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1.
Following a report of skeletal muscle regeneration from bone marrow cells, we investigated whether hepatocytes could also derive in vivo from bone marrow cells. A cohort of lethally irradiated B6D2F1 female mice received whole bone marrow transplants from age-matched male donors and were sacrificed at days 1, 3, 5, and 7 and months 2, 4, and 6 posttransplantation (n = 3 for each time point). Additionally, 2 archival female mice of the same strain who had previously been recipients of 200 male fluorescence-activated cell sorter (FACS)-sorted CD34(+)lin(-) cells were sacrificed 8 months posttransplantation under the same protocol. Fluorescence in situ hybridization (FISH) for the Y-chromosome was performed on liver tissue. Y-positive hepatocytes, up to 2.2% of total hepatocytes, were identified in 1 animal at 7 days posttransplantation and in all animals sacrificed 2 months or longer posttransplantation. Simultaneous FISH for the Y-chromosome and albumin messenger RNA (mRNA) confirmed male-derived cells were mature hepatocytes. These animals had received lethal doses of irradiation at the time of bone marrow transplantation, but this induced no overt, histologically demonstrable, acute hepatic injury, including inflammation, necrosis, oval cell proliferation, or scarring. We conclude that hepatocytes can derive from bone marrow cells after irradiation in the absence of severe acute injury. Also, the small subpopulation of CD34(+)lin(-) bone marrow cells is capable of such hepatic engraftment.  相似文献   

2.
目的 验证骨髓细胞是否可以转化为肝细胞。方法 通过放射致死剂量照射的BALB/C雌性小鼠接受周龄相配的同系雄性小鼠的全骨髓移植后,分别在移植后1,2,4周和2个月分批处死移植存活的小鼠。分别在游离的肝细胞和肝脏的石蜡切片上用荧光原位杂交法检测Y染色体阳性肝细胞。结果 在移植后2个月的小鼠肝脏游离细胞和石蜡切片上均发现有Y染色体阳性肝细胞,数量极少,但确实存在。结论 在接受放射致死剂量照射但没有导致严重的急性肝脏损伤情况下,骨髓细胞可以转化为成熟的肝细胞。  相似文献   

3.
OBJECTIVE: To investigate whether hepatocytes can be derived from bone marrow cells in vivo. METHODS: A cohort of lethally irradiated BALB/C female mice received whole bone marrow transplants from age‐matched male donors and were killed at 1, 2, 4 and 8 weeks post transplantation. Fluorescence in situ hybridization (FISH) for the Y‐chromosome was performed using liver tissue. RESULTS: A few Y‐chromosome positive hepatocytes were found in the liver tissues at 2 months post transplantation. CONCLUSION: Hepatocytes can be derived from bone marrow cells after transplantation in lethally irradiated mice without severe acute hepatic injury.  相似文献   

4.
BACKGROUND AND AIM: Recent studies indicated that hepatic stem cells in the bone marrow could differentiate into mature hepatocytes, suggesting that bone marrow cells could be used for replacement of damaged hepatocytes in a variety of liver diseases. Hepatocellular carcinoma (HCC) is thought to arise from hepatic stem cells. In this study, we investigated the malignant potential of hepatic stem cells derived from the bone marrow in a mouse model of chemical hepatocarcinogenesis. METHODS: Bone marrow cells were obtained from the male beta-galactosidase (beta-gal) transgenic mouse and transplanted into female recipient mice. Hepatocarcinogenesis was induced by a year of treatment with diethylnitrosamine and phenobarbital (NDEA/PB). One year later, the liver was removed from each treated mouse and evaluated by x-gal staining, immunohistochemistry, and fluorescence in situ hybridisation (FISH). RESULTS: Forty per cent of recipient mice survived and developed multiple HCC. Clusters of beta-gal positive mature hepatocytes were detected sporadically in the entire liver of NDEA/PB treated mice who underwent bone marrow transplantation (BMT) with while no such hepatocytes were identified in the liver of BMT mice that were not treated with NDEA/PB. The Y chromosome was detected with the same frequency as the donor male liver in clusters of beta-gal positive mature hepatocytes by FISH. However, no HCC was positive for beta-gal or the Y chromosome. Immunohistochemically, beta-gal positive mature hepatocytes did not express CD34 or alpha-fetoprotein. CONCLUSIONS: Our results suggest that hepatic stem cells derived from the bone marrow have low malignant potential, at least in our model.  相似文献   

5.
The bone marrow contains stem cells that have the potential to differentiate into a variety of organ-specific mature cells, including the liver and the pancreas. Recently, the origin of hepatic progenitors and hepatocytes was identified to be the bone marrow. However, evidence that describes which cells, among all bone marrow cells, differentiate into hepatocytes, has not yet been presented. Based on recent reports, hematopoietic and hepatic stem cells share characteristic markers such as CD34, c-kit, and Thy1. In particular, both hematopoietic and hepatic stem cells express the Thy1 antigen. We investigated whether rat Thy1-positive bone marrow cells express liver-specific genes in vitro, and whether transplanted Thy1 BM cells differentiate into mature hepatocytes in vivo. For collection of Thy1 cells from bone marrow, FITC-conjugated anti-Thy1.1 monoclonal antibody was used with a Fluorescence-Activated Cell Sorter system. A coculture system of 2 separate layers was used for culture of Thy bone marrow cells. Cultured Thy1 cells expressed albumin protein, which was analyzed by immunofluorescent staining. Thy1 bone marrow cells obtained from wild-type dipeptidyl peptidase IV (DPPIV(+)) male rat were directly transplanted into the injured liver of DPPIV mutant (DPPIV(−)) Fisher 344 female rats and differentiated into mature hepatocytes in recipient liver on 60 days. Donor-derived hepatocytes were confirmed by DPPIV staining and Y-chromsome in situ hybridization. Our results suggest that Thy1-positive bone marrow cells have the potential to generate liver-specific genes in vitro and can differentiate into mature hepatocytes in adult liver in vivo. Thy1-positive bone marrow stem cells may represent preexisting hepatocyte-specific stem cells.  相似文献   

6.
Langerhans cells (LC) are bone marrow-derived dendritic antigen-presenting cells found in the epidermis. In an effort to determine the origin (host versus donor) of LC at different intervals following bone marrow transplantation, we performed skin biopsies in 16 recipients of sex-mismatched marrow. LC were identified using monoclonal antibody OKT6 in an indirect immunoperoxidase assay and their donor or host origin determined according to the presence or absence of Y body. The presence of Y-positive (donor) LC could be demonstrated in all (6/6) skin biopsies of female recipients of male marrow tested between days 39 and 730 post-transplant. Persistence of host LC in male recipients of female marrow was documented in all (6/6) recipients studied on day 39 and in two out of seven patients tested on day 120 post-transplant. From day 365 onward, no residual host LC could be detected, suggesting that by this time all epidermal LC are donor-derived. Our study demonstrates that host LC usually persist for 39 and up to 120 d following bone marrow transplantation. The relevance of this observation to the possible role of LC and other host dendritic antigen-presenting cells in the graft-versus-host reaction is discussed.  相似文献   

7.
Transplanted bone marrow generates new neurons in human brains   总被引:58,自引:0,他引:58  
Adult bone marrow stem cells seem to differentiate into muscle, skin, liver, lung, and neuronal cells in rodents and have been shown to regenerate myocardium, hepatocytes, and skin and gastrointestinal epithelium in humans. Because we have demonstrated previously that transplanted bone marrow cells can enter the brain of mice and differentiate into neurons there, we decided to examine postmortem brain samples from females who had received bone marrow transplants from male donors. The underlying diseases of the patients were lymphocytic leukemia and genetic deficiency of the immune system, and they survived between 1 and 9 months after transplant. We used a combination of immunocytochemistry (utilizing neuron-specific antibodies) and fluorescent in situ hybridization histochemistry to search for Y chromosome-positive cells. In all four patients studied we found cells containing Y chromosomes in several brain regions. Most of them were nonneuronal (endothelial cells and cells in the white matter), but neurons were certainly labeled, especially in the hippocampus and cerebral cortex. The youngest patient (2 years old), who also lived the longest time after transplantation, had the greatest number of donor-derived neurons (7 in 10,000). The distribution of the labeled cells was not homogeneous. There were clusters of Y-positive cells, suggesting that single progenitor cells underwent clonal expansion and differentiation. We conclude that adult human bone marrow cells can enter the brain and generate neurons just as rodent cells do. Perhaps this phenomenon could be exploited to prevent the development or progression of neurodegenerative diseases or to repair tissue damaged by infarction or trauma.  相似文献   

8.
The plasticity of bone marrow has been confirmed by the analysis of autopsy findings in female recipients of bone marrow cells transplanted from male donors. To establish new clinical cell therapies using autologous bone marrow cells for patients with liver failure, we developed a new in vivo model, the “green fluorescent protein (GFP)/carbon tetrachloride (CCl4) model”. Using the GFP/CCl4 model, we found that transplanted Liv8-negative cells efficiently repopulated into cirrhotic liver tissue and trans-differentiated into albumin-producing hepatocytes under conditions of persistent liver damage induced by CCl4. Moreover, one marrow cell transplantation into liver cirrhosis mice improved their liver function, ameliorated liver fibrosis, and improved their survival rate. Results from the GFP/CCl4 model showed that cell therapy using autologous bone marrow cells has the potential to become an effective treatment for patients with liver failure. Here we describe the findings from the GFP/CCl4 model and the scope of the translational research project.  相似文献   

9.
AIM:To investigate the malignant potential of hepatic stem cells derived from the bone marrow stromal cells (BMSCs) in a mouse model of chemical hepatocarcinogenesis.
METHODS:BMSCs from male BALB/c mice were harvested and cultured, then transplanted into female syngenic BALB/ c mice via portal vein. Hepato-carcinogenesis was induced by 6 mo of treatment with diethylnitrosamine (DEN). Six months later, the liver was removed from each treated mouse and evaluated by immunohistochemistry and fluorescence in situ hybridization (FISH).
RESULTS:Twenty-six percent of recipient mice survived and developed multiple hepatocellular carcinomas (HCCs). Immunohistochemically, HCC expressed placental form of glutathione-S-transferase (GST-P) and α-fetoprotein, but did not express cytokeratin 19. Y chromosome positive hepatocytes were detected by fluorescent in situ hybridization (FISH) in the liver of mice treated with DEN after BMSCs transplantation while no such hepatocytes were identified in the liver of mice not treated with DEN. No HCC was positive for the Y chromosome by FISH.
CONCLUSION:Hepatic stem cells derived from the bone marrow stromal cells have a low malignant potential in our mouse model of chemical hepatocarcingenesis.  相似文献   

10.
AIM: To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis (PBC).METHODS: Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsies from disease controls [3 patients with hepatitis B (HBV) virus, 3 patients with hepatitis C virus (HCV), 3 patients with non-alcoholic steatohepatitis and 3 patients with acute alcoholic hepatitis (AAH)]. As healthy controls, we used tissue specimens adjacent to metastatic liver adenocarcinoma. Normal serum was taken from staff members of the unit. The determination of the cell type targeted by autoantibodies present in the patients sera was performed by indirect immunofluorescence (IIF) analysis using paraffin-embedded liver sections as a substrate. Sera from homologous or heterologous PBC patients or sera from the disease control group were used as primary antibodies. The presence of autoantibodies was identified using confocal microscopy.RESULTS: In total, 18/21 (85.7%) PBC patients exhibited positive staining in the sinusoidal cells, 10/21 (47.6%) in lymphocytes, 8/21 (38%) in cholangiocytes and 7/21 (33.3%) in hepatocytes, when homologous serum and fluorescein isothiocyanate-conjugated immunoglobulin type G (IgG) secondary antibody were used. PBC sections incubated with heterologous PBC serum showed reduced staining (20% for sinusoidal cells, 20% for lymphocytes, 20% for cholangiocytes and 13.3% for hepatocytes). When IgM immunoglobulin, instead of IgG, was used as secondary antibody, positive staining was observed in 75% of lymphocytes, 62.5% of cholangiocytes, 37.5% of hepatocytes and 50% of the sinusoidal cells with a much stronger staining intensity. No staining was observed when either normal or PBC sera were used as a primary antibody on liver sections from the disease control group. When PBC sera were incubated with healthy control sections, weak positive staining of cholangiocytes was observed in 3/21 (14.3%) PBC serum samples. Steatohepatitis serum on PBC sections gave a positive staining of some hepatocytes and lymphocytes but no staining on viral hepatitis sections. Incubation with HBV sera stained some hepatocytes, cholangiocytes and intra-sinusoidal or portal lymphocytes of PBC, HBV and AAH patients but not HCV patients.CONCLUSION: In this study, for the first time in diseased liver tissue, we have demonstrated that a large proportion of PBC patients have disease specific autoantibodies against liver sinusoidal cells.  相似文献   

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