hepatic stellate cells, and endothelial cells have been transplanted under the abdominal skin in immunodeficient mice with a liver failure [ 147 ]. The transplanted organoids provided a functional support up to 4 weeks post-transplantation [ 147 ]. While these studies are very encouraging, it is not yet feasible to transplant organoids via blood vessels, due to their large size, making routine deployment difficult.…”