Faculty Bibliography

The mammalian interstitium is a body-wide network of fluid-filled, prelymphatic spaces. Recent studies demonstrate that it exists at three scales in continuity both within and between organs, comprising intercellular, pericapillary, and large (or fascial) interstitial spaces, the latter including fascia, dermis, organ submucosae and capsules, vascular adventitia, and perineurium. Hyaluronic acid fills all interstitial spaces, but large interstitial spaces also contain additional structurally complex and varied extracellular matrices that support soluble factor, mechanical, and potentially electrical signaling. Here we review areas where the new anatomic concept of the interstitium has led to the re-examination of previous findings, including data on interstitial matrix composition and cell trafficking. We also identify new questions arising specifically from the finding that the interstitium is multiscale and body-wide, including questions about the characteristics and drivers of interstitial fluid flow and the role of the interstitium as a rich and active basolateral signaling compartment.

The lines defining Hepatocellular Adenoma (HCA) and Focal Nodular Hyperplasia (FNH) can be blurred when they occur outside their prototypical clinico-pathological contexts. A terminology going beyond HCA and FNH with comments on possible malignant potential, the status of the background liver and/or underlying unusual clinical scenario is thereby justified. Indeed, both more sophisticated contrast-enhanced characterization and the identification of specific immunohistochemical and molecular markers for well-differentiated hepatocellular lesions have enabled a greater understanding of their presentation and biology. The traditional concepts of HCA and FNH occurring in livers that are "otherwise histologically normal or near normal" has given way to understanding that these lesions can also occur in livers affected by chronic liver conditions. When this is the case, morpho-molecular overlap exists between the two entities. Hence, it is now necessary to set a new approach for HCA and FNH, considering not only their intrinsic morphologic and molecular features, but also the background liver in which they are arising, and the clinical context in which they are occurring. The dichotomous paradigm of benign vs. malignant also becomes more nuanced. To raise the diagnostic uncertainty in unusual clinico-pathological scenarios, the International Liver Pathology Study Group suggests designating these lesions as well-differentiated hepatocellular lesions, HCA-like (and subtype when applicable) or FNH-like. This nuanced terminology enables pathologists to highlight these outliers to the hepatobiliary multidisciplinary team that will adapt the clinical management accordingly. It also provides a framework for further collaborative studies. In conclusion, we propose a more nuanced terminology, beyond conventional HCA and FNH, to consider, alongside histological and molecular features, abnormalities in the background liver and unusual clinical scenarios.

The lines defining Hepatocellular Adenoma (HCA) and Focal Nodular Hyperplasia (FNH) can be blurred when they occur outside their prototypical clinico-pathological contexts. A terminology going beyond HCA and FNH with comments on possible malignant potential, the status of the background liver and/or underlying unusual clinical scenario is thereby justified. Indeed, both more sophisticated contrast-enhanced characterization and the identification of specific immunohistochemical and molecular markers for well-differentiated hepatocellular lesions have enabled a greater understanding of their presentation and biology. The traditional concepts of HCA and FNH occurring in livers that are "otherwise histologically normal or near normal" has given way to understanding that these lesions can also occur in livers affected by chronic liver conditions. When this is the case, morpho-molecular overlap exists between the two entities. Hence, it is now necessary to set a new approach for HCA and FNH, considering not only their intrinsic morphologic and molecular features, but also the background liver in which they are arising, and the clinical context in which they are occurring. The dichotomous paradigm of benign vs. malignant also becomes more nuanced. To raise the diagnostic uncertainty in unusual clinico-pathological scenarios, the International Liver Pathology Study Group suggests designating these lesions as well-differentiated hepatocellular lesions, HCA-like (and subtype when applicable) or FNH-like. This nuanced terminology enables pathologists to highlight these outliers to the hepatobiliary multidisciplinary team that will adapt the clinical management accordingly. It also provides a framework for further collaborative studies. In conclusion, we propose a more nuanced terminology, beyond conventional HCA and FNH, to consider, alongside histological and molecular features, abnormalities in the background liver and unusual clinical scenarios.

BACKGROUND & AIMS/OBJECTIVE:Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Over 75% of HCC cases are associated with chronic viral infections. Mechanistic studies and preclinical therapeutic development for virus-associated HCC have been limited by a paucity of small animal models of chronic hepatotropic virus infection that faithfully recapitulate human disease. METHODS AND RESULTS/RESULTS:Here we demonstrate the induction of chronic hepatitis, progressive liver fibrosis, and HCC in immunocompetent laboratory mice upon chronic viral infection with Norway rat hepacivirus (NrHV) - a virus closely related to hepatitis C virus (HCV). NrHV-elicited tumors resemble HCV-associated tumors and liver transcriptome analyses reveal numerous similarities between chronic NrHV and HCV. CONCLUSIONS:These findings establish an experimentally tractable, physiologically relevant, and immunocompetent mouse model of virus-elicited progressive liver fibrosis and oncogenesis. IMPACT AND IMPLICATIONS: (lay summary); The NrHV-HCC model represents the first immunocompetent infectious system that faithfully recapitulates the multistage progression from chronic viral hepatitis to spontaneous hepatocellular carcinoma, bridging a long-standing translational gap between mechanistic mouse studies and human liver cancer. By mirroring the immunopathological, molecular, and sex-associated features of chronic HCV infection, this model provides an unparalleled platform to investigate virus-host interactions underlying fibrosis and oncogenesis. High HCC penetrance and the genetically tractable C57BL/6 background further enhance experimental utility, enabling precise mechanistic dissection and genetic manipulation in a physiologically relevant setting. The capacity to study spontaneous tumor development in the context of natural infection allows for rigorous testing of antifibrotic and anti-cancer strategies, while the persistence of oncogenic potential after viral clearance raises important questions about irreversible disease reprogramming and elevated cancer risk following viral cure - issues of direct relevance to patients cured of HCV.

Founders of quantum mechanics (QM) anticipated that revisions to classical physics due to strange elements of quantum reality, would necessitate similar changes in biology. Complexity theory, systems biology and quantum biology provide possible solutions indicating that subject/object separation is a useful fiction for reductive science. Direct correlates to such QM observational/measurement issues as Complementarity and Uncertainty may justify the introduction of an analog of Heisenberg's uncertainty and the Planck constant for living systems. The phase space of "adjacent possibles" for biological systems from which one "actual" is selected resembles the collapse of the QM wave function. Since biological systems are hierarchical, this occurs across organizational scales resulting in biological coherence. The location of a quantum/classical boundary is unclear due to complexity. Whether biological systems' characteristics arise directly from QM or are of a different origin remains unsettled. To combine non-linear with quantum properties across biological scales we propose the Method of Coherent Structures (MCS), developed for quantum many-body systems. In MCS, a higher-level scale provides a classical envelope for quantum fluctuations at the lower scale. It yields a seamless transition from non-linear classical fields to quantum excitations and accounts for the emergence of complexity by incorporating metabolic energy supply.

Vascular liver pathology represents a heterogenous group of diseases impacted by the dual blood supply to the liver at each distinct microanatomic site. Portal vein-based disease is well described in association with portal vein thrombosis but may also precede or occur in the absence of thrombosis. Central vein-based disease is also well described in association with right heart failure and Budd Chiari syndrome but may show similar features with sinusoidal obstruction. Sinusoidal-based vascular disease is not as well characterized, and several emerging concepts are reviewed in this article.

Bodies have continuous reticular networks, comprising collagens and other extracellular matrix components, through all tissues and organs. We recently validated fluid flow through human interstitium and demonstrated that they are filled with hyaluronic acid by staining with biotinylated hyaluronic acid binding protein. Their continuity across tissue boundaries (skin and subcutis), and between organs (colon and mesentery) and along vessels (within adventitia) and nerves (within perineurium) has been demonstrated in this manner. We aim to evaluate the continuity of interstitium within human pancreas and beyond into adjoining tissues. Tissue blocks of histologically normal pancreas from nine pancreatectomy specimens were sectioned in parallel for staining with hematoxylin and eosin, Picrosirius red, and biotinylated hyaluronic acid binding protein. Also, specimens of invasive pancreatic cancer were assessed for interstitial tumor invasion. Picrosirius red ensheathes all microscopic units of the endocrine and exocrine pancreas, including acini, islets, and ducts, adventitia of blood vessels and perineurium, and into adjacent duodenum. Interstitial spaces within the fibrous tissue are filled with hyaluronic acid by staining and are also continuous through all microscopic structures of the pancreas, into adjoining duodenum and along vessels (within adventitia) and nerves (within perineurium). Invasive carcinoma is seen spreading through pre-existing interstitial spaces. Interstitium of the human pancreas is continuous within and beyond the pancreas. This continuity suggests the capacity to be a route of molecular, microbiome, and cellular trafficking and communication. In particular, it is a route of cancer spread.

There is a body-wide network of interstitial spaces that includes three components: a large-scale fascial network made up of fluid-filled spaces containing collagens and other extracellular matrix components like hyaluronic acid (HA), the peri-vascular/capillary interstitium, and intercellular interstitial spaces. Staining for HA within the colon, skin, and liver has demonstrated spatial continuity of the fascial interstitium across tissue layers and between organs, while continuity of HA staining between perineurial and adventitial sheathes beyond organ boundaries confirmed that they also participate in this body-wide network. We asked whether the pulmonary interstitium comprises a continuous organ-wide network that also connects to the body-wide interstitium via routes along nerves and the vasculature. We studied archival lung lobectomy specimens containing normal tissues inclusive of all lung anatomical units from six females and three males (mean age 53+/- 16.5 years). For comparison, we also studied normal mouse lung. Multiplex immunohistochemical cocktails were used to identify: (1) HA, CD34, and vimentin - highlighting interstitium; (2) HA, CD34, and podoplanin (D2-40) - highlighting relationships between the interstitium, vasculature, and lymphatics. Sizes of extracellular APP were measured. Tissues from nine patients (six females, three males, mean age 53+/- 16.5 years) were studied. HA staining was continuous throughout the five major anatomic compartments of the lung: alveolar walls, subpleural connective tissue, centrilobular peribronchovascular compartment, interlobular septal compartment, and axial peribronchovascular of the hilum, with similar findings in murine lung tissue. Continuity with interstitial spaces of the perineurium and adventitia was confirmed. The distribution of APP corresponded to known routes of lymphatic drainage, superficial and deep. APP within perineurium and perivascular adventitia further demonstrated continuity between intra- and extrapulmonary interstitium. To conclude, all segments of the lung interstitium are connected and are linked along nerves and the vascular tree to a body-wide communication network. These findings have significant implications for understanding lung physiology and pathobiology, suggesting routes of passage for inflammatory cells and mediators, malignant cells, and infectious agents. Interstitial spaces may be important in microbiome signaling within and beyond the lung and may be a component of the lung-brain axis.