Function of hepatocyte spheroids in bioactive microcapsules is enhanced by endogenous and exogenous hepatocyte growth factor.

The ability to maintain functional hepatocytes has important implications for bioartificial liver development, cell-based therapies, drug screening, and tissue engineering. Several approaches can be used to restore hepatocyte function in vitro, including coating a culture substrate with extracellular matrix (ECM), encapsulating cells within biomimetic gels (Collagen- or Matrigel-based), or co-cultivation with other cells. This paper describes the use of bioactive heparin-based core-shell microcapsules to form and cultivate hepatocyte spheroids.

Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response.

Hepatitis delta virus (HDV), a satellite virus of HBV, is regarded as the most severe type of hepatitis virus because of the substantial morbidity and mortality. The IFN system is the first line of defense against viral infections and an essential element of antiviral immunity; however, the role of the hepatic IFN system in controlling HBV-HDV infection remains poorly understood. Herein, we showed that HDV infection of human hepatocytes induced a potent and persistent activation of the IFN system whereas HBV was inert in triggering hepatic antiviral response.

Long-term cell fate and functional maintenance of human hepatocyte through stepwise culture configuration.

Human hepatocyte culture system represents by far the most physiologically relevant model for our understanding of liver biology and diseases; however, its versatility has been limited due to the rapid and progressive loss of genuine characteristics, indicating the inadequacy of in vitro milieu for fate maintenance. This study, therefore, is designed to define environmental requirements necessary to sustain the homeostasis of terminally differentiated hepatocytes. Our study reveals that the supplementation of dimethyl sulfoxide (DMSO) is indispensable in mitigating fate deterioration and promoting adaptation to the in vitro environment, resulting in the restoration of tight cell-cell contact, cellular architecture, and polarity.

Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis.

Background And Aims: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation.

Approach And Results: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay.

Humanized liver mouse model with transplanted human hepatocytes from patients with ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is a metabolic and genetic disease caused by dysfunction of the hepatocytic urea cycle. To develop new drugs or therapies for OTCD, it is ideal to use models that are more closely related to human metabolism and pathology. Primary human hepatocytes (HHs) isolated from two patients (a 6-month-old boy and a 5-year-old girl) and a healthy donor were transplanted into host mice (hemi-, hetero-OTCD mice, and control mice, respectively).

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice.

Advancement in both bioengineering and cell biology of the liver led to the establishment of the first-generation humanized liver chimeric mouse (HLCM) model in 2001. The HLCM system was initially developed to satisfy the necessity for a convenient and physiologically representative small animal model for studies of hepatitis B virus and hepatitis C virus infection. Over the last two decades, the HLCM system has substantially evolved in quality, production capacity, and utility, thereby growing its versatility beyond the study of viral hepatitis.

Changes in Bile Acid Concentrations after Administration of Ketoconazole or Rifampicin to Chimeric Mice with Humanized Liver.

Drug-induced liver injury (DILI) is a common side effect of several medications and is considered a major factor responsible for the discontinuation of drugs during their development. Cholestasis is a DILI that results from impairment of bile acid transporters, such as the bile salt export pump (BSEP), leading to accumulation of bile acids. Both in vitro and in vivo studies are required to predict the risk of drug-induced cholestasis.

Hepatic IFN-Induced Protein with Tetratricopeptide Repeats Regulation of HCV Infection.

Interferons (IFNs) suppress viral infection through the induction of >400 interferon-stimulated genes (ISGs). Among ISGs, IFN-induced protein with tetratricopeptide repeats (IFITs) is one of the most potent and well-characterized ISGs. IFIT family consists of 4 cluster genes.

The whole transcriptome effects of the PPARα agonist fenofibrate on livers of hepatocyte humanized mice.

Background: The role of PPARα in gene regulation in mouse liver is well characterized. However, less is known about the role of PPARα in human liver. The aim of the present study was to better characterize the impact of PPARα activation on gene regulation in human liver.

Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug-drug interactions.

As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug-drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O-benzylguanine as substrates.

Increased expression of the stromal fibroblast-secreted periostin in canine squamous cell carcinomas.

Canine squamous cell carcinoma (SCC) shows highly invasive and locally destructive growth. In animal models and human cancer cases, periostin plays a critical role in the enhancement of cancer growth; however, the mechanism of involvement in canine cancers remains unknown. The aim of this study was to examine the involvement of periostin in the pathophysiology of SCC in dogs.

A study on periostin involvement in the pathophysiology of canine atopic skin.

Atopic dermatitis (AD) is a chronic, pruritic, and allergic skin disease in humans and animals, particularly dogs. Canine AD (cAD) has received attention as a spontaneous atopic animal model because domesticated dogs inhabit a human environment, and cAD shares several clinicopathological features with human AD (hAD). In hAD, periostin (PO) is suggested to play a critical role in the enhancement and chronicity of allergic skin inflammation; however, PO involvement in the pathogenesis of cAD is unknown.

Subcutaneous malignant mast cell tumor in a Japanese macaque (Macaca fuscata).

The histopathological, immunohistochemical, and ultrastructural morphologic characteristics of a tumor in the subcutaneous tissue of the chest of a 19-year-old female Japanese macaque were investigated. Consequently, the mass was diagnosed as a malignant mast cell tumor (MCT). Tumors were present in both mammary gland portions of the anterior thorax.

Canine mammary minute oncocytomas with neuroendocrine differentiation associated with multifocal acinar cell oncocytic metaplasia.

Two solitary and minute tumors of 1 and 1.5 mm diameter were identified by microscopy in the left fourth mammary gland of a 13-year-old female Labrador Retriever dog, in addition to multiple mammary gland tumors. The former tumors were well circumscribed and were composed of small-to-large polyhedral neoplastic oncocytes with finely granular eosinophilic cytoplasm, and were arranged in solid nests separated by fine fibrovascular septa.

Identification of a Unique Amyloid Sequence in AA Amyloidosis of a Pig Associated With Streptococcus Suis Infection.

Here we report a pig with amyloid A (AA) amyloidosis associated with Streptococcus suis infection and identification of a unique amyloid sequence in the amyloid deposits in the tissue. Tissues from the 180-day-old underdeveloped pig contained foci of necrosis and suppurative inflammation associated with S. suis infection.

Cutaneous epitheliotropic T-cell lymphoma with systemic dissemination in a dog.

Cutaneous epitheliotropic T-cell lymphoma (CETL) is characterized by neoplastic T-cell infiltration of the epidermis, adnexal structures, and oral mucosa. The objective of this report was to describe the pathological findings of a canine case of terminal-stage CETL. A 10-year-old, mixed-breed, neutered male dog was presented with erosion of the oral mucosa and mucocutaneous junction.

Expression of phospholipase A2 receptor in primary cultured podocytes derived from dog kidneys.

Phospholipase A2 receptor (PLA2R) expressed in human podocytes has been highlighted as a causative autoantigen of human idiopathic membranous nephropathy. However, its expression was found to be minimal or absent in murine and rat podocytes. In this study, immunofluorescence revealed the expression of PLA2R in the glomerular podocytes in the kidney tissue sections of dogs.

Spontaneous early-onset glomerulonephritis in a 8-week-old male Crj:CD1 (ICR) mouse.

Glomerular lesions including membranoproliferative glomerulonephritis occur spontaneously in aged mice, but they are rare in young animals. In our laboratory, spontaneous glomerulonephritis was observed in an 8-week-old male Crj:CD1 (ICR) mouse. Macroscopically, the bilateral kidneys were discolored, but no edema or ascites was observed.

Clinical and histopathological features resembling those of human focal segmental glomerulosclerosis in a cat with nonimmune-mediated glomerulonephropathy.

Background: Nonimmune-mediated glomerulonephropathies are rarely reported in domestic animals with the exception of amyloidosis. Here we describe the pathological features and clinical course of a feline with protein-losing nonimmune-mediated glomerulonephropathy characterized by segmental glomerulosclerosis and severe podocyte injury.

Case Presentation: A castrated male Japanese domestic cat aged 3 years and 8 months had hypertension, persistent proteinuria, and azotemia.

Pathological features of proteinuric nephropathy resembling Alport syndrome in a young Pyrenean Mountain dog.

The renal biopsy tissue from a 9-month-old, male Pyrenean Mountain dog with renal disorder and severe proteinuria was examined. Ultrastructural examination revealed multilaminar splitting and fragmentation of the glomerular basement membrane (GBM) and diffuse podocyte foot process effacement. Immunofluorescent staining for α(IV) chains revealed presence of α5(IV) and complete absence of α3(IV) and α4(IV) chains in the GBM.

Expression of Periostin in Normal, Atopic, and Nonatopic Chronically Inflamed Canine Skin.

In humans, periostin plays a critical role in the enhancement and chronicity of allergic skin inflammation; however, whether it is involved in the pathogenesis of canine dermatitis remains unknown. The aim of this study was to examine the expression patterns of periostin in healthy, atopic, and nonatopic chronically inflamed canine skin. Biopsy specimens from 47 dogs with skin disease and normal skin tissue from 5 adult beagles were examined by light microscopy, immunohistochemistry, and in situ hybridization.

Lymphangiosarcoma with bone formation of the auricle in a dog.

A 12-year-old mixed-breed neutered female dog was referred with cutaneous tumors at the left auricle. Histologically, the cutaneous tumor located in the dermis comprised numerous clefts and cavernous channels lined by neoplastic endothelial cells with no erythrocytes. Bone tissue without direct contact with neoplastic cells was seen in the well-developed stromal connective tissue.

Restenosis after balloon valvuloplasty in a dog with pulmonary stenosis.

A two-month-old female Chihuahua was diagnosed as severe pulmonary valvular stenosis (PS). Although balloon valvuloplasty (BV) was successfully performed, restenosis was observed 19 months after the procedure. Euthanasia was chosen due to low output syndrome during the surgical repair attempted when the dog was 5 years old.