赵春华
长期从事干细胞生物学、组织工程基础与临床研究。
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- 姓名:赵春华
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学术头衔:
博士生导师, 国家杰出青年科学基金获得者
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学科领域:
内科学
- 研究兴趣:长期从事干细胞生物学、组织工程基础与临床研究。
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12
赵春华, Baijun Fang, Mingxia Shi, Lianming Liao, Shaoguang Yang, Yuhao Liu, and Robert Chunhua Zhao
,-0001,():
-1年11月30日
Background. Fibrosis is the common end stage of most liver diseases, for which, unfortunately, there is no effective treatment available currently. It has been shown that mesenchymal stem cells (MSCs) from bone marrow (BM) could engraft in the lung after bleomycin exposure and ameliorate its fibrotic effects. This study was designed to evaluate the effect of Flk1+ MSCs from murine BM (termed here Flk1+ mMSCs) on fibrosis formation induced by carbon tetrachloride (CCl4). Methods. A CCl4-induced hepatic fibrosis model was used. Flk1+ mMSCs were systemically infused immediately or 1 week after mice were challenged with CCl4. Control mice received only saline infusion. Fibrosis index and donor-cell engraftment were assessed 2 or 5 weeks after CCl4 challenge. Results. Wefound that Flk1+ mMSCs transplantation immediately, but not 1 week after exposure to CCl4, significantly reduced CCl4-induced liver damage and collagen deposition. In addition, levels of hepatic hydroxyproline and serum fibrosis markers in mice receiving immediate Flk1+ mMSCs transplantation after CCl4 challenge were significantly lower compared with those of control mice. More importantly, histologic examination suggested that hepatic damage recovery was much better in these immediately Flk1+ mMSCs-treated mice. Immunofluorescence, polymerase chain reaction, and fluorescence in situ hybridization analysis revealed that donor cells engrafted into host liver, had epitheliumlike morphology, and expressed albumin, although at low frequency. Conclusion. These results suggest that Flk1+ mMSCs might initiate endogenous hepatic tissue regeneration, engraft into host liver in response to CCl4 injury, and ameliorate its fibrogenic effects.
Mesenchymal stem cells,, Liver fibrosis,, Transplantation.,
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赵春华, Baijun Fang, Chunmei Zheng, Lianming Liao, Qin Han, Zhao Sun, Xueying Jiang, and Robert C. H. Zhao
,-0001,():
-1年11月30日
Overwhelming evidence from leukemia research has shown that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation. There are rare stem cells within the leukemic population that possess extensive proliferation and self-renewal capacity not found in the majority of the leukemic cells. These leukemic stem cells are necessary and sufficient to maintain the leukemia. Interestingly, the BCR/ABL fusion gene, which is present in chronic myelogenous leukemia (CML), was also detected in the endothelial cells of patients with CML, suggesting that CML might originate from hemangioblastic progenitor cells that can give rise to both blood cells and endothelial cells. Here we isolated fetal liver kinase-1-positive (Flk1+) cells carrying the BCR/ABL fusion gene from the bone marrow of 17 Philadelphia chromosomepositive (Ph+) patients with CML and found that these cells could differentiate into malignant blood cells and phenotypically defined endothelial cells at the single-cell level. These findings provide direct evidence for the first time that rearrangement of the BCR/ABL gene might happen at or even before the level of hemangioblastic progenitor cells, thus resulting in detection of the BCR/ABL fusion gene in both blood and endothelial cells. (Blood. 2005; 105: 2733-2740)
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赵春华, WEI ZHANG, WEI GE, CHANGHONG LI, SHENGGUO YOU, LIANMING LIAO, QIN HAN, WEIMIN DENG, and ROBERT C.H. ZHAO
STEM CELLS AND DEVELOPMENT13:263-271(2004),-0001,():
-1年11月30日
Mesenchymal stem cells (MSCs) reportedly inhibit the mixed lymphocyte reaction. Whether this effect is mediated by dendritic cells (DCs) is still unknown. In this study, we used an in vitro model to observe the effects of MSCs and their supernatants on the development of monocyte-derived DCs. Phenotypes and the endocytosic ability of harvested DCs were determined by flow cytometry; interleukin 12 (IL-12) secreted by DCs was evaluated by enzyme-linked immunosorbent assay (ELISA); and the antigen-presenting function of DCs was evaluated by MLR. Our results show that MSCs inhibit the up-regulation of CD1a, CD40, CD80, CD86, and HLA-DR during DC differentiation and prevent an increase of CD40, CD86, and CD83 expression during DC maturation. MSCs supernatants had no effect on DCs differentiation, but they inhibited the up-regulation of CD83 during maturation. Both MSCs and their supernatants interfered with endocytosis of DCs, decreased their capacity to secret IL-12 and activate alloreactive T cells. Thus, effects of MSCs on DCs contribute to immunoregulation and development.
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【期刊论文】Hemangioblastic Characteristics of fetal marrow-derived Flk1+CD31-CD34-cells
赵春华, Hong Guo, Baijun Fang, Lianming Liao, Zhigang Zhao, Jiewen Liu, Huishu Chen, Steven H. Hsu, Qi Cui, and Robort Chunhua Zhao
Experimental Hematology 31(2003)650-658,-0001,():
-1年11月30日
Objective. To investigate whether Flk1+CD31-CD34-cells islated from fetal bone marrow (BM) have characteristies of hemanghioblasts, i. e., progenitors of endothlial and hemato-poietic cells. Materials and Methods. Mononuclear cells from fetal BM were negatively sorted by CD45, Gly A, and Cd34 micromagnetic beads, then cultured to form cell colonies. Asingle colony was harvested. Culture-expanded cells were seeded on ECM gel or semisolid media supplemented with endothelial and hematopoietic trowth factors, respectively. Immuno-chemistry staining and RT-PCR were performed for cell characterization. Results. 99% of cells from the single colony maintained Flk1+and CD31/CD34-during passaging. On ECM gel, Flk1+CD31-CD34-cells could grow into vascular structure that was positive for CD31 and v WF. Tgere were round CD34+cells around the vascular structure. When angiogenesis inhibitor suramin was added before tube formation, formation of vascular structure was blocked, Additionally, Flk1+CD31-CD34-cells cultured on hematopietic condition could differentiate into hematopoietic cells which expressed GATA-1, 2, and γ, β globin gene. After being replated in methylcellulose medium. they formed typical erythroid colonies. Conclusions. Flk1+CD31-CD34-cells derived from fetal BM could differentiate into endothelial and hematopoietic cells The rresults suggested that these Flk1+CD31-CD34-cells after embryo stage bear characteristies of hemangioblast and mayhave potential application for the hematopoietic and vascular diseases.
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【期刊论文】Isolation and identification of mesenchymal stem cells from human fetal pancreas
赵春华, YING HU, LIANMING LIAO, QIUYING WANG, LI MA, GUANJIE MA, XUEYING JIANG, and ROBERT CHUNHUA ZHAO
J Lab Clin Med Volume 141, Number 5,-0001,():
-1年11月30日
Mesenchymal stem cells (MSCs) have been cultured from many sources, including bone marrow and liver. To further support our hypothesis that MSCs exist in most postnatal tissues, we isolated a clonogenic, multipotent, rapidly proliferating population of cells from a fetal pancreas and termed them "pancreas-derived mesenchymal stem cells" (PMSCs). They withstood being passaged as many as 30 times without sustaining significant structural changes. In this study, we showed that PMSCs are positive for CD44, CD29, and CDI3 but negative for CD34 and HLA-DR and that they stained with collagen I and III but not with von Willebrand factor antibody. During the log phase of growth, PMSCs proliferated, doubling in population in about 30 hours. Cell-cycle analysis showed that more than 90% of cells were in the G0 and G1 phases, whereas a small subpopulation of cells were actively engaged in proliferation (S+G2+M=3.55%). Under differentiation culture conditions, PMSCs differentiated into cells of osteogenic, chondrogenic, and adipogenic lineages. These results demonstrate that PMSCs can be isolated from human fetal pancreas by means of their adherent ability and that they are capable of self-renewal, propagation, and multipotent differentiation. (J Lab Clin Med 2003; 141: 342-9)
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赵春华, Hikaru Nakajima, *, Robert Zhao, Troy C. Lund, Jeanne Ward, Michelle Dolan, †, Betsy Hirsch, and Jeffrey S. Miller*
The Journal of Immunology, 643~650,-0001,():
-1年11月30日
NK cells from the blood of chronic myelogenous leukemia (CML) patients are progressively decreased in number as the disease progresses from chronic phase to blast crisis. We hypothesize that BCR/ABL may be directly responsible by interfering with NK cell differentiation. CD34+HLA-DR+cells from CML patients were studied for their capacity to differentiate into NK cells. The NK cell cloning frequency was significantly decreased from CML CD34+HLA-DR+cells compared with cells from normal donors, yet CD34+HLA-DR+cells gave rise to BCR/ABL NK cells in some patients. This finding prompted us to further investigate circulating NK cells from the blood of CML patients. CD56+CD3- NK cells were sorted from CML patients and examined by fluorescence in situ hybridization (FISH). In contrast to chronic phase CML, significant numbers of NK cells from advanced phase CML patients were BCR/ABL, whereas T cells were always BCR/ABL-regardless of the disease stage. To test the effects of BCR/ABL as the sole genetic abnormality, BCR/ABL was transduced into umbilical cord blood CD34 cells, and NK development was studied. p210-enhanced green fluorescence protein-transduced cells gave rise to significantly decreased numbers of NK cells compared with enhanced green fluorescence protein transduction alone. In addition, the extrinsic addition of BCR/ABL-transduced autologous CD34+cells suppressed the NK cell differentiation of normal umbilical cord blood CD34+CD38- cells. This study provides the first evidence that BCR/ABL is responsible for the altered differentiation of NK cells and that the NK cell lineage can be involved with the malignant clone in advanced stage CML. The Journal of Immunology, 2002, 168: 643-650.
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赵春华, Robert C. Zhao, Yuehua Jiang, and Catherine M. Verfaillie
BLOOD, 15 APRIL 2001,-0001,():
-1年11月30日
Most insights into the molecular mechanisms underlying transformation by the p 210BCR/ABL oncoprotein are derived from studies in which BCR/ABL cDNA was introduced into hematopoietic or fibroblast cell lines. However, such cell line models may not represent all the features of chronic myelogenous leukemia (CML) caused by additional genetic abnormalities and differences in the biology of cell lines compared with primary hematopoietic progenitor and stem cells. A primary human hematopoietic progenitor cell model for CML was developed by the transduction of b3a2 BCR/ABL cDNA in normal CD341 cells. Adhesion of BCR/ ABL-transduced CD341 cells to fibronectin was decreased, but migration over fibronectin was enhanced compared with that of mock-transduced CD341 cells. Adhesion to fibronectin did not decrease the proliferation of BCR/ABL-transduced CD341 cells but decreased the proliferation of mock-transduced CD341 cells. This was associated with elevated levels of p27Kip in p 210BCR/ABL-expressing CD341 cells. In addition, the presence of p 210BCR/ABL delayed apoptosis after the withdrawal of cytokines and serum. Finally, significantly more and larger myeloid colony-forming units grew from BCR/ABL than from mock-transduced CD341 cells. Thus, the transduction of CD341 cells with the b3a2-BCR/ABL cDNA recreates most, if not all, phenotypic abnormalities seen in primary CML CD341 cells. This model should prove useful for the study of molecular mechanisms associated with the presence of p 210BCR/ABL in CML. (Blood. 2001;97:2406-2412).
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赵春华, Yuehua Jiang, Robert C. H. Zhao, and Catherine M. Verfaillie*
PNAS September 12, 2000 vol. 97 no.19 10538-10543,-0001,():
-1年11月30日
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赵春华, Weimin Denga, b, Qin Hana, *, Lianming Liaoa, Changhong Lia, Wei Gea, Zhigang Zhaoa, Shengguo Youa, Hongye Dengb, and Robert C.H. Zhaoa
Experimental Hematology 32(2004)861-867,-0001,():
-1年11月30日
Objective. To investigate the possibility of flk-1+Sca-1- bone marrow-derived mesenchymal stem cells (bMSCs) to induce stable mixed chimerism and donor-specific graft tolerance. Methods. Allogeneic flk-1+Sca-1- bMSCs and syngeneic bone marrow (BM) cells were cotransplanted into lethally irradiated (8.5 Gy) recipient mice. FACS was used to analyzethe chimerism 150 days later. Donor-type skin transplantation was performed to observe donorspecific immunotolerance in recipient mice. Mixed lymphocyte reaction (MLR) and mitogen proliferative assays were performed to evaluate proliferative response of splenocytes from recipient mice. Results. More than 5% donor-derived CD3+ cells were detected in splenocytes of recipientmice. Long-term survival of donor-type skin grafts was observed. MLR and mitogen proliferative assays showed that recipient mice had low immunoresponse to donor cells butretained normal ConA-induced proliferative response compared with normal mice. Conclusion. Our results show for the first time that induction of stable mixed hematopoietic chimerism can be achieved with allogeneic flk-1+Sca-1- bMSC transplantation, which leadsto permanent donor-specific immunotolerance in allogeneic host and results in long-term allogeneic skin graft acceptance.
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赵春华, By Robert C.H. Zhao, R. Scott McIvor, James D. Griffin, and Catherine M. Verfaillie
Blood, Vol 90, No12 (December 15), 1997: pp 4687-4698,-0001,():
-1年11月30日
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