Faculty Bibliography

Hepatic stellate-cell lipidosis due to hypervitaminosis A can lead to cirrhosis, which can be averted by restricting vitamin A intake. Other causes, including the use of synthetic retinoids, have been postulated. We studied the frequency and etiology of stellate-cell lipidosis in patients undergoing liver biopsy for reasons other than vitamin A abuse. Fourteen cases (1.1%) were identified retrospectively among 1,235 nontransplant liver biopsy specimens examined from January 1995 through December 1999. Diagnostic criteria included the following: lipid-laden cells in the space of Disse; small, dark, crescent-shaped nuclei with inconspicuous nucleoli; and wispy cytoplasmic strands separating fat droplets. Patient details, reason for biopsy, and medication use were studied. Reasons for biopsy included hepatitis C (10 cases), abnormal liver enzyme levels (2 cases), methotrexate use (1 case), and alcohol abuse (1 case). Hypervitaminosis A was not suspected clinically in the 5 patients who used oral vitamin A or 3 who used topical tretinoin (Retin-A). In 6 patients, no cause of stellate-cell lipidosis was discerned. Stellate-cell lipidosis should be reported to alert clinicians to a potentially preventable form of liver injury

The sensitivity of magnetic resonance imaging (MRI) in patients who undergo transplantation for hepatocellular carcinoma (HCC) and cirrhosis is not known. We prospectively evaluated 24 patients with known HCC who underwent MRI and subsequent transplantation within 60 days (mean, 20 days). Using a phased-array coil at 1.5T, breath-hold turbo STIR and T2-weighted MR images were performed. Dynamic gadolinium-enhanced MRI was performed using a two- or three-dimensional gradient echo pulse sequence with images obtained in the hepatic arterial, portal venous, and equilibrium phases. The prospective interpretation of the MR study was directly compared with thin-section pathology evaluation of the explanted livers. All 24 patients had at least one HCC, and MR diagnosed tumor in 21 (88%) of these patients. On a lesion-by-lesion basis, MRI depicted 39 of 118 HCC for an overall sensitivity of 33%. MRI detected five (100%) of five lesions >5 cm, 20 (100%) of 20 lesions >2 cm but not exceeding 5 cm, 11 (52%) of 21 lesions between 1 and 2 cm, and three (4%) of 72 lesions <1 cm. Of the nine patients with carcinomatosis (innumerable lesions less than 1 cm), MR detected three lesions in one patient. Of the 15 dysplastic nodules found at pathology, MRI depicted a single 1.8-cm high-grade lesion, for a sensitivity of 7%. In conclusion, MRI is sensitive for the detection of HCC measuring at least 2 cm in diameter but is insensitive for the diagnosis of small HCC (<2 cm) and carcinomatosis

The existence of hepatic stem or progenitor cells has been controversial for decades, though it was presumed that if such cells existed, they would lie within the liver. There is now consensus, however, that not only do facultative hepatic stem cells exist within the liver, but also that cells from extra-hepatic sites, in particular the bone marrow, can contribute to hepatocyte and cholangiocyte regeneration. Despite confidence that engraftment of marrow cells in the liver occurs, the mechanistic details of this process remain poorly understood. Moreover, the physiological importance and therapeutic utility of this phenomenon remains controversial

Gene therapy application to pulmonary airways and alveolar spaces holds tremendous promise for the treatment of lung diseases. However, safe and effective long-term gene expression using viral and nonviral vectors has not yet been achieved. Adenoviral vectors, with a natural affinity for airway epithelia, have been partially effective, but are inflammatory and induce only transient gene expression. We investigate the novel approach of using retrovirally transduced multipotent bone marrow-derived stem cells (BMSC) to deliver gene therapy to lung epithelium. We have shown previously that up to 20% of lung epithelial cells can be derived from marrow following BMSC transplantation. Here, irradiated female mice were transplanted with male marrow that had been transduced with retrovirus encoding eGFP. Transgene expressing lung epithelial cells were present in all recipients analyzed at 2, 5, or 11 mo after transplant (n = 10), demonstrating that highly plastic BMSC can be stably transduced in vitro and retain their ability to differentiate into lung epithelium while maintaining long-term transgene expression

OBJECTIVE: To better understand the process by which pneumocytes can be derived from bone marrow cells, we investigated the in vivo kinetics of such engraftment following lethal irradiation. METHODS: A cohort of lethally irradiated B6D2F1 female mice received whole bone marrow transplants (BMT) from age-matched male donors and were sacrificed at days 1, 3, 5, and 7 and months 2, 4, and 6 post-BMT (n = 3 for each time point). Additionally, 2 female mice who had received 200 male fluorescence-activated cell sorter (FACS)-sorted CD34(+)lin(-) cells were sacrificed 8 months post-BMT. RESULTS: Lethal irradiation caused histologic evidence of pneumonitis including alveolar breakdown and hemorrhage beginning at day 3. To identify male-derived pneumocytes, simultaneous fluorescence in situ hybridization (FISH) for Y-chromosome and surfactant B messenger RNA was performed on lung tissue. Y(+) type II pneumocytes were engrafted as early as day 5 posttransplant, and eventually from 2 to 14% of the pneumocytes were donor derived in individual mice. Co-staining for epithelial-specific cytokeratins demonstrated that by 2 months, marrow-derived pneumocytes could comprise entire alveoli, suggesting that type I cells derived from type II pneumocytes. CONCLUSIONS: We conclude that alveolar lining cells derive from bone marrow cells immediately after acute injury. Also, the CD34(+)lin(-) subpopulation is capable of such pulmonary engraftment

BACKGROUND/AIMS: An adequate model to study liver regeneration in humans is presently unavailable. We explored the feasibility of studying liver regeneration in a genetically similar species to man, the non-human primate Rhesus macaque.METHODS: Five animals were studied; two underwent 60% hepatectomy, one underwent 30% hepatectomy, and cholecystectomy alone was performed on two animals. Laparoscopic-guided or open liver biopsies were performed on days 1, 2, 7, 14, 21, 30 and 60 following all surgeries. Liver regeneration was evaluated by measuring Ki-67, proliferating cell nuclear antigen expression and mitotic index, calculating changes in the surface area of the liver remnant and assessing intrahepatic production of cytokines.RESULTS: Significant liver regeneration was induced in the animals that underwent 60% hepatectomy, peaking between days 21-30 postoperatively. Regeneration was minimal in all other animals studied. Cytokine production followed a similar pattern. Maximal liver regeneration correlated with restoration of surface area in the liver remnant.CONCLUSIONS: Sixty percent hepatectomy in a non-human primate model induced significant liver regeneration, maximizing 21-30 days following partial hepatectomy, suggesting a significant interspecies difference when compared to a rodent hepatectomy model. A partial hepatectomy model in Rhesus macaques may allow further characterization of liver regeneration in a species closer to humans

Recent discoveries demonstrating surprising cell plasticity in animals and humans call into question many long held assumptions regarding differentiative potential of adult cells. These assumptions reflect a classical paradigm of cell lineage development projected onto both prenatal development and post-natal maintenance and repair of tissues. The classical paradigm describes unidirectional, hierarchical lineages proceedings step-wise from totipotent or pluripotent stem cells through intermediate, ever more restricted progenitor cells, leading finally to 'terminally differentiated' cells. However, in light of both the recent discoveries and older clinical or experimental findings, we have suggested principles comprising a new paradigm of cell plasticity, summarized here