Since the certification of the initial “class” of board-certified Pediatric Transplant Hepatologists, 89 certificates have been awarded in our subspecialty as of December, 2012.[112] The Accreditation Council for Graduate Medical Education (ACGME) was then responsible for

establishing the criteria for accreditation of training programs Stem Cell Compound Library cell line in transplant hepatology. This ensured that a variety of educational objectives were in place, along with a curriculum, to allow individuals to become adequately trained and monitored. There are currently five ACGME-certified programs in Pediatric Transplant Hepatology in the US. In my opinion the goals and expectations of the AASLD task force, which had the vision of certification of liver disease specialists, have been met. The end result is a thriving clinical and academic subspecialty that continues to attract the “best and the brightest,” carry out high-quality basic and translational research, buy AUY-922 and use innovative strategies to improve patient care. The certification process ensures that those caring for patients of any age with advanced liver disease possess the necessary

knowledge and training. The latter is governed by the high standards set by the ACGME. Buoyed by the success, the trend of “subspecialization” within the broad field of gastroenterology is viewed as likely to continue.[113] It is still a bit unclear as to the optimal process for training the next generation of transplant hepatologists. It this website has been suggested that the current model of a dedicated year of training in Transplant Hepatology after a 3-year fellowship in gastroenterology may be “unworkable and unsustainable.” [114-116] This additional year of postgraduate training may not be a popular option,

a concern predominantly related to the perceived financial disincentives. One proposal emanating from gastroenterology subspecialty groups suggests that subspecialty training such as Transplant Hepatology be incorporated within the 3-year gastroenterology core fellowship. The endpoints for training and the criteria for credentialing might then focus not on process measurement but on the measurement of actual accomplishments or outcomes—the acquisition of competencies within the field.[114] In fact, pilot programs in Internal Medicine are being established that incorporate specialty specific milestones that trainees must attain as they progress.[114, 117, 118] Of course, the ultimate desired outcome is the quality of care provided to our patients. The lessons for me are enduring—focus, persevere, commit. While times may be different, I recall that Bill Schubert fostered independence and that Alan Hofmann was kind enough to take the time to listen to an unknown young fellow. These traits remain key ingredients to successful mentoring/career development of trainees. I also emphasize to trainees the value of dedicating time to work within a community of like-minded individuals.

In the pivotal study, glycerol phenylbutyrate met its predefined endpoint of noninferiority to NaPBA with respect to ammonia control, assessed as NH3-AUC0–24hr. Consistent with the results of each of the prior two Phase 2 studies, NH3-AUC0–24hr was directionally lower during treatment with glycerol phenylbutyrate and the 24-hour profiles for both blood ammonia concentration and U-PAGN excretion MK-1775 cost were consistent with slow release behavior of glycerol phenylbutyrate.6, 8 Similarities in study design (e.g., study population, efficacy measures, analytical approach) and dosing (PBA mole-equivalent doses of NaPBA and

HPN-100) among protocols UP 1204-003, HPN-100-005, and HPN-100-006 allowed for pooling of data from these studies. In the pooled analysis, NH3-AUC0–24hr was significantly lower during treatment with glycerol phenylbutyrate, a difference that was entirely attributable to better control during late afternoon and overnight hours, when UCD patients might be expected to be particularly vulnerable. These findings were consistent among all predefined subgroups. Furthermore, mean blood ammonia levels remained within the normal range for up to 12 months in both adult and pediatric patients. Glutamine

also tended to be lower on glycerol phenylbutyrate as compared with NaPBA by post-hoc analyses in each study individually and was significantly lower in the pooled analysis. Glutamine not only represents a precursor for PD-1 inhibitor PAGN formation, but it correlates with ammonia control, selleckchem it is often used as a dosing biomarker, and its intracellular accumulation in glial cells is believed to be one of the factors responsible for cerebral edema, a potentially lethal complication in UCD.12, 13, 14 These encouraging biochemical findings in short-term studies were corroborated by the findings in the long-term follow-up studies, which included ∼40% fewer hyperammonemic crises and improvement in executive functioning among pediatric patients, for whom mean fasting ammonia averaged approximately half the ULN. These changes in executive function are of particular interest, as

problems with behavioral regulation, planning, monitoring progress, purposeful problem solving, etc., are known to compromise the day-to-day function of UCD patients including those with normal IQ.3, 4 While necessarily uncontrolled, the absence of change in other neuropsychological test scores during the 12 months of treatment, particularly the CBCL, which is a parent report measure of the child’s functioning in their day-to-day environment, suggests that these improvements in executive function do not represent a placebo response. Moreover, the improvement in executive function while taking GPB suggests that UCD patients exhibit neuropsychological abnormalities that may be reversible with effective treatment.

Pain management in LDs needs to be improved to ensure safety while providing better pain control

with zero tolerance for respiratory events. Disclosures: Deforolimus Robert S. Brown – Consulting: Salix, Janssen, Vertex; Grant/Research Support: Gilead, Merck, Vertex, AbbVie, Salix, Janssen, BI; Speaking and Teaching: Genentech, Gilead, Merck The following people have nothing to disclose: Daniela Ladner, Robert A. Fisher, Elizabeth A. Pomfret, Mary Ann Simpson, Amna Daud, Kathryn Waitzman, John R. Joseph, Donna Woods tumors express less CAR protein than normal liver. Conclusions: TCP rescues mice exposed to SFSS after extended liver resections and liver transplantation. Molecular changes induced by CAR activation act on downstream targets of pathways promoting cell cycle progression (Foxm1b) and uncoupling from organ size control (miR375/YAP) to override the regenerative deficits of marginal liver remnants. Reduced CAR expression in tumors suggests a subset of HCCs may not respond to CAR activation, pointing to a patient group amenable to this treatment. Studies in humanized mice and on ex vivo human liver tissue will address the clinical potential of CAR activation by enhancing liver regeneration after extended resections for primarily unresectable liver tumors. Disclosures: check details The following people have nothing to disclose: Christoph Tschuor, Ekaterina Kachaylo,

Perparim Limani, Amedeo Columbano, Andrea Schlegel, Jae Hwi Jang, Dimitri A. Raptis, Emmanuel Melloul, Yinghua Tian, Rolf Graf, Bostjan Humar, Pierre A. Clavien Background: Resectability selleck chemicals llc of liver tumors is limited since patients left with marginal liver remnants are at risk for developing the Small-for-Size Syndrome (SFSS). SFSS is characterized by an insufficient recovery due to delayed regeneration. Strategies are needed to overcome regenerative limits, rendering large liver tumors resectable. Activation of the constitutive androstane receptor (CAR), a nuclear receptor expressed in the liver, induces liver hyperplasia. We investigated the potential of the CAR agonist TCPOBOP (TCP) to ameliorate experimental SFSS, thereby enabling extended oncological liver resections.

Methods: The effects of TCP on liver regeneration were assessed in four murine models: 68% hepatectomy (Hx) (control), 86% Hx (model of SFSS), 91% Hx (lethal model), and 30% liver transplantation (SFSS transplantation model) in BL6 and CAR-/- mice. Serum bilirubin, ALKP, and albumin served as measures of SFSS-like features. Proliferation-associated molecules, including Foxm1b, p21 and miR375/YAP-dependent pathways were analysed. Functional relevance of the molecules was assessed via siRNA knockdown. Humanized mice and human tissue microarrays (TMA) served for evaluation of the translational potential. Results: Reduced survival in SFSS is associated with deficient regeneration due to deregulation of Foxm1b and YAP/miR375 pathways along with p21 upregulation.

This compound, which corresponds to

the 337.25 m/z band (Fig. 3B), exhibited a modest increment upon UDCA infusion. The instability of GSNO under MS conditions might explain why this band is not predominant in the spectrum. However, Selleck Palbociclib as shown in Fig. 3B, the relative intensity of a 319.24 m/z band (seemingly corresponding to dehydrated GSNO) was manifestly higher in UDCA-stimulated bile versus basal bile. These data support the concept that UDCA infusion induces an increase of GSNO in bile. We also assessed the involvement of glutathione in the transport of NO to bile by determining biliary NO in rats after depleting their livers of glutathione with BSO. As we previously reported,26 UDCA increased hepatic glutathione levels in normal rats (Fig. 4A). However, in rats that received BSO, liver glutathione was markedly reduced, regardless of UDCA administration (Fig. 4A). An analysis of UDCA in bile from UDCA-infused normal rats and BSO-treated rats showed that biliary UDCA secretion was similar in both situations (Supporting Fig. 2), and this indicates

that the secretion of UDCA to bile is not prevented in the absence of glutathione. In contrast, the secretion of NO species after UDCA infusion does depend on glutathione, as it was virtually abolished in BSO-treated animals (Fig. 4B), even though their hepatic NOS activity was increased Fer-1 chemical structure to levels similar to those found in UDCA-infused normal rats (data not shown). These findings are consistent with the notion that glutathione has a major role as a carrier for the transport of NO to bile. Glutathione and glutathione conjugates are known to be secreted at the canaliculi through the ABCC/Mrp2 pump. Therefore, we performed UDCA infusion experiments in TR− rats, which exhibit defective canalicular transport of those

compounds because of an ABCC2 mutation.27 In these animals, the levels of biliary glutathione fall 3 logs with respect to normal values, but the compound is still secreted to bile in the micromolar range.28 As shown in Fig. 5A,B, UDCA-infused TR− rats exhibited a significant decrease in both the concentration and biliary output of NO species in comparison with UDCA-infused normal rats. The increment in biliary NO secretion upon UDCA infusion in TR− rats was less than half of that observed in normal animals selleck (P < 0.05; see the inset in Fig. 5B). In the mutant rats, the levels of both total SNOs and LMw-SNOs increased after UDCA administration, but the values were about one-third of those observed in UDCA-treated normal rats (Supporting Fig. 3). These findings indicate that the glutathione carrier ABCC2/Mrp2 contributes at least partially to biliary NO secretion and provide further support for a role of glutathione as a vehicle for the transport of NO along the biliary tree. To determine whether GSNO could play a role in stimulating ductal secretion in vivo, we performed a retrograde infusion of 150 μL of 250 μM GSNO through the common bile duct in the isPRL model.

However, GW182, a critical component of processing bodies (GW bodies) that is recruited by Ago2 to target messenger RNA (mRNA), has not been assessed in HCV

infection. To characterize the role of GW182 in the pathogenesis of HCV infection, we determined its transcription and protein expression in an HCV J6/JFH1 RG7204 in vivo culture system. Transcript and protein levels of GW182 as well as HCV RNA and protein expression increased with alcohol exposure. Specific silencing of mRNA expression by small interfering RNA against GW182 significantly decreased HCV RNA and protein expression. Overexpression of GW182 significantly increased HCV RNA and protein expression in HCV J6/JFH1 infected Huh7.5 cells. Furthermore, GW182 colocalized and coimmunoprecipitated with heat shock protein 90 (HSP90), which increased upon alcohol exposure with and without HCV infection

and enhanced HCV gene expression. The use of an HSP90 inhibitor or knockdown of HSP90 decreased GW182 and miR-122 expression and significantly reduced HCV replication. Conclusion: Overall, our results suggest that GW182 protein that is linked to miR-122 biogenesis and HSP90, which has been shown to stabilize the RISC, are novel host proteins selleck chemicals that regulate HCV infection during alcohol abuse. (HEPATOLOGY 2013) Hepatitis C virus (HCV) is estimated to infect at least 2%-3% of the world’s population. Despite clinical observation

and medical advice regarding the devastating consequence of alcohol use during HCV infection, some patients consume alcohol with the increased risk of rapid disease progression to liver cirrhosis, fibrosis, and even hepatocellular carcinoma.1-6 The molecular mechanisms of how alcohol exacerbates HCV infection and worsens HCV disease outcome remain to be elucidated. HCV, a positive-sense RNA virus of the Flaviviridae family, can hijack host cofactors to facilitate its replication. Of those, microRNA-122 (miR-122), an miRNA representing 70% of all miRNAs in hepatocytes,7, 8 was recently identified to play a critical role in the HCV life cycle9-11 and has been a promising target for antiviral drug development.12 Several groups, including ours, have demonstrated that ethanol can modulate microRNA expression in selleck chemicals llc the liver.13-16 Traditionally, miRNAs function by binding to the 3′ untranslated region (UTR) of target genes suppressing gene transcription and translation. However, miR-122 binds to the 5′ UTR of the viral genome promoting HCV replication.9, 17, 18 It is unknown whether miR-122 regulation of HCV RNA translation or RNA accumulation requires direct association with protein complexes similar to the miRNA-induced silencing complex, or if the activity of miR-122 involves HCV RNA translocation to messenger RNA (mRNA)-processing bodies (P-bodies).

The core promoter dictates the expression of the HBV e antigen, core

protein, and DNA polymerase. The X promoter controls the transcription of the X RNA. After its synthesis, the core protein packages the core RNA, which is larger than the genome size and is also known as the pregenomic RNA (pgRNA), to form the core particle. The pgRNA then serves as the template to direct the synthesis of the partially double-stranded viral DNA genome, using the viral DNA polymerase that is also packaged. The core RNA plays a pivotal role in the HBV life cycle and its increased expression has been shown to enhance viral replication.3, 4 The identification of host factors that interact with the HBV DNA genome has made significant contributions to our understanding of mechanisms that regulate HBV gene

expression. Indeed, both liver-enriched and ubiquitous transcription factors, such as hepatocyte Palbociclib price nuclear factor 1 (HNF1), HNF3, HNF4, CCAAT enhancer-binding protein (C/EBP), chicken ovalbumin upstream promoter transcription factor (COUP-TF), nuclear transcription factor Y (NF-Y), and specificity protein 1 (Sp1), have been shown to regulate the expression Etoposide cell line of the S and C genes.5-13 The liver specificity of the preS1 promoter, the major surface promoter, and the core promoter is attributed to the need of liver-enriched transcription factors for their activities.10, 14-18 In this study, we used a yeast one-hybrid screen to identify additional transcription factors that could activate the major surface promoter. Using cDNA libraries prepared from the human hepatoma cell line, Huh7, and mouse liver, we identified several selleck members of the Krüppel-like factor (KLF) family as potential activators of the surface promoter (T. Tan and T.S.B. Yen, unpublished

data). KLF family members are characterized by their three carboxy-terminal C2H2 zinc fingers and share a high degree of homology with Sp1-like proteins. At least 21 Sp1/KLF proteins have been identified in the human genome. They have highly conserved DNA-binding domains, but show significant variations in the transactivation domain in their amino terminus.19, 20 Krüppel-like factor 15 (KLF15) has been shown to regulate the expression of a number of genes involved in many aspects of physiological homeostasis, including glucose uptake and adipogenesis.21-25 Moreover, KLF15 is highly expressed in the human liver.25 These observations led us to hypothesize that KLF15 might be a potential activator for HBV gene expression. Indeed, our results indicate that KLF15 can activate the expression of the HBV S and C genes both in vitro and in vivo. Our results thus uncovered previously unrecognized functions of KLF15 in HBV gene expression.

pylori R-M systems. “
“Elastography point quantification (ElastPQ) was a newly non-invasive method for the assessment GDC-0449 order of liver fibrosis by measuring liver stiffness. We aimed at evaluating the reproducibility of ElastPQ technology in the determination of liver stiffness and to investigate the value of ElastPQ in liver fibrosis staging among chronic hepatitis B patients. A total of

291 successive patients who underwent liver partial hepatectomy or biopsy were examined with the ElastPQ technology for the measurement of liver stiffness. Ten ElastPQ measurements were obtained in the right lobe of the liver through the seventh to the tenth intercostal space for every patient. The reproducibility of ElastPQ technology was analyzed with intraclass correlation (ICC) of reliability analysis. Comparing the median of 10 measurements of ElastPQ with liver fibrosis, necroinflammatory activity, and steatosis pathologically, as well as gender and age, potential factors affecting liver stiffness were explored by multiple linear regression analysis, and the performances of ElastPQ were evaluated with repeated measures anova and receiver operating characteristic (ROC) curve. The ICC of 10 measurements of liver stiffness with ElastPQ technique was 0.798, which indicated a good reproducibility.

Liver fibrosis and necroinflammatory activity were positively correlated with ElastPQ (P = 0.00, 0.01 < 0.05) while other factors had no effect on ElastPQ. There was significant difference of ElastPQ between S1 (5.60 ± 2.55 kPa)

check details and S2 (7.44 ± 3.43 kPa) (P = 0.01 < 0.05), and S3 (8.71 ± 3.14 kPa) and S4 (10.87 ± 5.25 kPa) (P = 0.01 < 0.05). The area under the ROC curve was 0.94 (6.99 kPa, the optimal cut-off value) for ElastPQ measured selleck kinase inhibitor with ElastPQ between S0–1 and S2–3, 0.89 (9.00 kPa) for ElastPQ between S2–3 and S4. ElastPQ is a valid and reproducible non-invasive technology in liver stiffness measurement among chronic hepatitis B patients. The stage of liver fibrosis and the grade of necroinflammatory activity are associated with values of ElastPQ while liver fibrosis is the dominating factor affecting liver stiffness measured by ElastPQ. “
“Interleukin 2 receptor antagonists (IL-2Ra) are frequently used as induction therapy in liver transplant recipients to decrease the risk of acute rejection while allowing the reduction of concomitant immunosuppression. We conducted a systematic review of prospective, controlled studies to test the hypothesis that the use of IL-2Ra is associated with a decrease in acute rejection and/or a decrease in the side effects of concomitant medication. We performed a search of all major databases and secondary sources from inception to December 2010. Random effects models were used to assess the incidence of acute rejection, graft loss, patient death, and adverse side effects, with or without IL-2Ra.

Con-focal microscopy and PLA of co-stained LHBs and CK8/18 in Huh7 expressing LHBs confirmed their colocalization. An interaction of LHBs with CK8/18 was seen by SPR technique. CK18 transfection in NIH3T3 expressing LHBs prevented the formation of large LHBs aggregates and led to a finely distributed LHBs pattern and strong colocalization with CK18. Contrarily, CK18-knockdown by RNAi caused perinuclear aggregates of CK and LHBs in Huh7 expressing LHBs. Treatment

of PTHs with Oka led to an increase in the infection rate by about two-fold, whereas no effect of Oka on HBsAg secretion could be seen in already HBV-infected PTHs. Conclusion: CK 8 and 18 are responsible for intracellular distribution of LHBs and might be relevant for HBV infectivity. These new findings might be relevant for new therapeutic options in HBV therapy. Disclosures: The following people have nothing to disclose: Martin Roderfeld, MK-1775 concentration Dirk Schroder, Yury Churin, Dieter Glebe, Elke Roeb Background: Viral infection activates innate immune receptors that promote interferon secretion. Interferon, in turn, triggers up-regulation of hundreds of interferon Selleck Dasatinib stimulated genes (ISGs) that establish a broad antiviral state hostile to viral replication. Examination of the role of interferon signaling and early innate immune responses in hepatitis B virus (HBV) has been impeded by the

difficulty of infecting cultured human hepatocytes. Methods: To overcome this limitation, we prepared fresh primary culture from livers of uPA-SCID mice transplanted with human hepatocytes, click here which enabled us to establish robust HBV infection. Cultures were inoculated

with high titer serum samples from a patient with chronic HBV infection, and changes in mRNA and miRNA expression were assayed by microarray and real time PCR. Protein profiles were analyzed by 2-D elec-trophoresis and mass spectrography. Results: HBV replicated in hepatocytes seeded at high density, but replication rates diminished at progressively lower cell densities. HBV infection induced expression of ISGs in primary cultured hepatocytes, including up-regulation of cytokines such as IL-8 and acute reactant proteins such as SAA1 and SAA2. Analysis of protein profiles also showed ISG up-regulation. To determine why cell dilution resulted in decreased HBV replication, we compared up and down regulated genes and proteins by microarray analysis and protein 2-D electrophoresis. Genes expected to be important for HBV infection and replication such as NTCP were down regulated by cell dilution. Some ISGs, such as MxA, were up-regulated during HBV infection, although conclusions from protein analysis were limited. Reduced cell density down-regulated factors involved in cell polarization and hepatocyte-specific activities, especially among HNF4a and PPARG-regulated genes. Conclusions: HBV infection is detected by hepatocytes and leads to robust ISG activation in primary cultured hepatocytes.

Con-focal microscopy and PLA of co-stained LHBs and CK8/18 in Huh7 expressing LHBs confirmed their colocalization. An interaction of LHBs with CK8/18 was seen by SPR technique. CK18 transfection in NIH3T3 expressing LHBs prevented the formation of large LHBs aggregates and led to a finely distributed LHBs pattern and strong colocalization with CK18. Contrarily, CK18-knockdown by RNAi caused perinuclear aggregates of CK and LHBs in Huh7 expressing LHBs. Treatment

of PTHs with Oka led to an increase in the infection rate by about two-fold, whereas no effect of Oka on HBsAg secretion could be seen in already HBV-infected PTHs. Conclusion: CK 8 and 18 are responsible for intracellular distribution of LHBs and might be relevant for HBV infectivity. These new findings might be relevant for new therapeutic options in HBV therapy. Disclosures: The following people have nothing to disclose: Martin Roderfeld, Selleck Ganetespib Dirk Schroder, Yury Churin, Dieter Glebe, Elke Roeb Background: Viral infection activates innate immune receptors that promote interferon secretion. Interferon, in turn, triggers up-regulation of hundreds of interferon find more stimulated genes (ISGs) that establish a broad antiviral state hostile to viral replication. Examination of the role of interferon signaling and early innate immune responses in hepatitis B virus (HBV) has been impeded by the

difficulty of infecting cultured human hepatocytes. Methods: To overcome this limitation, we prepared fresh primary culture from livers of uPA-SCID mice transplanted with human hepatocytes, click here which enabled us to establish robust HBV infection. Cultures were inoculated

with high titer serum samples from a patient with chronic HBV infection, and changes in mRNA and miRNA expression were assayed by microarray and real time PCR. Protein profiles were analyzed by 2-D elec-trophoresis and mass spectrography. Results: HBV replicated in hepatocytes seeded at high density, but replication rates diminished at progressively lower cell densities. HBV infection induced expression of ISGs in primary cultured hepatocytes, including up-regulation of cytokines such as IL-8 and acute reactant proteins such as SAA1 and SAA2. Analysis of protein profiles also showed ISG up-regulation. To determine why cell dilution resulted in decreased HBV replication, we compared up and down regulated genes and proteins by microarray analysis and protein 2-D electrophoresis. Genes expected to be important for HBV infection and replication such as NTCP were down regulated by cell dilution. Some ISGs, such as MxA, were up-regulated during HBV infection, although conclusions from protein analysis were limited. Reduced cell density down-regulated factors involved in cell polarization and hepatocyte-specific activities, especially among HNF4a and PPARG-regulated genes. Conclusions: HBV infection is detected by hepatocytes and leads to robust ISG activation in primary cultured hepatocytes.

These CD49fHCD41H FL cells respond to ADP and thrombin stimulation, rapidly XL765 order differentiating in vitro, as described for embryonic MEPs in semisolid assays.5, 6 Indeed, after 24 hours in culture, cytoplasmic elongations develop and proplatelets are generated in a process dependent upon the reorganization of the actin cytoskeleton, similar to that described in mature MKs.8, 22 Our observation that proplatelets are present in vivo under physiological conditions in isolated cellular FL preparations is particularly

relevant until, as recently, proplatelet development by MKs was demonstrated to occur in vivo after TPO treatment.23 The CD49fHCD41H MKPs found in the FL represent a potential source of pure MKPs that are readily isolated by FACS or immunomagnetic methods, in contrast to the BM clonogenic MK population that is relatively small.4, 16 As observed in adult BM MKs, c-KitDCD49fHCD41H cells from E11.5 FL express several integrin receptors. The engagement of α4β1, and not αVβ3, has been proposed to enhance TPO-induced megakaryopoiesis.24 In FL c-KitDCD49fH CD41H cells, we observed weaker

α4 expression in relation to the αV chain, which may be related to the TPO-independent maturation of these cells in vitro. This observation is consistent with learn more findings from c-Mpl-deficient mice, in which MK generation occurs in a TPO-independent manner before E9.5 in the YS and before E14.5 in the FL.6, 25 The α6 integrin chain (CD49f) associates with either β1 (CD29) or β4 (CD104) integrin chains to form receptors for laminin and kalininis, respectively, and has been implicated in adhesion and in vivo homing. This chain is expressed by HSCs and myeloid progenitors in E14.5 FL and BM,26 among other cells, and by MKs and platelets generated in vitro.27 However, to the best of our knowledge, CD49f has

not commonly been associated with MKs ex vivo. In contrast to the adult BM MK-lineage cells (including selleck inhibitor mature MKs) and other embryonic myeloid cells, embryonic CD49fHCD41H MKPs do not express the hematopoietic marker (CD45). Several of the cell-surface markers presented by the CD49fHCD41H MKPs present in the FL at E11.5 differ from those in other hematopoietic niches (manuscript in preparation). Specifically, these cells express endothelial and hepatoepithelial proteins, the latter probably being taken up by endocytosis in the liver (where they would be produced by the HeP), because CD49fHCD41H MKPs appear to only weakly or not at all express HNF-1, HNF-4α, and HNF-3β. Similarly, most CD49fHCD41H MKPs are Dlk−CD13−, indicating that they are not liver stem/progenitor cells. The possible relationship between the few CD49fHDlk+ cells and the more-abundant CD49fD Dlk+CD13+ cells will require further analysis.