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Yuhchyau Chen - One of the best experts on this subject based on the ideXlab platform.
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eltrombopag a thrombopoietin receptor agonist enhances human umbilical cord blood hematopoietic stem primitive progenitor cell expansion and promotes multi lineage hematopoiesis
Stem Cell Research, 2012Co-Authors: Hongliang Sun, Ying Tsai, Irena Nowak, Jane L Liesveld, Yuhchyau ChenAbstract:Umbilical cord blood (UCB) transplantation has emerged as a promising therapy, but it is challenged by scarcity of stem cells. Eltrombopag is a non-peptide, thrombopoietin (TPO) receptor agonist, which selectively activates c-Mpl in humans and chimpanzees. We investigated eltrombopag's effects on human UCB hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) expansion, and its effects on hematopoiesis in vivo. Eltrombopag selectively augmented the expansion of human CD45+, CD34+, and CD41+ cells in bone marrow compartment without effects on mouse bone marrow cells in the NOD/SCID mice xenotransplant model. Consequently, eltrombopag increased peripheral human platelets and white blood cells. We further examined effects in the STAT and AKT signaling pathways in serum-free cultures. Eltrombopag expanded human CD34+ CD38-, CD34+, and CD41+ cells. Both eltrombopag and recombinant human TPO (rhTPO) induced phosphorylation of STAT5 of CD34+ CD41-, CD34- CD41+, and CD34- CD41- cells. rhTPO preferentially induced pSTAT3, pAKT, and more pSTAT5 in CD34- C41+ cells, while eltrombopag had no effects on pSTAT3. In conclusion, eltrombopag enhanced expansion of HSCs/HPCs of human UCB in vivo and in vitro, and promoted multi-lineage hematopoiesis through the expansion of bone marrow HSCs/HPCs of human UCB in vivo. Eltrombopag differed somewhat from rhTPO in the signal transduction pathways by favoring earlier HSC/HPC populations.
Igor I Slukvin - One of the best experts on this subject based on the ideXlab platform.
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hematopoietic and endothelial differentiation of human induced pluripotent stem cells
Stem Cells, 2009Co-Authors: Kyung Dal Choi, Maxim A Vodyanik, James A. Thomson, Kim Smugaotto, Giorgia Salvagiotto, William M Rehrauer, Igor I SlukvinAbstract:Induced pluripotent stem cells (iPSCs) provide an unprecedented opportunity for modeling of human diseases in vitro, as well as for developing novel approaches for regenerative therapy based on immunologically compatible cells. In this study, we employed an OP9 differentiation system to characterize the hematopoietic and endothelial differentiation potential of seven human iPSC lines obtained from human fetal, neonatal, and adult fibroblasts through reprogramming with POU5F1, SOX2, NANOG, and LIN28 and compared it with the differentiation potential of five human embryonic stem cell lines (hESC, H1, H7, H9, H13, and H14). Similar to hESCs, all iPSCs generated CD34(+)CD43(+) hematopoietic progenitors and CD31(+)CD43(-) endothelial cells in coculture with OP9. When cultured in semisolid media in the presence of hematopoietic growth factors, iPSC-derived primitive blood cells formed all types of hematopoietic colonies, including GEMM colony-forming cells. Human induced pluripotent cells (hiPSCs)-derived CD43(+) cells could be separated into the following phenotypically defined subsets of primitive hematopoietic cells: CD43(+)CD235a(+)CD41a(+/-) (erythro-megakaryopoietic), lin(-)CD34(+)CD43(+)CD45(-) (multipotent), and lin(-)CD34(+)CD43(+)CD45(+) (myeloid-skewed) cells. Although we observed some variations in the efficiency of hematopoietic differentiation between different hiPSCs, the pattern of differentiation was very similar in all seven tested lines obtained through reprogramming of human fetal, neonatal, or adult fibroblasts with three or four genes. Although several issues remain to be resolved before iPSC-derived blood cells can be administered to humans for therapeutic purposes, patient-specific iPSCs can already be used for characterization of mechanisms of blood diseases and for identification of molecules that can correct affected genetic networks.
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leukosialin cd43 defines hematopoietic progenitors in human embryonic stem cell differentiation cultures
Blood, 2006Co-Authors: Maxim A Vodyanik, James A. Thomson, Igor I SlukvinAbstract:During hematopoietic differentiation of human embryonic stem cells (hESCs), early hematopoietic progenitors arise along with endothelial cells within the CD34+ population. Although hESC-derived hematopoietic progenitors have been previously identified by functional assays, their phenotype has not been defined. Here, using hESC differentiation in coculture with OP9 stromal cells, we demonstrate that early progenitors committed to hematopoietic development could be identified by surface expression of leukosialin (CD43). CD43 was detected on all types of emerging clonogenic progenitors before expression of CD45, persisted on differentiating hematopoietic cells, and reliably separated the hematopoietic CD34+ population from CD34+CD43–CD31+KDR+ endothelial and CD34+CD43–CD31–KDR– mesenchymal cells. Furthermore, we demonstrated that the first-appearing CD34+CD43+CD235a+CD41a+/–CD45– cells represent precommitted erythro-megakaryocytic progenitors. Multipotent lymphohematopoietic progenitors were generated later as CD34+CD43+CD41a–CD235a–CD45– cells. These cells were negative for lineage-specific markers (Lin–), expressed KDR, VE-cadherin, and CD105 endothelial proteins, and expressed GATA-2, GATA-3, RUNX1, C-MYB transcription factors that typify initial stages of definitive hematopoiesis originating from endothelial-like precursors. Acquisition of CD45 expression by CD34+CD43+CD45–Lin– cells was associated with progressive myeloid commitment and a decrease of B-lymphoid potential. CD34+CD43+CD45+Lin– cells were largely devoid of VE-cadherin and KDR expression and had a distinct FLT3highGATA3lowRUNX1lowPU1highMPOhighIL7RAhigh gene expression profile.
Hongliang Sun - One of the best experts on this subject based on the ideXlab platform.
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eltrombopag a thrombopoietin receptor agonist enhances human umbilical cord blood hematopoietic stem primitive progenitor cell expansion and promotes multi lineage hematopoiesis
Stem Cell Research, 2012Co-Authors: Hongliang Sun, Ying Tsai, Irena Nowak, Jane L Liesveld, Yuhchyau ChenAbstract:Umbilical cord blood (UCB) transplantation has emerged as a promising therapy, but it is challenged by scarcity of stem cells. Eltrombopag is a non-peptide, thrombopoietin (TPO) receptor agonist, which selectively activates c-Mpl in humans and chimpanzees. We investigated eltrombopag's effects on human UCB hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) expansion, and its effects on hematopoiesis in vivo. Eltrombopag selectively augmented the expansion of human CD45+, CD34+, and CD41+ cells in bone marrow compartment without effects on mouse bone marrow cells in the NOD/SCID mice xenotransplant model. Consequently, eltrombopag increased peripheral human platelets and white blood cells. We further examined effects in the STAT and AKT signaling pathways in serum-free cultures. Eltrombopag expanded human CD34+ CD38-, CD34+, and CD41+ cells. Both eltrombopag and recombinant human TPO (rhTPO) induced phosphorylation of STAT5 of CD34+ CD41-, CD34- CD41+, and CD34- CD41- cells. rhTPO preferentially induced pSTAT3, pAKT, and more pSTAT5 in CD34- C41+ cells, while eltrombopag had no effects on pSTAT3. In conclusion, eltrombopag enhanced expansion of HSCs/HPCs of human UCB in vivo and in vitro, and promoted multi-lineage hematopoiesis through the expansion of bone marrow HSCs/HPCs of human UCB in vivo. Eltrombopag differed somewhat from rhTPO in the signal transduction pathways by favoring earlier HSC/HPC populations.
Ning Mao - One of the best experts on this subject based on the ideXlab platform.
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isolation and identification of mesenchymal stem cells from perfusion of human umbilical cord vein
Journal of Experimental Hematology, 2007Co-Authors: Xiaodan Liu, Bing Liu, Ning MaoAbstract:This study was aimed to investigate whether mesenchymal stem cells (MSCs) existed in human umbilical cord vein and to establish the methods of isolation and expansion in vitro. The MSCs derived for perfusion of umbilical cord vein (UVMSCs) were collected after parturition of Healthy pregnant women. The morphology of MSCs and their differentiation potential into osteoblast, adipocyte and chondrocyte were observed the phenotype and cell cycle of MSCs were determined by using flow cytometry. The result showed that the mesenchymal stem cells separated from umbilical cord vein gave rise to a population of adherent cells with a typical fibroblast-like morphology. Similarly to bone marrow-derived MSCs, they highly expressed CD29, HLA-ABC, CD166, CD105, CD73 and CD44, and were negative for any hematopoietic and endothelial markers (CD45, CD34, CD14 and CD144). Functionally, they could differentiate into the osteoblast, adipocyte and chondrocyte. It is concluded that MSCs exist in the human umbilical cord vein perfusion. Their read amplification in vitro contribute to clinical applications for cell therapy and tissue engineering.
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human placenta derived mesenchymal progenitor cells support culture expansion of long term culture initiating cells from cord blood cd34 cells
Experimental Hematology, 2004Co-Authors: Yi Zhang, Xiaoxia Jiang, Shuangxi Zhang, Bing Liu, Peihsien Tang, Ning MaoAbstract:Abstract Objective Allogeneic transplantation with umbilical cord blood (UCB) in adult recipients is limited mainly by a low CD34 + cell dose. To overcome this shortcoming, human placenta as a novel source of human mesenchymal progenitor cell (MPC) was incorporated in an attempt to expand CD34 + cells from UCB in vitro. Materials and methods Human placenta MPC was isolated and characterized by morphologic, immunophenotypical, and functional analysis. UCB CD34 + cells were expanded by coculture with placental MPC. Suitable aliquots of cells were used to monitor cell production, clonogenic activity, and long-term culture-initiating culture (LTC-IC) output. Finally, the immunoregulatory effect of placental MPC was evaluated by T-cell proliferation assay. Results In its undifferentiated state, placental MPC displayed fibroblastoid morphology; was CD73, CD105, CD29, CD44, HLA-ABC, and CD166 positive; produced fibronectin, laminin, and vimentin; but was negative for CD14, CD31, CD34, CD45, HLA-DR, and α-smooth muscle actin. Functionally, it could be induced into adipocytes, osteocytes, and chondrocytes. In vitro expansion of UCB hematopoietic cells, when cocultured with placental MPC in the presence of cytokines, was significantly enhanced: CD34 + cells by 14.89 ± 2.32 fold; colony-forming cell (CFC) by 36.73 ± 5.79 fold; and LTC-IC by 7.43 ± 2.66 fold. Moreover, placental MPC could suppress T-cell proliferation induced by cellular stimuli. Conclusion These results strongly suggest that human placental MPC may be a suitable feeder layer for expansion of hematopoietic progenitors from UCB in vitro.
Feng Wang - One of the best experts on this subject based on the ideXlab platform.
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a novel mouse model of human breast cancer stem like cells with high CD44 cd24 lower phenotype metastasis to human bone
Cancer Research, 2009Co-Authors: Lijun Ling, Shui Wang, Xiaoan Liu, Enchao Shen, Qiang Ding, Qinhong Cao, Hong Zhu, Feng WangAbstract:CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #4155 Background: At present, our understanding of the development of bone metastasis is limited. Therefore, little progress has been made in preventing skeletal metastasis in the breast cancer patient. A satisfactory animal model that avoids the species-specific factor and simultaneously shares similarities to the clinical pathophysiological progression of breast cancer metastasizing to bone is unavailable. A subpopulation (CD44+/CD24-/lower) of breast cancer cells possesses stem/progenitor cell properties (cancer stem-like cell). CD44 potentiates the adherence of metastatic breast cancer cells to bone marrow endothelial cells. In the present study, we used hepatocyte growth factor to enhance the proportion of CD44+/CD24-/lower subpopulation in the human breast cancer cell line MDA-MB-231. We used these human breast cancer stem-like cells and implantation of human bone to build a novel human-source model of human breast cancer skeletal metastasis. Methods: The human breast cancer cell line MDA-MB-231 was cultured in serum-free DMEM-F12 supplemented with growth factors. Cells in different subpopulations were separated by Percoll gradient centrifugation and incubated in the presence of 50 ng/mL hepatocyte growth factor. The proportion of CD44+/CD24-/lower subpopulation in the human breast cancer cell line MDA-MB-231 was detected with flow cytometry. Before injection with human breast cancer stem-like cells, the experimental animals were implanted with human bone in the right or left dorsal flanks. Animals in Groups A, B, and C were injected with 1 X 105, 1 X 106 human breast cancer stem-like cells, and 1 X 106 parental MDA-MB-231 cells, respectively. A positive control group (D) without implantation of human bone (non-human source model) was also injected with 1 X 106 MDA-MB-231 cells. A group of negative controls (E) with human bone implantation was injected with isotonic sodium chloride. For each group, Micro-SPECT was performed at weeks 4 and 7, and all animals were sacrificed at week 8. Immunohistochemistry was performed for CD34, CD105, SMA, CD44, CD24, CK, CXCR4, and OPN. mRNA levels of CD44, CD24, CXCR4, and OPN in bone metastasis tissues were analyzed by real-time quantitative polymerase chain reaction. Results: New vessels and connective tissue were found on the surface of implanted human bones and cells stained positive for antibodies against human CD105, SMA, and CD34, indicating that implanted human bones were viable and functional. Histologic and immunohistochemical analysis confirmed the metastases as cancer cells. Importantly, the results demonstrated that cells in implanted human bones of group B, which received 1 X 106 cancer stem-like cells, stained strongly positive for CD44, CXCR4, and OPN, whereas that of other groups showed no or minimum staining. Moreover, group B had the highest incidence of human bone metastasis (77.8%, P = 0.0230) and no accompaniment of other tissue metastasis. The real-time polymerase chain reaction (PCR) showed an increase of CD44 mRNA in metastatic bone tissues in group B compared with that of groups C and D (15.2- and 21.1-fold, respectively). The mRNA levels of CXCR4 and OPN (8.4- and 28.4-fold, respectively) in bone metastasis tissues of group B were all higher than that of groups C and D (4.8- and 11.6-fold; respectively). The levels of CD24 mRNA in group B were lowest, measuring only 30 percent of that in groups C and D. Conclusion: This study indicates that in the novel human source model of breast cancer, breast cancer stem-like cells demonstrate a higher human bone-seeking ability, which may contribute to increase metastasis incidence and attenuate species-specific influences. Its mechanism might be related to the higher expressions of CD44, CXCR4 and OPN, and the lower expression of CD24 in breast cancer stem-like cells. The model shares more similarities with clinical pathological features of bone metastatic patients. It will be helpful for further study of the mechanisms and subclinical diagnosis of bone metastasis. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4155.
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a novel mouse model of human breast cancer stem like cells with high CD44 cd24 lower phenotype metastasis to human bone
Chinese Medical Journal, 2008Co-Authors: Lijun Ling, Shui Wang, Xiaoan Liu, Enchao Shen, Qiang Ding, Qinhong Cao, Hong Zhu, Feng WangAbstract:BACKGROUND A satisfactory animal model of breast cancer metastasizing to bone is unavailable. In this study, we used human breast cancer stem-like cells and human bone to build a novel "human-source" model of human breast cancer skeletal metastasis. METHODS Human breast cancer stem-like cells, the CD44+/CD24-/lower subpopulation, was separated and cultured. Before injection with the stem-like cells, mice were implanted with human bone in the right or left dorsal flanks. Animals in Groups A, B, and C were injected with 1 x 10(5), 1 x 10(6) human breast cancer stem-like cells, and 1 x 10(6) parental MDA-MB-231 cells, respectively. A positive control group (D) without implantation of human bone was also injected with 1 x 10(6) MDA-MB-231 cells. Immunohistochemistry was performed for determination of CD34, CD105, smooth muscle antibody, CD44, CD24, cytokine, CXC chemokine receptor-4 (CXCR4), and osteopontin (OPN). mRNA levels of CD44, CD24, CXCR4, and OPN in bone metastasis tissues were analyzed by real-time quantitative polymerase chain reaction (PCR). RESULTS Our results demonstrated that cells in implanted human bones of group B, which received 1 x 10(6) cancer stem-like cells, stained strongly positive for CD44, CXCR4, and OPN, whereas those of other groups showed no or minimum staining. Moreover, group B had the highest incidence of human bone metastasis (77.8%, P = 0.0230) and no accompaniment of other tissue metastasis. The real-time PCR showed an increase of CD44, CXCR4, and OPN mRNA in metastatic bone tissues in group B compared with those of groups C and D, however the expression of CD24 mRNA in group B were the lowest. CONCLUSIONS In the novel "human source" model of breast cancer, breast cancer stem-like cells demonstrated a higher human bone-seeking ability. Its mechanism might be related to the higher expressions of CD44, CXCR4, and OPN, and the lower expression of CD24 in breast cancer stem-like cells.