Abstract:
:End-stage liver diseases represent major health problems that are currently treated by liver transplantation. However, given the world-wide shortage of donor livers novel strategies are needed for therapeutic treatment. Adult stem cells have the ability to self-renew and differentiate into the more specialized cell types of a given organ and are found in tissues throughout the body. These cells, whose progeny are termed progenitor cells in human liver and oval cells in rodents, have the potential to treat patients through the generation of hepatic parenchymal cells, even from the patient's own tissue. Little is known regarding the nature of the hepatic progenitor cells. Though they are suggested to reside in the most distal part of the biliary tree, the canal of Hering, the lack of unique surface markers for these cells has hindered their isolation and characterization. Upon activation, they proliferate and form ductular structures, termed "ductular reactions", which radiate into the hepatic parenchyma. The ductular reactions contain activated progenitor cells that not only acquire a phenotype resembling that observed in developing liver but also display markers of differentiation shared with the cholangiocytic or hepatocytic lineages, the two parenchymal hepatic cell types. Interactions between the putative progenitor cells, the surrounding support cells and the extracellular matrix scaffold, all constituting the progenitor cell niche, are likely to be important for regulating progenitor cell activity and differentiation. Therefore, identifying novel progenitor cell markers and deciphering their microenvironment could facilitate clinical use. The aims of the present PhD thesis were to expand knowledge of the hepatic progenitor cell niche and characterize it both during development and in disease. Several animal models of hepatic injury are known to induce activation of the progenitor cells. In order to identify possible progenitor cell markers and niche components, we examined several genes upregulated in a global gene expression array conducted on one of these models, in which progenitor cells are activated. The protein expression patterns were evaluated in our collections of human embryonic and fetal livers, human liver diseases, and rodent hepatic injury models. When analyzing standard histological liver sections underlying connections and tissue architecture are not immediately evident. We therefore developed models for digitally reconstructing not only protein expression in serially cut tissue sections, but also vessels of the portal area. Article I constituted our earliest attempts to create 3D reconstructions of biological material. Human embryonic stem cell cultures were previously thought to consist of homogenously undifferentiated cells. The protocols for 3D reconstructions developed in this study demonstrated micro heterogeneity in expression of differentiation markers and provided the basis for later reconstructions of hepatic tissues. In article II we examined the expression patterns of chosen proteins seen upregulated in the gene array as well as classical hepatocytic and cholangiocytic markers in human liver disease and during prenatal development. Previous studies had indicated direct connections between activated progenitor cells apparently isolated in the parenchyma and the intrahepatic biliary tree. Our developed protocols for 3D reconstructions visually demonstrated direct connections between these entities. Analysis of protein expression in prenatal liver revealed the formation of the intrahepatic tree to occur through a special form of asymmetric tubulogenesis, only recently described in mice. In order to describe the composition of the hepatic progenitor cell niche and the localization of cell surface proteins in article III, the expression patterns of certain genes upregulated in the gene array analysis were analyzed in different models of rodent liver regeneration. We observed that the extracellular matrix molecules collagen 1a1, laminin, nidogen-1 and agrin embraced the biliary cells and sharply defined the hepatic progenitor cell niche, which was encircled by desmin positive support cells. In all injury models biliary cells expressed the cell surface proteins matriptase and HAI-1. However, in the so-called 2-AAF/PHx model of progenitor cell activation, a subpopulation of hepatic progenitor cells was positive for Dlk1. 3D reconstructions clarified that the Dlk1-subpopulation was entirely located in the portal area periphery, and connected to the bile ducts via HAI-1 positive biliary cells. The heterogeneous expression patterns of matriptase, HAI-1 and Dlk1 in this particular injury model indicate the presence of a cellular hierarchy containing possibly less differentiated Dlk1-positive hepatic progenitor cells. In conclusion, our studies characterized the hepatic progenitor cell niche in humans and rodents. We successfully developed protocols for digitally visualizing, not only hepatic, but virtually any tissue through two fundamentally distinct approaches. The identification of an asymmetric form of tubulogenesis in humans added new knowledge to the development of the intrahepatic biliary tree, and thereby the formation of the progenitor cell niche. The identification of heterogeneously expressed cell surface proteins and extracellular matrix components provided knowledge of the constituents defining the niche. These pieces of information are important for future isolation and characterization studies of biliary subpopulations and their differentiation abilities in vitro.
journal_name
Dan Med Jjournal_title
Danish medical journalauthors
Vestentoft PSsubject
Has Abstractpub_date
2013-05-01 00:00:00pages
B4640issue
5issn
2245-1919pii
B4640journal_volume
60pub_type
杂志文章,评审abstract:INTRODUCTION:A routine follow-up urine sample (FUS) in the form of a midstream urine sample (MSU) is recommended after treatment for urinary tract infection (UTI) according to the Danish Paediatric Society (DPS) and "Lægehåndbogen" published by Danish Regions. We studied the effect of FUS with a focus on patients witho...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2015-01-01 00:00:00
abstract:INTRODUCTION:Body packing takes advantage of the human storage capacity within the alimentary tract. Body packing is used for the smuggling of drugs such as heroin, cocaine, amphetamine, hashish and ecstasy. Most body packers are asymptomatic. However, packets may rupture or obstruct the alimentary tract. Preventive su...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2013-11-01 00:00:00
abstract:INTRODUCTION:The prevalence of sarcopenia varies extensively depending on the definitions and studied populations. The aim of this study was to assess the prevalence of sarcopenia in a Danish geriatric out-patient population using criteria from the European Working Group on Sarcopenia (EWGSOP). METHODS:Patients referr...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2018-06-01 00:00:00
abstract:INTRODUCTION:Patients' non-attendance is a significant problem in modern healthcare. Non-attendance delays treatment, reduces efficiency and increases healthcare costs. For several years, the introduction of financial incentives such as a non-attendance fee has been discussed in Denmark. Set in the context of a tax-fin...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2016-07-01 00:00:00
abstract:INTRODUCTION:Difficult airway management is associated with an increased risk of morbidity and mortality. Several preoperative risk factors associated with airway management difficulties have been proposed; however, no clear guideline for airway assessments exists. We therefore hypothesised that Danish airway assessmen...
journal_title:Danish medical journal
pub_type: 杂志文章,多中心研究
doi:
更新日期:2016-10-01 00:00:00
abstract::Heart failure is a complex clinical syndrome and one of the leading causes of morbidity and mortality with a prevalence of 1%-2% of the adult population. The prognosis is poor with a 5-year mortality rate of 50%, which partly can be attributed to the presence of concomitant comorbidity, including neurological and psyc...
journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2018-04-01 00:00:00
abstract::Background Asthma is a serious global health issue and the most prevalent chronic disorder among Danish pregnant women. Exacerbations of asthma during pregnancy have been associated with increased risk of adverse pregnancy and perinatal outcomes, and by that making asthma a potential serious medical condition during ...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2017-12-01 00:00:00
abstract:INTRODUCTION:There is no consensus among hip surgeons in Denmark on how to follow up patients after total hip arthroplasty (THA). Agreement on the need for radiographic examinations is also lacking. The purpose of this study was to evaluate if routine outpatient post-operative radiographs, obtained three and 12 months ...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2013-04-01 00:00:00
abstract:INTRODUCTION:Spontaneous reporting of adverse drug reactions (ADRs) is used for continuous risk-benefit evaluation of marketed pharmaceutical products and for signal detection. The Adverse Drug Event Manager (ADEM) is a service offered to clinicians employed at hospitals in the Capital Region of Denmark. The ADEM assis...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2017-01-01 00:00:00
abstract:INTRODUCTION:Knowledge of trauma patients is often based on US studies. However, these may not be representative of the Scandinavian population. Knowing which trauma patients are at risk of dying might help us target and optimise their treatment. The purpose of this study was to examine the epidemiological characterist...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2014-10-01 00:00:00
abstract::Fertility treatment has been associated with obstetrical and perinatal complications. It is, however, uncertain whether fertility treatment or parental subfertility is associated with long-term development of the children. We aimed to assess the growth and mental health of children and adolescents conceived after fert...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2014-10-01 00:00:00
abstract:INTRODUCTION:Reliable dietary information is crucial for measuring the habitual diet of healthy participants and patients with dyslipidaemia and/or coronary heart disease (CHD). Even so, methods are often complicated and time-consuming for everyone involved. We aimed to validate the new food frequency questionnaire (FF...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2018-11-01 00:00:00
abstract::Biological rhythms are essential for the regulation of many life processes. Disturbances of the circadian rhythm are known to affect human health, performance and well-being and the negative consequences are numerous and widespread. Cognitive dysfunction, fatigue, pain, sleep disturbances and mood disorders, such as a...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2014-09-01 00:00:00
abstract::Bariatric surgery (e.g. Roux-en-Y gastric bypass (RYGB)) has proven the most effective way of achieving sustainable weight losses and remission of type 2 diabetes (T2D). Studies indicate that the effectiveness of RYGB is mediated by an altered gastrointestinal tract anatomy, which in particular favours release of the ...
journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2016-11-01 00:00:00
abstract:INTRODUCTION:Despite rehabilitation programmes offered to all patients with newly diagnosed type 2 diabetes in Denmark, a number of patients either never accomplish good diabetes regulation or the regulation deteriorates with time. Therefore, new approaches are needed. The aim of the present study is to examine whether...
journal_title:Danish medical journal
pub_type: 杂志文章,随机对照试验
doi:
更新日期:2013-12-01 00:00:00
abstract:INTRODUCTION:This study explored whether health-related quality of life (HRQOL) changes following Roux-en-Y gastric bypass surgery were associated with identifiable socio-demographic or clinical characteristics, and it examined the impact on health outcomes of changes in the Danish criteria for bariatric surgery. MATE...
journal_title:Danish medical journal
pub_type: 临床试验,杂志文章
doi:
更新日期:2014-07-01 00:00:00
abstract:INTRODUCTION:Pain and distress during minor hospital-related procedures is a familiar problem in many children. Inadequate relief of children's procedural pain and distress not only affects the experience of the children and their parents, but also adversely impacts procedural success. We aimed to review the safety and...
journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2013-06-01 00:00:00
abstract:INTRODUCTION:Our aim was to study the association between pregnant women's referral status for occupational risk assessment, and their risk of preterm delivery (< 37 weeks), low birth weight (LBW) (< 2,500 g) and small for gestational age (SGA). METHODS:In a cohort study, 1,202 deliveries among pregnant women referred...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2015-08-01 00:00:00
abstract:INTRODUCTION:This is a systematic review of existing literature on the diagnostic modalities and treatment of traumatic abdominal wall hernia caused by bicycle handlebar injury in children. METHODS: A systematic literature search was conducted covering incidents involving children below 17 years of age. Data were extr...
journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2018-01-01 00:00:00
abstract:INTRODUCTION:From the clinical forensic examination reports made at the Department of Forensic Medicine, the University of Copenhagen, in 2007 concerning rape, attempted rape and sexual assault (RAS), information about the assault, including both violence and the perpetrator's line of sexual action was extracted, analy...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2014-09-01 00:00:00
abstract::Strategies to reduce the burden of blood pressure attributable diseases require knowledge of secular trend in PBP and its determinants. The issues were investigated in the Copenhagen City Heart Study. The design of CCHS is a repeated measures study. Such designs are uniquely suited to studying changes of an outcome an...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2017-03-01 00:00:00
abstract:INTRODUCTION:The aim of this study was to assess the complication rates of total thyroidectomy in a regional hospital setting in Denmark for permanent hypoparathyroidism, recurrent laryngeal nerve palsy and post-operative bleeding. Furthermore, the long-term outcomes in the management of hypoparathyroidism were investi...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2015-11-01 00:00:00
abstract:INTRODUCTION:Adjuvant treatment of early-stage breast cancer has been associated with bone loss in randomised trials, but evidence from unselected populations is needed. In a single-center study, we assessed the annual percentage change in bone mineral density (∆BMDt) and risk of osteoporosis from two to five years aft...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2020-10-20 00:00:00
abstract:INTRODUCTION:The primary purpose of reconstructive and cosmetic breast surgery is to improve patients' quality of life, and patient-reported outcome measurements are important in outcome assessment of breast surgery. The BREAST-Q questionnaire measures changes in quality of life and patient satisfaction in patients und...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2020-05-01 00:00:00
abstract:INTRODUCTION:Hemithyroidectomy for benign thyroid disease has traditionally been considered an inpatient procedure due to concerns about post-operative complications, in particular the risk of post-thyroidectomy bleeding (PTB). Hemithyroidectomy in an outpatient setting has not yet been evaluated in a Danish context. T...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2020-09-29 00:00:00
abstract:INTRODUCTION:Extant studies on arterial trauma originate from outside Denmark and their findings may therefore not apply to a Danish setting. The aim of the present study was to investigate the long-term mortality and clinical characteristics of patients with arterial trauma treated in Odense University Hospital (OUH)....
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2015-03-01 00:00:00
abstract:INTRODUCTION:Marfan syndrome is an autosomal, dominantly inherited disorder of the connective tissue. We report the clinical data and results of a genetic analysis of a large Danish Marfan family. METHODS:Sanger sequencing of FBN1 was initially performed on genomic DNA from the index patient. Subsequently, four affect...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2014-11-01 00:00:00
abstract:INTRODUCTION:Patient blood management strategies for total hip and knee arthroplasty are controversial. They range from pre-operative haemoglobin optimisation to intra- and post-operative interventions. The aim of this study was to assess the various treatment modalities with respect to blood loss, haemoglobin levels a...
journal_title:Danish medical journal
pub_type: 杂志文章,评审
doi:
更新日期:2015-12-01 00:00:00
abstract:INTRODUCTION:Since 1992 the Danish Patient Insurance Association (DPIA) has been receiving claims from patients who had suffered an injury during examination or treatment in Danish healthcare. We have presently collected more than 85,000 patient cases in our database, which we make accessible to research that can promo...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2013-08-01 00:00:00
abstract:INTRODUCTION:The aim was to illustrate current use of temporary pacing (TP) in Denmark by replicating a questionnaire study from 1986 and to compare the results of the two studies. MATERIAL AND METHODS:The questionnaire was sent to Danish hospitals treating patients with acute myocardial infarction (AMI). To illustrat...
journal_title:Danish medical journal
pub_type: 杂志文章
doi:
更新日期:2012-02-01 00:00:00