The chiaroscuro stem cell: a unified stem cell theory

Hematopoiesis has been considered hierarchical in nature, but recent data suggest that the system is not hierarchical and is, in fact, quite functionally plastic. Existing data indicate that engraftment and progenitor phenotypes vary inversely with cell cycle transit and that gene expression also varies widely. These observations suggest that there is no progenitor/stem cell hierarchy, but rather a reversible continuum. This may, in turn, be dependent on shifting chromatin and gene expression with cell cycle transit. If the phenotype of these primitive marrow cells changes from engraftable stem cell to progenitor and back to engraftable stem cell with cycle transit, then this suggests that the identity of the engraftable stem cell may be partially masked in nonsynchronized marrow cell populations. A general model indicates a marrow cell that can continually change its surface receptor expression and thus responds to external stimuli differently at different points in the cell cycle.     

The leukemic stem cell

Malignant stem cells have recently been described as the source of several types of human cancer. These unique cell types are typically rare and possess properties that are distinct from most other tumor cells. The properties of leukemic stem cells indicate that current chemotherapy drugs will not be effective. The use of current cytotoxic agents is not effective in leukemia because the agents target both the leukemic and normal stem cell populations. Consequently, new strategies are required that specifically and preferentially target the malignant stem cell population, while sparing normal stem cells. Several well known agents are lethal for the leukemic stem cell in preclinical testing. They include parthenolide, commonly known as feverfew, and TDZD-8. They have undergone various levels of preclinical development, but have not been used in patients as yet in the cancer setting. These drugs and combinations of existing therapies that target the leukemic stem cell population may provide a cure in this disease. This article summarizes recent findings in the leukemic stem cell field and discusses new directions for therapy.     

胰腺干细胞的分子标志物

目前,人们已越来越认识到胰腺干细胞的重要性.其中,对胰腺干细胞研究最多的是,用胰岛细胞移植治疗糖尿病,对于胰腺干细胞治疗各种胰腺损伤、胰腺炎、胰腺癌的研究仍在进行当中.对胰腺干细胞分子标志物的掌握是胰腺干细胞治疗研究的基础和重点,但目前缺乏唯一的干细胞标志物和可信的评价指标.此文将介绍干细胞、目前已知的胰腺干细胞分子标志物及其现状,如目前关注较多的PDX1、巢素蛋白、神经元素3、细胞角蛋白、波形蛋白、Notch信号及其他的分子标志物及其现状.     

干细胞因子在骨髓干细胞心肌内移植治疗中的作用研究

目的探讨干细胞因子（SCF）在骨髓干细胞心肌内移植中的作用机制及对移植治疗的影响。方法对急性心肌梗死（AMI）大鼠进行骨髓干细胞心肌内移植治疗,RT—PCR方法检测骨髓中SCF表达水平的变化,并用SCF表达水平不同的骨髓干细胞进行心肌内移植治疗,超声心动图检测心脏结构、功能的变化;ELISA方法检测心肌组织、血和骨髓中SCF蛋白水平的变化。结果AMI1周时骨髓中SCF mRNA表达明显降低（P〈0．01）,接受移植治疗大鼠骨髓中SCF mRNA表达未出现降低。不同SCF表达水平的骨髓干细胞进行心肌内移植治疗均能使心脏射血分数达到70％,各组之间差异无统计学意义。移植治疗后1周血清中SCF蛋白的表达水平明显低于正常对照（P〈0．05）。结论骨髓干细胞心肌内移植可能通过SCF产生骨髓动员作用;心肌梗死或曾接受移植治疗个体的骨髓干细胞同样可用于心肌内移植治疗,不影响心功能的改善。     

The marrow stem cell: the continuum

The marrow hematopoietic stem cell is currently being redefined as to all aspects of its phenotype and its total differentiation capacity. This redefinition now includes its plasticity as to production of nonhematopoietic and hematopoietic cell types, the determinants of its in vivo engraftment potential and its expression of stem cell functional characteristics.     

Embryonic stem cell

Mouse embryonic stem (ES) cells are the cells that possess pluripotential differentiation activity into not only all somatic cells but also germ cells. Genetic alteration of mouse ES cells can be easily achieved and such genetic modification can be introduced into the animal, since ES cells are differentiated into germ cells in vivo. This technology enables us to analyze the function of any particular genes of interest in mice. And in vitro differentiation induction of mouse ES cells into various cell lineages, such as blood cells, neural cells, and cardiac muscle cells, has been studied. In vitro hematopoietic differentiation experiments were carried out most extensively and can be regarded as a model system of induction. Recently, human ES cells have been established. Many scientists, clinicians and even mass media have entertained the idea that human ES cells can be used after changing the cells into lineage-specific stem cells or progenitor cells such as hematopoietic stem cells and neural progenitor cells.     

肠道干细胞

引言干细胞具有自我更新能力和向多种分化的潜能,其中造血干细胞向多种血细胞分化及造血干细胞移植对某些血液病的治疗作用已被认识和熟悉,近年来研究认为,肠道也存在干细胞,且肠道干细胞研究取得了一些进展,肠道干细胞可分化为肠上皮的所有细胞系,参与正常肠黏膜组织更新的生理过程及一些病理过程.迄今国内对肠道干细胞的研究报道较少,本文复习了近年来国外有关肠道干细胞研究的文献并综述如下:     

The hepatic stem cell niche: identification by label-retaining cell assay

Label retention assays remain the state-of-the-art approach to identify the location of intraorgan epithelial stem cell niches, in situ and in vivo. They are commonly used in organs with rapid cell turnover but have not been applied to the liver, where cell turnover is very slow. We used a sublethal dose of acetaminophen administered coincident with bromodeoxyuridine to load possible hepatic stem cells in mice with label and then administered a second, sublethal chase of acetaminophen to accomplish "washout" of label from transit amplifying cell populations. CONCLUSION: Four possible hepatic stem cell niches are identified by this approach: the canal of Hering (proximal biliary tree), intralobular bile ducts, periductal "null" mononuclear cells, and peribiliary hepatocytes. These results confirm several different and often contradictory lines of investigation regarding the intrahepatic location of stem/progenitor cells and suggest that the liver has a multi-tiered, flexible system of regeneration rather than a single stem/progenitor cell location.     

胰腺干细胞

引言近年研究发现,成年胰腺中存在干细胞,胰腺干细胞能分化形成胰腺导管、胰岛及胰腺外分泌腺泡等特定的胰腺组织细胞,并具有无限分裂和自我更新能力胰腺干细胞属未分化细胞,可表达干细胞的一些分子     

肝干细胞

干细胞是指组织中最原始的具有多潜能性、自我更新的细胞,但不同于组织中的一些前体细胞。虽然前体细胞也具有自我更新能力,但自我更新时间较为短暂。目前通常将干细胞分为三类：①全能干细胞：如胚胎干细胞可以分化形成所有的成体组织细胞,甚至发育成完整个体。②多能干细胞：具有多向分化潜能,可以分化形成除自身组织细胞外的其他组织细胞,如造血干细胞、间充质干细胞和肝干细胞等。③专能干细胞：维持某一特定组织细胞的自我更新,如肠上皮干细胞等。     

The continuum model of marrow stem cell regulation

PURPOSE OF REVIEW: We review the continuum model of stem cell regulation. A series of studies on purified lineage negative rhodamine low Hoechst low murine stem cells driven through cell cycle by cytokine exposure have shown that many phenotypic features show reversible changes with cycle progression. RECENT FINDINGS: We and others have shown that purified murine marrow stem cells are a cycling population. Features that are labile with cycle progression are in-vivo engraftment, progenitor numbers, expression of adhesion proteins and cytokine receptors, global gene expression and differentiation into granulocytes and megakaryocytes. These observations have led to a theory that regulation of hematopoietic stem cells is on a continuum and not in a hierarchy. Out-of-tissue plasticity in which marrow cells show a capacity to produce nonhematopoietic cells in non-marrow tissues also exists. We have shown 'robust' production of lung and skeletal muscle cells by marrow cells in the presence of appropriate tissue injury and demonstrated that the capacity of marrow cells to produce nonhematopoietic cells in the lung also varies reversibly with cell cycle status. SUMMARY: Thus, stem cells show a plastic plasticity and the continuum appears to hold for both nonhematopoietic and hematopoietic lineages.     

The use of radioimmunoconjugates in stem cell transplantation

Radiolabeled monoclonal antibodies have been used with encouraging results in conjunction with stem cell transplantation for patients with hematologic malignancies targeting a variety of surface antigens including CD33, CD45 and CD66 for leukemias, CD20 and CD22 for non-Hodgkin's lymphomas, and ferritin for Hodgkin's disease. The results obtained targeting epithelial antigens on solid tumors, however, have generally been less encouraging, primarily due to the relative insensitivity of these malignancies to ionizing radiation. In this report we review clinical studies that have incorporated myeloablative doses of targeted radiation using radiolabeled antibodies in conjunction with stem cell transplant regimens.     

The epigenetic basis of hematopoietic stem cell aging

Highly proliferative tissues such as the gut, skin, and bone marrow lose millions of cells each day to normal attrition and challenge from different biological adversities. To achieve a lifespan beyond the longevity of individual cell types, tissue-specific stem cells sustain these tissues throughout the life of a human. For example, the lifespan of erythrocytes is about 100 days and adults make about two million new erythrocytes every second. A small pool of hematopoietic stem cells (HSCs) in the bone marrow is responsible for the lifetime maintenance of these populations. However, there are changes that occur within the HSC pool during aging. Biologically, these changes manifest as blunted immune responses, decreased bone marrow cellularity, and increased risk of myeloid diseases. Understanding the molecular mechanisms underlying dysfunction of aging HSCs is an important focus of biomedical research. With advances in modern health care, the average age of the general population is ever increasing. If molecular or pharmacological interventions could be discovered that rejuvenate aging HSCs, it could reduce the burden of age related immune system compromise as well as open up new opportunities for treatment of hematological disorders with regenerative therapy.     

Minireview: The stem cell next door: skeletal and hematopoietic stem cell "niches" in bone

Long known to be home to hematopoietic stem cells (HSC), the bone/bone marrow organ and its cellular components are directly implicated in regulating hematopoiesis and HSC function. Over the past few years, advances on the identity of HSC "niche" cells have brought into focus the role of cells of osteogenic lineage and of marrow microvessels. At the same time, the identity of self-renewing multipotent skeletal progenitors (skeletal stem cells, also known as mesenchymal stem cells) has also been more precisely defined, along with the recognition of their own microvascular niche. The two sets of evidence converge in delineating a picture in which two kinds of stem cells share an identical microanatomical location in the bone/bone marrow organ. This opens a new view on the manner in which the skeleton and hematopoiesis can cross-regulate via interacting stem cells but also a novel view of our general concept of stem cell niches.     

Risk assessment in haematopoietic stem cell transplantation: stem cell source

Bone marrow (BM) has been used for many years as the unique source of progenitor cells for allogeneic transplantation. However, two other sources of progenitor cells, peripheral blood (PB) and umbilical cord (UC), are being increasingly used. The type of graft is one of the most important factors in determining the speed and robustness of the reconstitution after the transplant of monocytes, T lymphocytes, B lymphocytes, NK cells, and dendritic cells. This fact is of especial relevance since the most important reactions after allogeneic transplants - e.g. graft-versus-host disease (GVHD), graft-versus-leukaemia effect (GvL), achievement of full donor chimerism, and fight against infections - are strongly influenced by a rapid and robust reconstitution of these cells. For this reason, the choice of the type of graft for allogeneic transplantation will influence the clinical outcome.     

The current role of T cell depletion in paediatric stem cell transplantation

Haematopoeitic stem cell transplantation (HSCT) is a curative procedure for children with malignant and non‐malignant haematological disease as well as an expanding number of inherited disorders. Most patients lack a human leucocyte antigen‐matched related donor, making alternative donors, such as closely matched unrelated donors, unrelated umbilical cord blood donations and haploidentical donors, necessary choices. T cell depletion (TCD) has been employed for over 30 years to reduce the risk of graft‐versus‐host disease (GvHD) associated with non‐genoidentical HSCT. However, until recently overall survival had not improved with TCD due to increased rates of graft failure, disease relapse and delayed immune reconstitution. Recent advances in graft manipulation and reduced toxicity conditioning regimens have offered renewed hope, particularly for children undergoing haploidentical HSCT, where encouraging results have been achieved using negative depletion techniques to retain beneficial accessory cells, which speed immune reconstitution and reduce disease relapse. Translational work building on megadose CD34⁺ selected grafts, including pathogen‐specific immunotherapy, suicide gene therapy and other adoptive cellular immunotherapies, has also offered improved outcomes for such patients.     

Hematopoietic stem cell transplantation for sickle cell disease: The changing landscape

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for sickle cell disease (SCD); however, its use is limited by lack of suitable human leukocyte antigen (HLA)-matched donors and decreased application in older patients with significant morbidity. Myeloablative, HLA-identical sibling transplantation in children with SCD offers excellent long-term survival, with overall and event-free survival rates of 95% and 92%, respectively. However, the risk of graft-versus-host-disease, infections, infertility, and other long-term transplant complications, further limits its widespread use. Recent approaches using reduced intensity conditioning (RIC) are associated with lower toxicity, allowing extension of this modality to children and adults with significant morbidity; however, these approaches are also associated with increased risk of graft failure. The optimal RIC regimen that strikes the optimal balance between maximizing the rate of stable engraftment while minimizing transplant-related morbidity and mortality is unknown. Alternative donor transplants, most prominently, partial HLA-mismatched related transplants (haploidentical), are being investigated with promising initial results. This review will discuss long-term results of HLA-matched sibling HSCT for SCD, and recent updates on HLA-matched unrelated donor and unrelated umbilical cord blood HSCT for SCD.