Upregulation of AKR1C1 in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells.

The leukaemic bone marrow microenvironment, comprising abnormal mesenchymal stromal cells (MSCs), is responsible for the poor prognosis of acute myeloid leukaemia (AML). Therefore, it is essential to determine the mechanisms underlying the supportive role of MSCs in the survival of leukaemia cells. Through in silico analyses, we identified a total of 271 aberrantly expressed genes in the MSCs derived from acute myeloid leukemia (AML) patients that were associated with adipogenic differentiation, of which aldo-keto reductase 1C1 (AKR1C1) was significantly upregulated in the AML-MSCs. Knockdown of AKR1C1 in the MSCs suppressed adipogenesis and promoted osteogenesis, and inhibited the growth of co-cultured AML cell lines compared to the situation in wild- type AML-derived MSCs. Introduction of recombinant human AKR1C1 in the MSCs partially alleviated the effects of AKR1C1 knockdown. In addition, the absence of AKR1C1 reduced secretion of cytokines such as MCP-1, IL-6 and G-CSF from the MSCs, along with inactivation of STAT3 and ERK1/2 in the co-cultured AML cells. AKR1C1 is an essential factor driving the adipogenic differentiation of leukaemic MSCs and mediates its pro-survival effects on AML cells by promoting cytokine secretion and activating the downstream pathways in the AML cells.

ATG5 regulates mesenchymal stem cells differentiation and mediates chemosensitivity in acute myeloid leukemia.

Autophagy is related to the development of several tumors including acute myeloid leukemia (AML). Inhibition of autophagy in AML cells can make them more susceptible to chemotherapy. However, the influence of autophagy in mesenchymal stem cells (MSCs) remains inconclusive. In the present study, we demonstrated that the expression of ATG5 and autophagy were elevated in MSCs derived from AML patients (AML-MSCs) compared to healthy donors (HD-MSCs). After inhibiting autophagy by 3-Methyladenine (3 MA) or silencing ATG5, the differentiation potential of AML-MSCs was decreased, the fraction of G0/G1 phase was increased while that of G2 phase was reduced, and the expression of CXCL12 was reduced in AML-MSCs. After co-culture of NB4 and THP1 with MSCs pretreated with 3 MA or ATG5 knockdown respectively, the sensitivity of AML cell lines to daunorubicin and doxorubicin was improved in a dose- and time-dependent manner compared to controls. The increased sensitivity of AML cells to genotoxic agents was related to ERK1/2 and AKT pathway. These results suggested ATG5 mediated potential differentiation capacities and cell cycle distribution of AML-MSCs, and targeting autophagy, especially ATG5 in AML-MSCs could improve the chemosensitivity of AML.

Interleukin-1ß inhibits normal hematopoietic expansion and promotes acute myeloid leukemia progression via the bone marrow niche.

Enhanced interleukin-1ß (IL-1ß) signaling is a common event in patients with acute myeloid leukemia (AML). It was previously demonstrated that chronic IL-1ß exposure severely impaired hematopoietic stem cell (HSC) self-renewal capability in mice and promoted leukemia cell growth in primary AML cells. However, the role of IL-1ß in the murine bone marrow (BM) niche remains unclear. Here, we explored the role of IL-1ß in the BM niche in Il-1r1-/- mice, chronic IL-1ß exposure mice and mixed lineage leukemia-AF9 fusion gene (MLL-AF9)-induced AML mice models. We demonstrated that IL-1R1 deficiency did not affect the function of HSCs or niche cells under steady-state conditions or during transplantation. Chronic exposure to IL-1ß decreased the expansion of Il-1r1-/- hematopoietic cells in Il-1r1+/+ recipient mice. These results indicated that IL-1ß exposure impaired the ability of niche cells to support hematopoietic cells. Furthermore, we revealed that IL-1R1 deficiency in niche cells prolonged the survival of MLL-AF9-induced AML mice. The results of our study suggest that inhibition of the IL-1ß/IL-1R1 signaling pathway in the niche might be a non-cell-autonomous therapy strategy for AML.

CXCL8 derived from mesenchymal stromal cells supports survival and proliferation of acute myeloid leukemia cells through the PI3K/AKT pathway.

The role of proinflammatory cytokines secreted by the bone marrow mesenchymal stromal cells (BM-MSCs) in the progression of acute myeloid leukemia (AML) is poorly understood. We compared C-X-C motif chemokine ligand (CXCL)8 expression levels in the BM-MSCs of patients with AML and normal control subjects and detected significantly higher levels in the former. Furthermore, CXCL8 was up-regulated in cocultures of BM-MSCs and leukemic cell lines compared with either monoculture. CXCL8 expression was significantly higher in MSCs compared with mononuclear cells in patients with de novo AML. To elucidate the function of paracrine CXCL8 in AML, we blocked CXCL8 binding to the C-X-C motif chemokine receptor (CXCR)2 in the AML cells using SB225002. Inhibition of CXCL8/CXCR2 binding decreased proliferation in the AML cells by inducing cell cycle arrest at the G0/G1 phase and apoptosis via decreased AKT phosphorylation. Blocking the PI3K/AKT signaling pathway by a specific inhibitor induced similar apoptosis induction and lower proliferation, suggesting that the PI3K/AKT signaling pathway was also involved in CXCL8 action. Taken together, our findings demonstrate that BM-MSCs are the main source of CXCL8 in the AML bone marrow microenvironment and promote leukemogenesis via the PI3K/AKT signaling pathway, indicating a novel therapeutic target.-Cheng, J., Li, Y., Liu, S., Jiang, Y., Ma, J., Wan, L., Li, Q., Pang, T. CXCL8 derived from mesenchymal stromal cells supports survival and proliferation of acute myeloid leukemia cells through the PI3K/AKT pathway.

CXCL8 is associated with the recurrence of patients with acute myeloid leukemia and cell proliferation in leukemia cell lines.

Acute myeloid leukemia (AML) blasts release a wide range of chemokines in which CXCL8 has recently been recognized to be important for tumor progression. To find out the function of CXCL8 in AML, we compared blood serum of AML patients and healthy donors and found that the average level of CXCL8 was higher in AML patients. Among patients, higher expression of CXCL8 was also a positive recurrence indicator which illustrated the critical role of CXCL8 in AML. Knocking down of CXCL8 in leukemic cell lines led to significant reduction of proliferation via inducing G0/G1 cell cycle arrest and apoptosis, which was accompanied by the inactivation of ERK1/2. Furthermore, inhibition of ERK1/2 by specific chemical inhibitors reconstructed the CXCL8 knocking down phenomenon. Overall, we demonstrated that expression level of CXCL8 had a positive relationship with recurrence probability in AML. And CXCL8 was strongly implicated in AML cells growth by activating the ERK1/2 signal pathway.

CIAPIN1 targets Na⁺/H⁺ exchanger 1 to mediate MDA-MB-231 cells' metastasis through regulation of MMPs via ERK1/2 signaling pathway.

Cytokine-induced antiapoptotic inhibitor 1 (CIAPIN1) was recently identified as an essential downstream effector of the Ras signaling pathway and has been confirmed to be closely associated with various malignant tumors. However, its potential role in regulating breast cancer metastasis remains unclear. Matrix metalloproteinases (MMPs) are a broad family of zinc-biding endopeptidases that participate in the extracellular matrix (ECM) degradation that accompanies cancer cell invasion, metastasis and angiogenesis. In this study, we found up-regulation of CIAPIN1 by lentiviral expression vector inhibited the migration, invasion and MMPs expression of MDA-MB-231 cells. Further, CIAPIN1 over-expression decreased NHE1 (Na(+)/H(+) exchanger 1) expression and ERK1/2 phosphorylation. Importantly, treating CIAPIN1 over-expressed MDA-MB-231 cells with the NHE1 specific inhibitor, Cariporide, further inhibited the metastatic capacity, MMPs expression and phosphorylated ERK1/2. Treatment with the MEK1 specific inhibitor, PD98059, induced nearly the same suppression of CIAPIN1 over-expression-dependent migration, invasion and MMPs expression as was observed with Cariporide. Further, Cariporide and PD98059 synergistically suppressed migration, invasion and MMPs expression of CIAPIN1 over-expressed MDA-MB-231 cells. Thus, our results revealed the mechanism by which CIAPIN1 targeted NHE1 to mediate migration and invasion of MDA-MB-231 cells through regulation of MMPs via ERK1/2 signaling pathway.

Decreased intracellular pH induced by cariporide differentially contributes to human umbilical cord-derived mesenchymal stem cells differentiation.

BACKGROUND/AIMS: Na+/H+ exchanger 1 (NHE1) is an important regulator of intracellular pH (pHi). High pHi is required for cell proliferation and differentiation. Our previous study has proven that the pHi of mesenchymal stem cells is higher than that of normal differentiated cells and similar to tumor cells. NHE1 is highly expressed in both mesenchymal stem cells and tumor cells. Targeted inhibition of NHE1 could induce differentiation of K562 leukemia cells. In the present paper we explored whether inhibition of NHE1 could induce differentiation of mesenchymal stem cells. METHODS: MSCs were obtained from human umbilical cord and both the surface phenotype and functional characteristics were analyzed. Selective NHE1 inhibitor cariporide was used to treat human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The pHi and the differentiation of hUC-MSCs were compared upon cariporide treatment. The putative signaling pathway involved was also explored. RESULTS: The pHi of hUC-MSCs was decreased upon cariporide treatment. Cariporide up-regulated the osteogenic differentiation of hUC-MSCs while the adipogenic differentiation was not affected. For osteogenic differentiation, ß-catenin expression was up-regulated upon cariporide treatment. CONCLUSION: Decreased pHi induced by cariporide differentially contributes to hUC-MSCs differentiation.

Neutrophil gelatinase-associated lipocalin regulates intracellular accumulation of Rh123 in cancer cells.

Multidrug resistance (MDR) is a major problem facing patients with cancer. Although Neutrophil gelatinase-associated lipocalin (NGAL) is highly expressed in various cancers, the possible role of NGAL in MDR is still obscure. In this article, we evaluated the effect of NGAL on Rh123 accumulation in cancer cells. NGAL was first down-regulated by short hairpin RNA-mediated interference. In correlation with the reduced NGAL expression, intracellular Rh123 accumulation was significantly decreased. We finally observed that inhibiting both of the ERK1/2 and p38 MAPK could seriously down-regulate NGAL expression and also decrease the intracellular accumulation of Rh123, indicating that NGAL-mediated Rh123 accumulation is regulated by the phosphorylation of ERK1/2 and p38 MAPK. Pretreatment of MDA-MB-231 with NGAL recombinant protein and antibody had significant effects on the intracellular accumulation of Rh123, whereas little effect was observed in K562 cells treated with the same method, suggesting that NGAL was involved in the regulation of Rh123 accumulation in these two types of cancers, although different pathways. Here we provide new evidence that directly shows the possibility of small chemical substances Rh123 intracellular accumulation that is regulated by NGAL. These results suggest the possibility of NGAL involvement in drug transportation and cancer MDR formation, and indicate the potential of NGAL in cancer therapy.

CD44 targets Wnt/ß-catenin pathway to mediate the proliferation of K562 cells.

BACKGROUND: Chronic myeloid leukemia is a clonal myeloproliferative disorder disease in which BCR/ABL plays an important role as an oncoprotein and molecular target. Despite the success of targeted therapy using tyrosine kinase inhibitors, CML remains largely incurable, most likely due to the treatment resistance after firstly chemical therapy. So know well the unique molecular pathway of CML is very important. METHODS: The expressions of CD44 in different leukemia patients and cell lines were detected by real-time PCR and western blotting. The effects of CD44 on proliferation of K562 cells were determined using the MTT and colony formation assays, and even in a nude mouse transplantation model. Then, the cell cycle changes were detected by flow cytometric analysis and the early apoptosis of cells was detected by the annexin V/propidium iodide double-staining assay. The expressions of the cycles and apoptosis-related proteins p21, Cyclin D1 and Bcl-2 were analyzed by western blot and real-time PCR assay. Finally, the decreased nuclear accumulation of ß-catenin was detected by western blotting and immunefluorescence. RESULTS: Firstly, we showed that CD44 expression was increased in several kinds of leukemia patients and K562 cells. By contrast, the down-regulation of CD44 resulted in decreased proliferation with a G0/G1 arrest of cell cycle in K562 cells according to the MTT assay and the flow cytometric analysis. And no significant induction of both the early and late phases of apoptosis was shown by the annexin V-FITC and PI staining. During this process, p21 and cyclin D1 are the major causes for cell cycle arrest. In addition, we found CD44 down-regulation decreased the expression of ß-catenin and increased the expression of phosphorylated ß-catenin. The instability of Wnt/ß-catenin pathway induced by increased expression of p-ß-catenin resulted in a decreased nuclear accumulation in CD44 silenced K562 cells. In the nude mouse transplantation model, we also found the same results. CONCLUSIONS: These results show that K562 cells depend to a greater extent on CD44 for proliferation, and CD44 down-regulation may induce a cell cycle arrest through Wnt/ß-catenin pathway. CD44 blockade may be beneficial in therapy of CML.

Analysis of monocyte and histiocytic cell populations in bone marrow of patients with confirmed and suspected cases of reactive histocytosis.

OBJECTIVE: To describe characteristics of monocytes and histiocytes in the bone marrow of patients with a confirmed and suspected diagnosis of reactive histiocytosis. METHODS: 14 patients with a confident diagnosis of reactive histiocytosis or with a suspected diagnosis were inpatients at the Tianjin Blood Diseases Hospital between 2008 and 2012. Nucleated cells from bone marrow were observed by light microscopy - morphologically and immunohistochemically for histiocyte antigens - and ultrastructurally by transmission electron microscopy. RESULTS: Monocytes, atypical histiocytes, macrophages, hemophagocytes, reticular cells and dendritic cells were significantly increased in 9, 9, 5, 3, 3 and 2, respectively, of the 14 cases. Atypical histiocytes expressed some morphological characteristics of promonocytes. CONCLUSION: Monocytes, atypical histiocytes, macrophages, hemophagocytes, reticular cells and dendritic cells were increased in different relative degrees in patients with bone marrow reactive histiocytosis or suspected reactive histiocytosis. The increase in numbers of monocytes, atypical histiocytes and macrophages was a particularly significant feature. It is argued that atypical histiocytes with immature monocyte features might be precursors of hemophagocytes, reticular cells or dendritic cells.

C/EBP ζ targets to neutrophil gelatinase-associated lipocalin (NGAL) as a repressor for metastasis of MDA-MB-231 cells.

Breast cancer is a leading cause of morbidity in women worldwide. neutrophil gelatinase-associated lipocalin (NGAL), a useful biomarker of ER negative (ER(-)) breast cancer, promotes local tumor invasion and lymph node metastasis. We first identified the distinctive expression of NGAL in two breast cancer cell lines MCF7 and MDA-MB-231 cells, and then confirmed NGAL as a critical inducer of metastasis. Finally, the transcriptional factor CCAAT enhancer-binding proteins ζ (C/EBP ζ) was overexpressed in MDA-MB-231 cells. Consistent with the effect of NGAL knockdown, C/EBP ζ overexpression caused the significant changes that could prevent cell metastasis. C/EBP ζ overexpression induced a strong decrease in NGAL and matrix metalloproteinases (MMPs) expressions as determined by quantitative real time PCR and Western blotting. To identify the potential role of C/EBP ζ on regulating of NGAL in breast cancer, we established the dual-luciferase reporter assay for NGAL in MDA-MB-231 cells cotransfected with C/EBP ζ. Promoter reporter assays determined that C/EBP ζ directly repressed the human NGAL gene promoter activity by inhibiting the NGAL transcription. Taken together, this work identified that the C/EBP ζ overexpression downregulated NGAL to inhibit migration and invasion of breast cancer, which could be used as a novel strategy for breast cancer therapy.

Nuclear accumulation of calcineurin B homologous protein 2 (CHP2) results in enhanced proliferation of tumor cells.

The interaction between calcineurin B homologous protein 2 (CHP2) and Na(+) /H(+) exchanger 1 (NHE1), two membrane proteins, is essential for protecting cells from serum deprivation-induced death. Although four putative EF-hands in CHP2 had been predicted for years, Ca²(+) -binding activities of these motifs have not been tested yet, their role in this process remain poorly understood. To identify Ca²(+) -binding motifs required for the stable formation of CHP2/NHE1 complexes, we developed a mutagenesis-based assay in PS120 cells. We found that (45) Ca²(+) bond to two EF-hand motifs (EF3 and 4) of CHP2 proteins with high affinity. Complex formation between CHP2 and the CHP2 binding domain of NHE1 resulted in a marked increase in the Ca²(+) -binding affinity of CHP2. Co-immunoprecipitation and distribution of GFP-tagged CHP2-EF3m/4m also indicated that Ca²(+) affected the membrane location of CHP2 to interact with NHE1. The C-terminal region of CHP2 contains a nuclear export sequence (NES). When the six leucines of NES were mutated to alanines, the resulting CHP2 protein was predominantly localized to the nucleus. Furthermore, mutation of the NES resulted in enhanced proliferation and oncogenic potential of HeLa cells. Together, these results show that calcium and NES control the subcellular distribution of CHP2 and then distinctively regulate cell proliferation.

Dexamethasone has variable effects on mesenchymal stromal cells.

BACKGROUND AIMS: Dexamethasone (Dex) is a potent synthetic member of the glucocorticoid class of steroid drugs. Frequently, Dex has been used to enhance osteogenic, chondrogenic and adipogenic differentiation of mesenchymal stromal cells (MSC). Recently, Dex was applied to promote MSC proliferation, because of the rare frequency of MSC in bone marrow, and could protect the cells from apoptosis. The effects of Dex on MSC cytobiology behavior needs to be investigated. METHODS: MSC were obtained from human umbilical cord. The surface phenotype and functional characterization of MSC cultured with different concentrations of Dex were investigated, in comparison with a control group, including MSC proliferation, apoptosis, cytokine expression and immunosuppression. RESULTS: Different concentrations of Dex exerted diverse effects on MSC proliferation and apoptosis. Dex was also able to affect the pattern of cytokine expression of MSC. Furthermore, Dex impaired immunosuppression of MSC on peripheral blood mononuclear cells. CONCLUSIONS: A low dose of Dex favors MSC expansion in vitro, and protects against apoptosis. It is not suitable for MSC to be pre-treated with Dex when they are to be used to treat immunologic disease. However, when MSC are applied to promote angiogenesis, it is beneficial for them to be pre-treated with 10(-9) mol/L Dex.

Na+/H+ exchanger 1 inhibition contributes to K562 leukaemic cell differentiation.

The effect of hypoxia on the differentiation of chronic myeloid leukaemic K562 cells were studied, as was the role of the NHE1 (Na+/H+ exchanger 1). Hypoxia induced differentiation of K562 cells as seen by modifications in their morphological features, up-regulation of C/EBPα (CCAAT/enhancer-binding protein α), and marked IL-8 (interleukin-8) release. Inhibition of NHE1 under hypoxia additionally enhanced the level of C/EBPα and further promoted leukaemic cells differentiation. Pharmacological inhibition of p38 MAPK (mitogen-activated protein kinase) also significantly suppressed C/EBPα expression under hypoxia conditions after NHE1 inhibition. These results indicate the enhancement of hypoxia-induced K562 differentiation by NHE1 inhibition, which may be due to up-regulation of C/EBPα via p38 MAPK signalling pathway, which suggests a possible therapeutic target of NHE1 under hypoxia microenvironment in the treatment of leukaemic diseases.

NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMP.

Na⁺/H⁺ exchanger 1 (NHE1), an important regulator of intracellular pH (pH(i)) and extracellular pH (pH(e)), has been shown to play a key role in breast cancer metastasis. However, the exact mechanism by which NHE1 mediates breast cancer metastasis is not yet well known. We showed here that inhibition of NHE1 activity, with specific inhibitor Cariporide, could suppress MDA-MB-231 cells invasion as well as the activity and expression of MT1-MMP. Overexpression of MT1-MMP resulted in a distinguished increase in MDA-MB-231 cells invasiveness, but treatment with Cariporide reversed the MT1-MMP-mediated enhanced invasiveness. To explore the role of MAPK signaling pathways in NHE1-mediated breast cancer metastasis, we compared the difference of constitutively phosphorylated ERK1/2, p38 MAPK and JNK in non-invasive MCF-7 cells and invasive MDA-MB-231 cells. Interestingly, we found that the phosphorylation levels of ERK1/2 and p38 MAPK in MDA-MB-231 cells were higher than in MCF-7 cells, but both MCF-7 cells and MDA-MB-231 cells expressed similar constitutively phosphorylated JNK. Treating MDA-MB-231 cells with Cariporide led to decreased phosphorylation level of both p38 MAPK and ERK1/2 in a time-dependent manner, but JNK activity was not influenced. Supplementation with MAPK inhibitor (MEK inhibitor PD98059, p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125) or Cariporide all exhibited significant depression of MDA-MB-231 cells invasion and MT1-MMP expression. Furthermore, we co-treated MDA-MB-231 cells with MAPK inhibitor and Cariporide. The result showed that Cariporide synergistically suppressed invasion and MT1-MMP expression with MEK inhibitor and p38 MAPK inhibitor, but not be synergistic with the JNK inhibitor. These findings suggest that NHE1 mediates MDA-MB-231 cells invasion partly through regulating MT1-MMP in ERK1/2 and p38 MAPK signaling pathways dependent manner.

NHE1 mediates migration and invasion of HeLa cells via regulating the expression and localization of MT1-MMP.

Na(+)/H(+) exchanger 1 (NHE1), acting as an important regulator of intracellular pH (pH(i)) and extracellular pH (pH(e)), has been known to play a key role in the metastasis of many solid tumours. However, the exact mechanism underlying these processes, especially in cervical cancer, is still poorly understood. In the current study, we first showed that the inhibition of NHE1 activity by the specific inhibitor cariporide could suppress migration and invasion of HeLa cells in vitro. Moreover, cariporide also reversed the enhanced migration and invasion in HeLa cells by overexpressed membrane-type 1 matrix metalloproteinase (MT1-MMP). Subsequently, our results showed that NHE1 regulated the expression of MT1-MMP at both messenger RNA and protein levels as well as its localization. Meanwhile, we observed slight modification in the morphology of HeLa cell after treating with cariporide. The present work indicates that NHE1 mediates HeLa cell metastasis via regulating the expression and localization of MT1-MMP and provides a theoretical basis for the development of novel therapeutic strategies targeting cervical cancer.

Multiple organ invasion by viruses: pathological characteristics in three fatal cases of the 2009 pandemic influenza A/H1N1.

To further understand the pathological characteristics of multiple organ involvement of the 2009 pandemic influenza A/H1N1 infection, tissues of bronchial mucosa, lung, myocardium, gastrocnemius, and liver from 3 patients with fatal A/H1N1 infections were investigated by light microscopy and transmission electron microscopy. In all 3 patients, bronchial mucosa showed necrotizing bronchiolitis, epithelial necrosis and desquamation, and squamous metaplasia, while lung consolidation or fibrosis was identified. Myocardium and gastrocnemius exhibited focal necrosis and fibrosis, surrounded by muscle cells showing features of cell damage. In liver, there was widespread fatty degeneration and necrosis, most often around the central lobular vein and portal area. Viral particles were found in all samples, frequently located in endothelium, epithelium, and muscle cells. The observations demonstrate that in fatal cases of A/H1N1 infection, viruses not only infect the respiratory system, but also engage in multiple organ invasions, causing pathologic changes.

Differentiation of human umbilical cord mesenchymal stromal cells into low immunogenic hepatocyte-like cells.

BACKGROUND AIMS: Mesenchymal stromal cells (MSC) isolated from several human tissues have been known to differentiate into the hepatic lineage in vitro, but the immunogenicity of the differentiated hepatocyte-like cells (DHC) has not been reported. Umbilical cord (UC) MSC are thought to be an attractive cell source for cell therapy because of their young age and low infection rate compared with adult tissue MSC. METHODS: Hepatic differentiation of UC-MSC was induced with a 2-step protocol. The expressions of hepatic markers were detected by RT-PCR and immunofluorescence staining. Albumin production and urea secretion were measured by ELISA and colorimetric assay respectively. The immunosuppressive properties of DHC was detected by mixed lymphocyte culture. RESULTS: After incubation with specific growth factors, including hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF), UC MSC exhibited a high hepatic differentiation ability in an adherent culture condition. The differentiated UC MSC showed hepatocyte-like morphology and expressed several liver-specific markers at gene and protein levels. Furthermore, the DHC exhibited hepatocyte-specific functions, including albumin secretion, low-density lipoprotein uptake and urea production. More importantly, DHC did not express major histocompatibility complex (MHC) II antigen and were not able to induce lymphocyte proliferation in mixed lymphocyte culture, as undifferentiated UC MSC did. CONCLUSIONS: Our results indicate that UC MSC are able to differentiate into functional hepatocyte-like cells that still retain their low immunogenicity in vitro. More importantly, DHC incorporated into the parenchyma of liver when transplanted into mice with CCl(4)-induced liver injury. Therefore, DHC may be an ideal source for cell therapy of liver diseases.

Myofibroblast transformation in metastatic extramedullary chronic myeloid leukemia: a case report.

Primary and metastatic carcinomas have a reactive stroma characterized by many myofibroblasts. These cells have also been documented in nonepithelial malignancies, such as sarcomas, malignant melanoma, and lymphoid tumors but in generally far fewer numbers. In non-Hodgkin's lymphoma, Hodgkin's disease, and leukemia, myofibroblasts are rather rarely documented. In particular, there appear to be no reports of myofibroblasts in either primary bone-marrow/peripheral blood leukemia or secondary deposits of leukemia. In this paper, a case of a relapsed chronic myeloid leukemia appearing in an inguinal lymph node is described, containing many myofibroblasts. The case is detailed and presented with a discussion on the role of myofibroblasts in the progression of nonepithelial cancers.

Invasion of erythroblasts by Pasmodium vivax: A new mechanism contributing to malarial anemia.

Severe malarial anemia causes considerable mortality and morbidity in endemic areas. Possible mechanisms underlying the anemia include lysis of parasitized and nonparasitized red cells as well as parasite product-mediated effects on erythropoiesis. The latter include suppression of erythropoiesis, dyserythropoiesis, and ineffective erythropoiesis. Present transmission electron microscope data in two cases of Pasmodium vivax malaria show a hitherto undescribed mechanism contributing to malarial anemia, namely, infection of erythroblasts by parasites and their subsequent degradation. No parasites were detected in the peripheral blood but parasites were found in the bone marrow. These findings emphasise the value of bone marrow examination in the diagnosis and eradication of malaria.