Organization of haemopoietic stem cells: the generation-age hypothesis.

This paper proposes that the previous division history of each stem cell is one determinant of the functional organization of the haemopoietic stem cell population. Stem cells from a lineage of stem cells which have generated many stem cells (older stem cells) are used in the animal to form blood before stem cells which have generated few stem cells (younger stem cells). The stem cell generating capacity of a lineage of stem cells is finite. After a given number of generations a stem cell is lost to the stem cell compartment by forming two committed precursors of the cell lines. Its part in blood formation is taken by the next oldest stem cell. We have called this proposal the generation-age hypothesis. Experimental evidence in support of the proposal is presented. We stripped away older stem cells from normal bone marrow and 13 day foetal liver with phase-specific drugs and revealed a younger population of stem cells whose capacity for stem cell generation was three- to four-fold greater than that of the average normal, untreated population. We aged normal stem cells by continuous irradiation and serial retransplantation and found that their stem cell generative capacity had declined eight-fold. We measured the stem cell generative capacity of stem cells in the bloodstream. It was a half to a quarter that of normal bone marrow stem cells and we found a subpopulation of circulating stem cells whose capacity for stem cell generation was an eighth to a fortieth that of normal femoral stem cells. This subpopulation was identified by its failure to express the brain-associated antigen which was present on 75% of normal femoral stem cells but was not found on their progeny, the committed precursors of granulocytes.     

ORGANIZATION OF HAEMOPOIETIC STEM CELLS: THE GENERATION-AGE HYPOTHESIS

This paper proposes that the previous division history of each stem cell is one determinant of the functional organization of the haemopoietic stem cell population. Stem cells from a lineage of stem cells which have generated many stem cells (older stem cells) are used in the animal to form blood before stem cells which have generated few stem cells (younger stem cells). The stem cell generating capacity of a lineage of stem cells is finite. After a given number of generations a stem cell is lost to the stem cell compartment by forming two committed precursors of the cell lines. Its part in blood formation is taken by the next oldest stem cell. We have called this proposal the generation-age hypothesis. Experimental evidence in support of the proposal is presented. We stripped away older stem cells from normal bone marrow and 12 day foetal liver with phase-specific drugs and revealed a younger population of stem cells whose capacity for stem cell generation was three- to four-fold greater than that of the average normal, untreated population. We aged normal stem cells by continuous irradiation and serial retransplantation and found that their stem cell generative capacity had declined eight-fold. We measured the stem cell generative capacity of stem cells in the bloodstream. It was a half, to a quarter that of normal bone marrow stem cells and we found a subpopulation of circulating stem cells whose capacity for stem cell generation was an eighth to a fortieth that of normal femoral stem cells. This subpopulation was identified by its failure to express the brain-associated antigen which was present on 75% of normal femoral stem cells but was not found on their progeny, the committed precursors of granulocytes.     

干细胞巢研究进展

干细胞巢即干细胞周围的微环境构成,一般包括干细胞的相邻细胞、粘附分子及基质等,但不同的干细胞有不同的巢结构。干细胞巢通过不同信号途径调控着干细胞的行为,使干细胞的自我更新和分化处于平衡状态。根据近年来有关干细胞巢的研究,本文从果蝇生殖系干细胞巢、哺乳动物造血干细胞巢、肠干细胞巢、毛囊表皮干细胞巢和神经干细胞巢等五个系统分别综述了干细胞巢的构成及其对干细胞的调节作用,探讨了干细胞巢作用于干细胞的内在机制。     

大兴安岭兴安落叶松(Larix gmelinii)天然林分级木转换特征

通过调查样地,作树干解析,分析了不同结构兴安落叶松天然林分级木（优势木、平均木和被压木）转换特征。研究表明：（1）不同结构的兴安落叶松天然林分级木转换年龄、方向和转换率均不同。兴安落叶松分级木转换率29.4%。分级木中,优势木、平均木和被压木转换率分别35.3%、41.2%、11.8%。分级木转换中,优势木与平均木相互转换比例较高,优势木转平均木占83.3%,平均木转优势木占85.7%;优势木向被压木转换比例仅为16.7%;被压木不能转换成优势木,只能转换成平均木,被压木中无转换占88.2%,在森林经营和抚育采伐中应考虑伐除这些被压木。（2）在林分年龄36～65a范围内,随着林分年龄增大,其转换率呈增加趋势。林分年龄30～39a、50～59a和60～69a时,其转换率分别0、33.3%和46.7%。（3）随着林分密度增加,分级木转换率呈增高趋势。当林分密度小于2500株.hm^-2时,主要于优势木与平均木间转换。当林分密度大于2500株.hm^-2时,才出现其它分级木与被压木相互转换现象。（4）不同林型分级木转换率和转换方向不同。草类-落叶松和杜香-落叶松林分级木转换率分别50%和9.5%。（5）不同水平格局林分分级木转换率不同。聚集分布和随机分布时,其转换率分别61.1%和13.3%。     

String (Cdc25) regulates stem cell maintenance, proliferation and aging in Drosophila testis

Tight regulation of stem cell proliferation is fundamental to tissue homeostasis, aging and tumor suppression. Although stem cells are characterized by their high potential to proliferate throughout the life of the organism, the mechanisms that regulate the cell cycle of stem cells remain poorly understood. Here, we show that the Cdc25 homolog String (Stg) is a crucial regulator of germline stem cells (GSCs) and cyst stem cells (CySCs) in Drosophila testis. Through knockdown and overexpression experiments, we show that Stg is required for stem cell maintenance and that a decline in its expression during aging is a critical determinant of age-associated decline in stem cell function. Furthermore, we show that restoration of Stg expression reverses the age-associated decline in stem cell function but leads to late-onset tumors. We propose that Stg/Cdc25 is a crucial regulator of stem cell function during tissue homeostasis and aging.     

The voyage of stem cell toward terminal differentiation: a brief overview

Presently, worldwide attempts are being made to apply stem cells and stem cell-derived products to a wide range of clinical applications and for the development of cell-based therapies. In order to harness stem cells and manipulate them for therapeutic application, it is very important to understand the basic biology of stem cells and identify the factors that govern the dynamics of these cells in the body. Several signaling pathways have emerged as key regulators of stem cells. Some of these signaling pathways regulate the stem cell's proliferative capacity and therefore act as direct regulators of the stem cell, whereas others are involved in shaping and maintaining the stem cell niche and therefore act as indirect regulators of the stem cell. It is difficult to identify which signaling pathways critically affect the stem cell's behavior and which are important for maintaining the quiescent population. A stem cell receives different extrinsic signals compared with the bulk population and responds to them differently. In order to manipulate these adult cells for therapeutic approaches it is crucial to identify how signaling pathways regulate stem cells either directly by regulating proliferative status or indirectly by influencing the niche. The main challenge is to identify whether different factors provide diverse extrinsic signals to the stem cell and its daughter cell population, or whether there are intrinsic differences in stem cell and daughter cell populations that is reflected in their behavior. In this study, we will focus on the various aspects of stem cell biology and differentiation, as well as exploring the potential strategies to intervene the differentiation process in order to obtain the desired yield of cells applicable in regenerative medicine.     

主要干性基因与衰老相关基因表达水平的相互拮抗关系

目前广泛地利用传统的体细胞衰老理论和方法对成体干细胞衰老进行研究,忽视了成体干细胞特有的自我更新功能和相应的干性基因的作用.干性基因的下调可能是导致间充质干细胞衰老的主要原因.通过查阅相关资料发现主要干性基因与衰老相关基因表达水平的相互拮抗关系,这体现在以下4个方面:a.干细胞衰老伴随着干性基因的下调;b.干性基因表达抑制细胞的衰老;c.干性基因抑制衰老相关基因的表达;d.抑制衰老相关基因促进干性基因的表达.干性基因与衰老相关基因的表达水平存在相互拮抗关系,这为成体干细胞衰老可能源于成体干细胞的干性降低的观点提供了坚实的分子基础.     

Characterisation of normal and cancer stem cells: One experimental paradigm for two kinds of stem cells

The characterisation of normal stem cells and cancer stem cells uses the same paradigm. These cells are isolated by a fluorescence‐activated cell sorting step and their stemness is assayed following implantation into animals. However, differences exist between these two kinds of stem cells. Therefore, the translation of the experimental procedures used for normal stem cell isolation into the research field of cancer stem cells is a potential source of artefacts. In addition, normal stem cell therapy has the objective of regenerating a tissue, while cancer stem cell‐centred therapy seeks the destruction of the cancer tissue. Taking these differences into account is critical for anticipating problems that might arise in cancer stem cell‐centred therapy and for upgrading the cancer stem cell paradigm accordingly.     

肿瘤干细胞及其耐药机制

肿瘤干细胞是存在于造血系统肿瘤和一些实体瘤中具有干细胞特性的细胞。肿瘤干细胞假说认为,经药物治疗后肿瘤复发和转移与肿瘤干细胞残存有密切关系。其原因可能是肿瘤干细胞高表达ABC转运蛋白和Bcl-2抗凋亡蛋白,同时其本身又具有一些干细胞特性。对肿瘤干细胞耐药机制的研究,将有助于发现新的肿瘤治疗靶点和更好的抗癌策略。     

The problem of stem cells in plants

The uppermost cells of the root and shoot apical meristems are considered as stem cells. They are similar, in many features, to the stem cells of animals. But, unlike animals, the stem cells can repeatedly arise in plants during morphogenesis and regeneration or in tissue culture from actively dividing or differentiated cells. When the stem cells are removed, they can be repeatedly restored from the actively dividing cells. The maintenance of the population of stem cells is determined by interaction between the stem cells and actively dividing cells located below according to the feedback principle. The protein synthesized in the stem cells determines how the lower located cells affect the stem cells. Specificity of stem cell identification in plants is discussed.     

The Problem of Stem Cells in Plants

The uppermost cells of the root and shoot apical meristems are considered as stem cells. They are similar, in many features, to the stem cells of animals. But, unlike animals, the stem cells can repeatedly arise in plants during morphogenesis and regeneration or in tissue culture from actively dividing or differentiated cells. When the stem cells are removed, they can be repeatedly restored from the actively dividing cells. The maintenance of the population of stem cells is determined by interaction between the stem cells and actively dividing cells located below according to the feedback principle. The protein synthesized in the stem cells determines how the lower located cells affect the stem cells. Specificity of stem cell identification in plants is discussed.     

CD9 is a surface marker on mouse and rat male germline stem cells

Spermatogenesis is dependent on a small population of stem cells. Despite the biological significance of spermatogonial stem cells, their analysis has been hampered by their scarcity. However, spermatogonial stem cells can be enriched by selection with an antibody against cell-surface molecules. In this investigation, we searched for new antigens expressed on spermatogonial stem cells. Using the spermatogonial transplantation technique, we examined expression of the CD9 molecule, which is commonly expressed on stem cells of other tissues. Selection of both mouse and rat testis cells with anti-CD9 antibody resulted in 5- to 7-fold enrichment of spermatogonial stem cells from intact testis cells, indicating that CD9 is commonly expressed on spermatogonial stem cells of both species. Therefore, CD9 may be involved in the common machinery in stem cells of many self-renewing tissues, and the identification of a common surface antigen on spermatogonial stem cells of different species has important implications for the development of a technique to enrich stem cells from other mammalian species.     

A Model of the Partitioning of New Above-ground Dry Matter

A model for the partitioning of new above-ground dry matterof a vegetative dicotyledonous plant is developed. It assumestwo distinct functional components of the stem tissues. One,the primary stem tissue, includes physiologically active tissuessuch as xylem, phloem and meristematic tissues, and the other,secondary stem tissue, includes the main mechanical structures.The model is used to examine the partitioning of dry matterbetween leaf and stem tissues, and its behavour is comparedwith experimental observations. Partitioning, leaf, stem, secondary stem tissues     

Functional assessment of self-renewal activity of male germline stem cells following cytotoxic damage and serial transplantation

Spermatogenesis is dependent on a small population of stem cells. Although stem cells are believed to expand infinitely, there is little functional evidence regarding whether spermatogonial stem cells can increase in their number. Using the spermatogonial transplantation technique, we evaluated the proliferative potential of spermatogonial stem cells in two models of regeneration. After busulfan injection to deplete stem cells, the surviving stem cells were able to expand by at least 15.8-fold within 2 mo. On the other hand, a serial transplantation study indicated that one transplanted stem cell was able to expand by 3.8- and 12-fold within 2 and 4 mo, respectively. These results provide direct functional evidence for the expansion of stem cells and establish the basis for further characterization of the stem cell self-renewal process.     

Stem cells in the eye

In the adult organism, all tissue renewal and regeneration depends ultimately on somatic stem cells, and the eye is no exception. The importance of limbal stem cells in the maintenance of the corneal epithelium has long been recognised, and such cells are now used clinically for repair of a severely damaged cornea. The slow cycling nature of lens epithelial cells and their ability to terminally differentiate into fiber cells are suggestive of a stem cell lineage. Furthermore, recent studies have identified progenitor cells in the retina and ocular vasculature which may have important implications in health and disease. Although the recent literature has become flooded with articles discussing aspects of stem cells in a variety of tissues our understanding of stem cell biology, especially in the eye, remains limited. For instance, there is no definitive marker for ocular stem cells despite a number of claims in the literature, the patterns of stem cell growth and amplification are poorly understood and the microenvironments important for stem cell regulation and differentiation pathways are only now being elucidated. A greater understanding of ocular stem cell biology is essential if the clinical potential for stem cells is to be realised. For instance; How do we treat stem cell deficiencies? How do we use stem cells to regenerate damaged retinal tissue? How do we prevent stem cell lineages contributing to retinal vascular disease? This review will briefly consider the principal stem cells in the mature eye but will focus in depth on limbal stem cells and corneal epithelium. It will further discuss their role in pathology and their potential for therapeutic intervention.     

Numerical simulation of the insertion process of an uncemented hip prosthesis in order to evaluate the influence of residual stress and contact distribution on the stem initial stability

The long-term success of a cementless total hip arthroplasty depends on the implant geometry and interface bonding characteristics (fit, coating and ingrowth) and on stem stiffness. This study evaluates the influence of stem geometry and fitting conditions on the evolution and distribution of the bone–stem contact, stress and strain during and after the hip stem insertion, by means of dynamic finite element techniques. Next, the influence of the mechanical state (bone–stem contact, stress and strain) resulted from the insertion process on the stem initial resistance to subsidence is investigated. In addition, a study on the influence of bone–stem interface conditions (friction) on the insertion process and on the initial stem stability under physiological loading is performed. The results indicate that for a stem with tapered shape the contact in the proximal part of the stem was improved, but contact in the calcar region was achieved only when extra press-fit conditions were considered. Changes in stem geometry towards a more tapered shape and extra press fit and variation in the bone–stem interface conditions (contact amount and high friction) led to a raise in the total insertion force. A direct positive relationship was found between the stem resistance to subsidence and stem geometry (tapering and press fit), bone–stem interface conditions (bone–stem contact and friction interface) and the mechanical status at the end of the insertion (residual stress and strain). Therefore, further studies on evaluating the initial performance of different stem types should consider the parameters describing the bone–stem interface conditions and the mechanical state resulted from the insertion process.     

Fibroblast growth factor signaling in embryonic and cancer stem cells

Cancer stem cells are cancer cells that originate from the transformation of normal stem cells. The most important property of any stem cell is the ability to self-renew. Through this property, there are striking parallels between normal stem cells and cancer stem cells. Both cell types share various markers of “stemness”. In particular, normal stem cells and cancer stem cells utilize similar molecular mechanisms to drive self-renewal, and similar signaling pathways may induce their differentiation.The fibroblast growth factor 2 (FGF-2) pathway is one of the most significant regulators of human embryonic stem cell (hESC) self-renewal and cancer cell tumorigenesis. Here we summarize recent data on the effects of FGF-2 and its receptors on hESCs and leukemic stem/progenitor cells. Also, we discuss the similarities of these findings with stem cell renewal and differentiation phenotypes.     

间充质干细胞过滤分离器制备人羊膜间充质干细胞的研究

自然存在的间充质干细胞数量少,限制了其研究应用。依靠自主发明的间充质干细胞过滤分离器,分离制备了人羊膜间充质干细胞,并对制备的干细胞进行了三维培养扩增。结果表明,制备的干细胞形态长势良好,并能诱导分化为类胰岛样组织。与常规方法相比,干细胞收获率提高了8倍以上,且细胞活性状态良好。间充质干细胞过滤分离器可以批量制备高质量的各种间充质干细胞,有利于高效率地建设各种间充质干细胞库,以促进间充质干细胞的研究应用。     

Generation,characterization and potential therapeutic applications of mature and functional hepatocytes from stem cells

Liver cancer is the sixth most common tumor in the world and the majority of patients with this disease usually die within 1 year. The effective treatment for end‐stage liver disease (also known as liver failure), including liver cancer or cirrhosis, is liver transplantation. However, there is a severe shortage of liver donors worldwide, which is the major handicap for the treatment of patients with liver failure. Scarcity of liver donors underscores the urgent need of using stem cell therapy to the end‐stage liver disease. Notably, hepatocytes have recently been generated from hepatic and extra‐hepatic stem cells. We have obtained mature and functional hepatocytes from rat hepatic stem cells. Here, we review the advancements on hepatic differentiation from various stem cells, including hepatic stem cells, embryonic stem cells, the induced pluripotent stem cells, hematopoietic stem cells, mesenchymal stem cells, and probably spermatogonial stem cells. The advantages, disadvantages, and concerns on differentiation of these stem cells into hepatic cells are highlighted. We further address the methodologies, phenotypes, and functional characterization on the differentiation of numerous stem cells into hepatic cells. Differentiation of stem cells into mature and functional hepatocytes, especially from an extra‐hepatic stem cell source, would circumvent the scarcity of liver donors and human hepatocytes, and most importantly it would offer an ideal and promising source of hepatocytes for cell therapy and tissue engineering in treating liver disease. J. Cell. Physiol. 228: 298–305, 2013. © 2012 Wiley Periodicals, Inc.