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Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property

null

《医学前沿（英文）》 2015年 第9卷 第4期   页码 412-420 doi: 10.1007/s11684-015-0423-x

摘要：

Genetic mutations are considered to drive the development of acute myeloid leukemia (AML). With the rapid progress in sequencing technologies, many newly reported genes that are recurrently mutated in AML have been found to govern the initiation and relapse of AML. These findings suggest the need to distinguish the driver mutations, especially the most primitive single mutation, from the subsequent passenger mutations. Recent research on DNA methyltransferase 3A (DNMT3A) mutations provides the first proof-of-principle investigation on the identification of preleukemic stem cells (pre-LSCs) in AML patients. Although DNMT3A mutations alone may only transform hematopoietic stem cells into pre-LSCs without causing the full-blown leukemia, the function of this driver mutation appear to persist from AML initiation up to relapse. Therefore, identifying and targeting preleukemic mutations, such as DNMT3A mutations, in AML is a promising strategy for treatment and reduction of relapse risk.

关键词： preleukemic stem cell     acute myeloid leukemia     relapse     DNMT3A    

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Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity

Chuanfeng Wu, Cynthia E. Dunbar

《医学前沿（英文）》 2011年 第5卷 第4期   页码 356-371 doi: 10.1007/s11684-011-0159-1

摘要： Virus-based vectors are widely used in hematopoietic stem cell (HSC) gene therapy, and have the ability to integrate permanently into genomic DNA, thus driving long-term expression of corrective genes in all hematopoietic lineages. To date, HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy (ALD), thalassemia, chronic granulomatous disease (CGD), and Wiskott-Aldrich syndrome (WAS). However, adverse events were observed during some of these HSC gene therapy clinical trials, linked to insertional activation of proto-oncogenes by integrated proviral vectors leading to clonal expansion and eventual development of leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity, with the aim of developing safer vectors and lower-risk gene therapy protocols. This review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors, discuss the available assays for predicting genotoxicity and mapping vector integration sites, and introduce newly-developed approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application.

关键词： gene therapy     hematopoietic stem cells     insertional mutagenesis     genotoxicity     induced pluripotent stem cell    

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Advancement of human leukocyte antigen-partially matched related hematopoietic stem cell transplantation

null

《医学前沿（英文）》 2013年 第7卷 第3期   页码 306-315 doi: 10.1007/s11684-013-0279-x

摘要：

Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective options for hematological malignancies, and human leukocyte antigen-partially matched related donors (PMRDs) are a valuable option for HSCT. Several protocols (with or without ex vivo T-cell depletion (TCD)) have been established worldwide. TCD including CD34+positive selection and CD3/CD19 depletion has successfully overcome the human leukocyte antigen disparity. However, TCD is associated with prolonged immune deficiencies, increased risks of infectious complications, and high transplantation-related mortality. PMRD HSCT without ex vivo TCD is well developed, and numerous patients have benefitted from it. Here, we review the literature on PMRD HSCT.

关键词： partially matched related donor     hematopoietic stem cell transplantation     allogeneic    

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In vivo imaging of hematopoietic stem cell development in the zebrafish

Panpan Zhang, Feng Liu

《医学前沿（英文）》 2011年 第5卷 第3期   页码 239-247 doi: 10.1007/s11684-011-0123-0

摘要： imaging is crucial for developmental biology and can further help to follow cell development/differentiation in normal and pathological conditions. Recent advances in optical imaging techniques has facilitated tracing of the developmental dynamics of a specific organ, tissue, or even a single cell. The zebrafish is an excellent model for imaging of hematopoiesis due to its transparent embryo at early stage; moreover, different zebrafish hematopoietic stem cells (HSCs) transgenic lines have been demonstrated as very useful tools for illustrating the details of the HSC developmental process. In this review, we summarize recent studies related to the non-invasive imaging of HSC transgenics, to show that zebrafish transgenic lines are powerful tools for developmental biology and disease. At the end of the review, the perspective and some open questions in this field will be discussed.

关键词： hematopoietic stem cell     hematopoiesis     in vivo imaging     transgenics     zebrafish    

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Lung transplantation for bronchiolitis obliterans syndrome after allogenic hematopoietic stem cell transplantation

null

《医学前沿（英文）》 2018年 第12卷 第2期   页码 224-228 doi: 10.1007/s11684-017-0538-3

摘要：

Bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HSCT) is a major cause of morbidity and mortality with limited treatment options. Lung transplantation (LTX) has been rarely reported as a treatment option for selected HSCT recipients with this problem. In the present study, we reported six patients who underwent LTX due to BOS after HSCT (two females, four males) from January 2012 to December 2014 in our center. The median time from HSCT to diagnosis of BOS was 2.5 years (ranging from 1 to 5 years). At a median time of 4 years (ranging from 2 to 5 years) after diagnosis of BOS, four patients received bilateral sequential LTX, and two patients received single LTX. One of the recipients suffered from mild acute rejection after LTX, another suffered from primary lung graft dysfunction on post-operation day 2, and three experienced fungal infections. The median time for follow-up after LTX was 19.5 months (ranging from 12 to 39 months). At present, all patients are alive with good functional capacity and no relapse of BOS and hematologic malignancy conditions. Patients who received bilateral LTX have better pulmonary functions than patients who received single LTX.

关键词： bronchiolitis obliterans syndrome (BOS)     hematopoietic stem cell transplantation (HSCT)     lung transplantation (LTX)    

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Risk stratification system for skin and soft tissue infections after allogeneic hematopoietic stem cell

《医学前沿（英文）》 2022年 第16卷 第6期   页码 957-968 doi: 10.1007/s11684-021-0910-1

摘要： Skin and soft tissue infections (SSTIs) refer to infections involving the skin, subcutaneous tissue, fascia, and muscle. In transplant populations with hematological malignancies, an immunocompromised status and the routine use of immunosuppressants increase the risk of SSTIs greatly. However, to date, the profiles and clinical outcomes of SSTIs in hematopoietic stem cell transplantation (HSCT) patients remain unclear. This study included 228 patients (3.67%) who developed SSTIs within 180 days after allogeneic HSCT from January 2004 to December 2019 in Peking University People’s Hospital. The overall annual survival rate was 71.5%. We compared the differences between survivors and non-survivors a year after transplant and found that primary platelet graft failure (PPGF), comorbidities of acute kidney injury (AKI), and hospital-acquired pneumonia (HAP) were independent risk factors for death in the study population. A PPGF–AKI–HAP risk stratification system was established with a mortality risk score of 1×PPGF+1×AKI+1×HAP. The areas under the curves of internal and external validation were 0.833 (95% CI 0.760–0.906) and 0.826 (95% CI 0.715–0.937), respectively. The calibration plot revealed the high consistency of the estimated risks, and decision curve analysis showed considerable net benefits for patients.

关键词： skin and soft tissue infections     hematopoietic stem cell transplantation     risk stratification system     mortality    

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Everyone has a donor: contribution of the Chinese experience to global practice of haploidentical hematopoieticstem cell transplantation

Meng Lv, Yingjun Chang, Xiaojun Huang

《医学前沿（英文）》 2019年 第13卷 第1期   页码 45-56 doi: 10.1007/s11684-017-0595-7

摘要： Human leukocyte antigen (HLA)-matched donors for hematopoietic stem cell transplantation (HSCT) have long been scarce in China. Haploidentical (haplo) donors are available for the vast majority of patients, but toxicity has limited this approach. Three new approaches for haplo-HSCT originated from Italy, China, and USA in 1990 and have been developed to world-renowned system up to now. The Chinese approach have been greatly improved by implementing new individualized conditioning regimens, donor selection based on non-HLA systems, risk-directed strategies for graft-versus-host disease and relapse, and infection management. Haplo-HSCT has exhibited similar efficacy to HLA-matched HSCT and has gradually become the predominant donor source and the first alternative donor choice for allo-HSCT in China. Registry-based analyses and multicenter studies adhering to international standards facilitated the transformation of the unique Chinese experience into an inspiration for the refinement of global practice. This review will focus on how the new era in which “everyone has a donor” will become a reality in China.

关键词： haploidentical hematopoietic stem cell transplantation     conditioning     graft-versus-host disease     relapse     infection     donor selection    

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Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult

null

《医学前沿（英文）》 2015年 第9卷 第3期   页码 304-311 doi: 10.1007/s11684-015-0400-4

摘要：

In the tyrosine kinase inhibitor (TKI) era, imatinib is the first-line therapy for patients with chronic myeloid leukemia (CML) in chronic or accelerated phase. Although second-generation TKIs (TKI2), including dasatinib and nilotinib, are appropriate treatment regimens for patients with disease that progressed to accelerated phase following imatinib therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy. This study retrospectively analyzed the efficacy of TKI2 and HSCT for treatment of CML in accelerated phase. Ninety-three patients with CML registered in the Chinese CML alliance database from February 2001 to February 2014 were enrolled and divided into the TKI2 (n?=?33) and allo-HSCT (n?=?60) groups. In the TKI2 group, 26 and 7 patients received nilotinib and dasatinib, respectively, as initial TKI2 and 11 patients transferred to the alternative TKI2 after failure to one TKI2. In the allo-HSCT group, 22 (36.7%), 35 (58.3%), and 3 (10%) patients underwent allo-HSCT from an HLA-matched sibling donor, HLA mismatched/haploidentical donor, and unrelated donor, respectively. All patients in the HSCT group were engrafted. Overall, 69.7%, 48.5%, and 45.5% of patients presented hematological, cytogenetic, and major molecular responses, respectively, to at least one of TKI2. All 60 patients (100%) achieved CHR and cytogenetic response in the HSCT group. Patients in the TKI2 group exhibited lower 5-year overall survival rate (42.9% vs. 86.4%, P = 0.002), 5-year event-free survival rate (14.3% vs. 76.1%, P<0.001), and 5-year progression-free survival (28.6% vs. 78.1%, P<0.001) than those in the allo-HSCT group. Multivariate analysis showed that male sex and TKI2therapy were predictors of poor overall survival, whereas hemoglobin<100 g/L and TKI2 therapy were predictors of poor event-free survival and progression-free survival. These results indicated that allo-HSCT may be superior to nilotinib and dasatinib for adult patients with CML in accelerated phase.

关键词： chronic myeloid leukemia     imatinib     dasatinib     nilotinib     allogeneic hematopoietic stem cell transplantation    

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Determination of telomerase activity in stem cells and non-stem cells of breast cancer

LI Zhi, HE Yanli, ZHANG Jiahua, ZHANG Jinghui, HUANG Tao

《医学前沿（英文）》 2007年 第1卷 第3期   页码 294-298 doi: 10.1007/s11684-007-0056-9

摘要： Although all normal tissue cells, including stem cells, are genetically homologous, variation in gene expression patterns has already determined the distinct roles for individual cells in the physiological process due to the occurrence of epigenetic modification. This is of special importance for the existence of tissue stem cells because they are exclusively immortal within the body, capable of selfreplicating and differentiating by which tissues renew and repair itself and the total tissue cell population maintains a steady-state. Impairment of tissue stem cells is usually accompanied by a reduction in cell number, slows down the repair process and causes hypofunction. For instance, chemotherapy usually leads to depression of bone marrow and hair loss. Cellular aging is closely associated with the continuous erosion of the telomere while activation of telomerase repairs and maintains telomeres, thus slowing the aging process and prolonging cell life. In normal adults, telomerase activation mainly presents in tissue stem cells and progenitor cells giving them unlimited growth potential. Despite the extensive demonstration of telomerase activation in malignancy (>80%), scientists found that heterogeneity also exists among the tumor cells and only minorities of cells, designated as cancer stem cells, undergo processes analogous to the self-renewal and differentiation of normal stem cells while the rest have limited lifespans. In this study, telomerase activity was measured and compared in breast cancer stem cells and non-stem cells that were phenotypically sorted by examining surface marker expression. The results indicated that cancer stem cells show a higher level of enzyme activity than non-stem cells. In addition, associated with the repair of cancer tissue (or relapse) after chemotherapy, telomerase activity in stem cells was markedly increased.
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Autologous peripheral hematopoietic stem-cell transplantation in a patient with refractory pemphigus

SUN Ledong, SUN Jing, ZENG Kang, MENG Fanyi, DIAO Youtao, XU Dan, HUANG Liang, ZHAO Jie, Liu Qifa

《医学前沿（英文）》 2008年 第2卷 第2期   页码 191-194 doi: 10.1007/s11684-008-0036-8

摘要： The aim of this study is to explore the effectiveness of autologous peripheral hematopoietic stem-cell transplantation in the treatment of refractory pemphigus. A 35-year-old male patient presented with a 4-year history of recurrent bullae on his trunk and extremities. The diagnosis of pemphigus was made on the basis of the clinical, histologic and immunofluorescence findings. The patient had shown resistance to conventional therapy with glucocorticoid and immunosuppressive agents. Two months before admission, he complained of hip joint pain. X-ray and CT scan revealed aseptic necrosis of the femoral head. Stem-cell mobilization was achieved by treatment with cyclophosphamide, granulocyte colony-stimulating factor (G-CSF) and rituximab. Peripheral blood stem cells were collected via leukapheresis and cryopreserved for later use. Immunoablation was accomplished by using cyclophosphamide (200 mg/kg; divided into 50 mg/kg on days -5, -4, -3, and -2), antithymocyte globulin (ATG; 10 mg/kg; divided into 2.5 mg/kg on days -6, -5, -4, and -3), and rituximab (1200 mg/d; divided into 600 mg/d on days 0 and 7). Autologous peripheral hematopoietic stem cell transplantation was followed by reconstitution of the immune system which was monitored by flow cytometry. The glucocorticoid was withdrawn immediately after transplantation. The pemphigus titer turned negative 6 weeks after transplantation and remained negative. The patient was in complete drug-free remission with no evidence of residual clinical or serological activity of pemphigus during 1 year of follow-up. The patient’s response suggests that autologous peripheral hematopoietic stem cell transplantation may be a potential “cure” for refractory pemphigus. However, further studies are needed to evaluate the risk-benefit ratio of this approach in patients with pemphigus showing resistance to conventional therapy.

关键词： serological activity     leukapheresis     peripheral hematopoietic     cyclophosphamide     resistance    

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Porcine pluripotent stem cells: progress, challenges and prospects

Jianyong HAN, Yi-Liang MIAO, Jinlian HUA, Yan LI, Xue ZHANG, Jilong ZHOU, Na LI, Ying ZHANG, Jinying ZHANG, Zhonghua LIU

《农业科学与工程前沿（英文）》 2019年 第6卷 第1期   页码 8-27 doi: 10.15302/J-FASE-2018233

摘要：

Pluripotent stem cells (PSCs) are characterized by their capacity for high self-renewal and multiple differentiation potential and include embryonic stem cells, embryonic germ cells and induced PSCs. PSCs provide a very suitable model for the studies of human diseases, drugs screening, regenerative medicine and developmental biology research. Pigs are considered as an ideal model for preclinical development of human xenotransplantation, therapeutic approaches and regenerative medicine because of their size and physiological similarity to humans. However, lack of knowledge about the derivation, characterization and pluripotency mechanisms of porcine PSCs hinders progress in these biotechnologies. In this review, we discuss the latest progress on porcine PSCs generation, evaluation criteria for pluripotency, the scientific and technical questions arising from these studies. We also introduce our perspectives on porcine PSC research, in the hope of providing new ideas for generating naive porcine PSCs and animal breeding.

关键词： embryonic germ cells     embryonic stem cells     induced pluripotent stem cells     pigs     pluripotent stem cells    

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The past, present and future of bovine pluripotent stem cells: a brief overview

Xiuchun TIAN

《农业科学与工程前沿（英文）》 2019年 第6卷 第1期   页码 3-7 doi: 10.15302/J-FASE-2018247

摘要：

Although the pursuit of bovine embryonic stem cells started more than 26 years ago for the purpose of gene-targeting, true pluripotent stem cells in this economically important species are still elusive. With the rapid advances in genome-editing and cloning using homologously recombined somatic cells, the need for pluripotent stem cells for precise genetic modification in any species became questionable. With the pig being the better model for human regenerative biology, the identification of the commonalities and uniqueness of the pluripotency circuitry across mammalian species may be the main objective for studying pluripotent stem cells in the bovine.

关键词： bovine     embryonic     induced     pluripotent stem cells    

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Umbilical cord-derived mesenchymal stem cells: strategies, challenges, and potential for cutaneous regeneration

null

《医学前沿（英文）》 2012年 第6卷 第1期   页码 41-47 doi: 10.1007/s11684-012-0175-9

摘要：

Umbilical cord mesenchymal stem cells (MSCs) are a unique, accessible, and non-controversial source of early stem cells that can be readily manipulated. As the most common pluripotent cell, bone marrow-derived MSCs display limitations with the progress of stem cell therapy. By contrast, umbilical cord-derived cells, which have plentiful resources, are more accessible. However, several uncertain aspects, such as the effect of donor selection or culture conditions, long-term therapeutic effects, product consistency, and potential tumorigenicity, are the bottleneck in this clinical therapy. MSCs are predicted to undergo an unprecedented development in clinical treatment when a generally acknowledged criterion emerges. In the current paper, we highlight the application of umbilical cord-derived MSCs in skin therapies based on our previous studies, as well as the achievements of our peers in this field. This paper focuses on the strategies, challenges, and potential of this novel therapy.

关键词： umbilical cord     mesenchymal stem cells     cutaneous regeneration    

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Mesenchymal stem cells hold promise for regenerative medicine

Shihua Wang, Xuebin Qu, Robert Chunhua Zhao

《医学前沿（英文）》 2011年 第5卷 第4期   页码 372-378 doi: 10.1007/s11684-011-0164-4

摘要： Regenerative medicine is an emerging interdisciplinary field of research that uses several technological approaches including stem cells to repair tissues. Mesenchymal stem cells (MSCs), a type of adult stem cell, have generated a great amount of interest over the past decade in this field. Numerous studies have explored the role of MSCs in tissue repair and modulation of allogeneic immune responses. The mechanisms through which MSCs exert their therapeutic potential rely on some key properties of the cells as follows: the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, cardiomyocytes, hepatocytes, endothelial, and neuronal cells; the ability to secrete multiple bioactive molecules capable of stimulating the recovery of injured cells and inhibiting inflammation; the lack of immunogenicity; and the ability to perform immunomodulatory functions. In the present review, we focus on these three aspects upon which the therapeutic effects of MSCs are mainly based. Furthermore, some pathological conditions under which the application of MSCs should be done with caution are also mentioned.

关键词： mesenchymal stem cells     differentiation     immunomodulation     regenerative medicine    

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Highlights for special issue on “Large Animal Stem Cells”

Jianyong HAN

《农业科学与工程前沿（英文）》 2019年 第6卷 第1期   页码 1-2 doi: 10.15302/J-FASE-2019251

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标题 作者 时间 类型 操作

Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property

null

期刊论文

Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity

Chuanfeng Wu, Cynthia E. Dunbar

期刊论文

Advancement of human leukocyte antigen-partially matched related hematopoietic stem cell transplantation

null

期刊论文

In vivo imaging of hematopoietic stem cell development in the zebrafish

Panpan Zhang, Feng Liu

期刊论文

Lung transplantation for bronchiolitis obliterans syndrome after allogenic hematopoietic stem cell transplantation

null

期刊论文

Risk stratification system for skin and soft tissue infections after allogeneic hematopoietic stem cell

期刊论文

Everyone has a donor: contribution of the Chinese experience to global practice of haploidentical hematopoieticstem cell transplantation

Meng Lv, Yingjun Chang, Xiaojun Huang

期刊论文

Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult

null

期刊论文

Determination of telomerase activity in stem cells and non-stem cells of breast cancer

LI Zhi, HE Yanli, ZHANG Jiahua, ZHANG Jinghui, HUANG Tao

期刊论文

Autologous peripheral hematopoietic stem-cell transplantation in a patient with refractory pemphigus

SUN Ledong, SUN Jing, ZENG Kang, MENG Fanyi, DIAO Youtao, XU Dan, HUANG Liang, ZHAO Jie, Liu Qifa

期刊论文

Porcine pluripotent stem cells: progress, challenges and prospects

Jianyong HAN, Yi-Liang MIAO, Jinlian HUA, Yan LI, Xue ZHANG, Jilong ZHOU, Na LI, Ying ZHANG, Jinying ZHANG, Zhonghua LIU

期刊论文

The past, present and future of bovine pluripotent stem cells: a brief overview

Xiuchun TIAN

期刊论文

Umbilical cord-derived mesenchymal stem cells: strategies, challenges, and potential for cutaneous regeneration

null

期刊论文

Mesenchymal stem cells hold promise for regenerative medicine

Shihua Wang, Xuebin Qu, Robert Chunhua Zhao

期刊论文

Highlights for special issue on “Large Animal Stem Cells”

Jianyong HAN

期刊论文