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Neil D Theise

Publications and source records attributed to Neil D Theise.

At least 19 recordsLinked to original sources
PubMed2004

Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers.

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.

Biliary Tract↗
PubMed2004

Perspective: stem cells react! Cell lineages as complex adaptive systems.

It may be argued that adult stem cell processes or, more precisely, the cell lineages that arise from them, represent complex reactive or adaptive systems. Approaching hematopoietic and other stem cell lineages from this perspective has direct bearing on current debates regarding the plasticity of these lineage systems as well as on interpretation and modeling of clinical data regarding many diseases.

Adaptation, Physiological↗
PubMed2004

Bone marrow-derived cells contribute to epithelial engraftment during wound healing.

Recent findings suggest that bone marrow-derived cells (BMDC) may contribute to tissue maintenance throughout the body. However, it is not yet known whether marrow-derived epithelial cells are capable of undergoing proliferation. Our laboratory has shown that BMDC engraft as keratinocytes in the skin at low levels (</= 1%) in the absence of injury. Here we show that skin damage affects the degree of engraftment of BMDC as keratinocytes and that the keratinocytes are actively cycling. Female mice reconstituted with sex-mismatched BM were wounded by punch biopsy and incision. At the wound site, engraftment of BMDC as epidermal cells increased within 1 day, and continued to increase to approximately 4% by 3 weeks after injury. Using a Cre-lox system, fusion of BMDC with epithelial cells was ruled out. BMDC-derived epithelial cells at the wound edges expressed Ki67, a marker for actively cycling cells, and this proliferation correlated with an increase in the number of donor-derived cells within the wound. Donor-derived cytokeratin 5-expressing cells were rare, suggesting that BMDC do not engraft as epidermal stem cells, and the level of engraftment peaked and then decreased over time, further suggesting that BMDC may assist in early wound healing by engrafting as transit-amplifying cells, which then differentiate into keratinocytes.

Animals↗
PubMed2004

The canals of hering might represent a target of methotrexate hepatic toxicity.

Methotrexate treatment for psoriasis is known to cause hepatic fibrosis in some patients, which might progress to cirrhosis. The fine, radiating, fibrous septa developing in this setting have a distribution that is reminiscent of the location of the canals of Hering (coH). To assess the possibility of fibrous obliteration of the coH in patients receiving methotrexate, we developed a staining technique by combining an immunohistochemical stain for cytokeratin 7 with a modified Masson trichrome. Sixteen biopsy specimens from 7 patients were evaluated. The biopsies had a variety of histologic changes, including steatosis, anisonucleosis, multinucleation, chronic inflammation, bile duct damage, and ductular reaction. Fibrosis was present in 13 biopsy specimens (81%) and was mild in 7, moderate in 3, and severe in 3 specimens. Compared with normal (control) liver specimens, biopsy specimensfrom patients receiving methotrexate had decreased numbers of coH (1.9 +/- 0.8 vs 5.2 +/- 1.7; P < .025). In specimens with moderate or severe fibrosis, fibrous septa sometimes extended along the coH. These findings suggest that scarring of the coH might be a consequence of the toxic effects of methotrexate.

Adult↗
PubMed2003

Regeneration of hepatocyte 'buds' in cirrhosis from intrabiliary stem cells.

BACKGROUND/AIMS: In massive hepatic necrosis, hepatic stem cells constitute a canal of Hering derived, cytokeratin 19 (CK19) positive 'ductular reaction' (DR). Whether DRs in cirrhosis are activated stem cells (so called 'buds') or biliary metaplasia of cholestatic, injured hepatocytes is still debated. We investigate derivation of intraseptal hepatocytes (ISHs) from DRs and from the biliary tree in cirrhosis. METHODS: Explants of hepatitis B and C, alcohol, primary biliary cirrhosis and primary sclerosing cholangitis-related cirrhosis were examined. ISHs were quantified and their associations with DRs and cholestasis recorded. 3D-reconstruction of ISHs and nearby bile ducts was performed in blocks from hepatitis C and primary sclerosing cholangitis cirrhosis. RESULTS: Seven hundred seventy five/830 (94%) ISHs were associated with CK19 positive DRs. ISHs without ductular reactions were more likely to show cholestatic features (P<0.0001). In 3D, ISHs were seen to bud directly from the biliary tree. In summary: ISHs: (1) are usually associated with stem cell-like DRs; (2) are rarely cholestatic, leaving the associated DRs unexplained; and (3) are linked to the biliary tree in 3D. Dynamic proliferation rates in hepatitis C over time suggest that hepatocyte replication diminishes in late stages, with an associated activation of the biliary stem cell compartment. CONCLUSIONS: We therefore suggest that the biliary tree, from at least its smaller branches up to the canals of Hering, are composed of or at least harbor facultative hepatic stem cells, and that ISH largely represent 'buds' of newly formed hepatocytes.

Biliary Tract↗
PubMed2003

In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion.

Bone marrow harbors cells that have the capacity to differentiate into cells of nonhematopoietic tissues of neuronal, endothelial, epithelial, and muscular phenotype. Here we demonstrate that bone marrow-derived cells populate pancreatic islets of Langerhans. Bone marrow cells from male mice that express, using a CRE-LoxP system, an enhanced green fluorescent protein (EGFP) if the insulin gene is actively transcribed were transplanted into lethally irradiated recipient female mice. Four to six weeks after transplantation, recipient mice revealed Y chromosome and EGFP double-positive cells in their pancreatic islets. Neither bone marrow cells nor circulating peripheral blood nucleated cells of donor or recipient mice had any detectable EGFP. EGFP-positive cells purified from islets express insulin, glucose transporter 2 (GLUT2), and transcription factors typically found in pancreatic beta cells. Furthermore, in vitro these bone marrow-derived cells exhibit - as do pancreatic beta cells - glucose-dependent and incretin-enhanced insulin secretion. These results indicate that bone marrow harbors cells that have the capacity to differentiate into functionally competent pancreatic endocrine beta cells and that represent a source for cell-based treatment of diabetes mellitus. The results generated with the CRE-LoxP system also suggest that in vivo cell fusion is an unlikely explanation for the "transdifferentiation" of bone marrow-derived cells into differentiated cell phenotypes.

Animals↗
PubMed2003

Stellate-cell lipidosis in liver biopsy specimens. Recognition and significance.

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.

Adipocytes↗
PubMed2003

Liver stem cells: prospects for treatment of inherited and acquired liver diseases.

It is now understood that there are three cell compartments which physiologically contribute to vertebrate liver parenchymal maintenance and regeneration after injury: mature liver cells (hepatocytes, cholangiocytes), intraorgan stem/progenitor cells (cells of the proximal biliary tree, periductal cells) and extraorgan stem cells (from the circulation and the bone marrow). All of these cell populations, as well as other, non-physiologic stem cells (e.g., mesenchymal stromal cells from the bone marrow, fetal hepatoblasts, embryonic stem [ES] cells), may be used therapeutically for treatment of inherited and acquired liver diseases. This article will summarise our current understanding of these various cell populations, and review possible approaches to their therapeutic use, including cell transplantation, bioartificial liver devices (BLDs), gene therapy and administration of exogenous factors to stimulate normal physiological responses to repair.

Animals↗
PubMed2003

Stem cell research: elephants in the room.

The degree to which these elephants are disruptive to the steady advancement of the adult stem cell field will become clear with time. In some ways they enliven the discourse, but in many ways they interfere with efficient progress. Naming these elephants is a first step toward dealing with them. If we remain aware of these issues when evaluating new research, we are less likely to make careless mistakes, and we are more likely to be able to hold scientists, politicians, journalists, and entrepreneurs accountable for their practices. Although all adult stem cell researchers will spend time profitably riding some of these elephants, we will all inevitably spend more time cleaning up after them. Perhaps open, careful, and unbiased discussions of these elephants will help the cleanup work be less odious and completed sooner, rather than later.

Adult↗
PubMed2002

Liver regeneration investigated in a non-human primate model (Macaca mulatta).

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.

Animals↗
PubMed2002

Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment from bone marrow.

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.

Animals↗
PubMed2002

Low-grade siderotic dysplastic nodules: determination of premalignant lesions on the basis of vasculature phenotype.

RATIONALE AND OBJECTIVES: The authors performed this study to determine whether, on the basis of the vascular profile, low-grade siderotic dysplastic nodules are premalignant lesions. MATERIALS AND METHODS: The authors used a monoclonal antibody specific for smooth muscle actin to stain 18 siderotic low-grade dysplastic nodules (mean size, 0.7 cm) from nine patients. Two pathologists counted the number of unpaired arteries per high-power field in siderotic dysplastic nodules and background siderotic regenerative nodules by using two techniques (conventional and hot spot). RESULTS: The number of unpaired arteries seen with the conventional counting technique in low-grade siderotic dysplastic nodules (range, 1-14; mean, 3.8) was significantly greater (P = .004) than that seen in background siderotic regenerative nodules (range, 0-3; mean, 1.2). Similarly, the number of unpaired arteries seen with the hot spot technique in low-grade siderotic dysplastic nodules (range, 0-14; mean, 5.2) was significantly greater (P = .005) than that seen in background siderotic regenerative nodules (range, 0-6; mean, 1.9). CONCLUSION: On the basis of the vascular profile, low-grade siderotic dysplastic nodules should be considered premalignant lesions. Further research is needed to help differentiate these lesions from siderotic regenerative nodules with magnetic resonance imaging.

Humans↗