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.     

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.     

An adult tissue-specific stem cell molecular phenotype is activated in epithelial cancer stem cells and correlated to patient outcome

Recent studies have shown that embryonic stem cell-like molecular phenotypes are commonly activated in human epithelial primary tumors and are linked to adverse patient prognosis. However it remains unclear whether these correlations to outcome are linked to the differentiation status of the human primary tumours1 or represent molecular reminiscences of epithelial cancer stem cells. In addition, while it has been demonstrated that leukemic cancer stem cells re-acquire an embryonic stem cell-like phenotype, the molecular basis of stem cell function in epithelial cancer stem cells has not been investigated. Here we show that a normal adult tissue-specific stem cell molecular phenotype is commonly activated in epithelial cancer stem cells and for the first time provide evidence that enrichment in cancer stem cells-specific molecular signatures are correlated to highly aggressive tumor phenotypes in human epithelial cancers.     

Therapeutic targeting of a stem cell niche

The specialized microenvironment or niche where stem cells reside provides regulatory input governing stem cell function. We tested the hypothesis that targeting the niche might improve stem cell-based therapies using three mouse models that are relevant to clinical uses of hematopoietic stem (HS) cells. We and others previously identified the osteoblast as a component of the adult HS cell niche and established that activation of the parathyroid hormone (PTH) receptor on osteoblasts increases stem cell number. Here we show that pharmacologic use of PTH increases the number of HS cells mobilized into the peripheral blood for stem cell harvests, protects stem cells from repeated exposure to cytotoxic chemotherapy and expands stem cells in transplant recipients. These data provide evidence that the niche may be an attractive target for drug-based stem cell therapeutics.     

Dynamics of the male germline stem cell population during aging of Drosophila melanogaster

Drosophila melanogaster has emerged as an important model system for the study of both stem cell biology and aging. Much is known about how molecular signals from the somatic niche regulate adult stem cells in the germline, and a variety of environmental factors as well as single point mutations have been shown to affect lifespan. Relatively little is known, however, about how aging affects specific populations of cells, particularly adult stem cells that may be susceptible to aging-related damage. Here we show that male germline stem cells (GSCs) are lost from the stem cell niche during aging, but are efficiently replaced to maintain overall stem cell number. We also find that the division rate of GSCs slows significantly during aging, and that this slowing correlates with a reduction in the number of somatic hub cells that contribute to the stem cell niche. Interestingly, slowing of stem cell division rate was not observed in long-lived methuselah mutant flies. We finally investigated whether two mechanisms that are thought to be used in other adult stem cell types to minimize the effects of aging were operative in this system. First, in many adult tissues stem cells exhibit markedly fewer cell cycles relative to transit-amplifying cells, presumably protecting the stem cell pool from replication-associated damage. Second, at any given time not all stem cells actively cycle, leading to 'clonal succession' from the reserve pool of initially quiescent stem cells. We find that neither of these mechanisms is used in Drosophila male GSCs.     

Interstitial stem cell proliferation in hydra: evidence for strain-specific regulatory signals.

We have examined the growth behavior of small numbers of interstitial stem cells transplanted into tissue of genetically unrelated strains of Hydra magnipapillata. We show that such stem cells, which are at low density following transplantation, proliferate more rapidly than the stem cells of the host, which are at normal density. The rapid proliferation is similar to the proliferation rate of stem cells transplanted into interstitial cell free tissue. The results suggest that stem cells transplanted into heterotypic tissue are unable to "sense" the presence of host stem cells and to adopt their growth rate to that of the surrounding cells. Thus, the feedback signal which negatively regulates stem cell growth as a function of stem cell density must be strain specific.     

Ectopic activation of Dpp signalling in the male Drosophila germline inhibits germ cell differentiation

The mechanisms that control differentiation of stem cells to specialised cell types probably include factors intrinsic to stem cells as well as extrinsic factors produced by the microenvironment of the stem cell niche. The Drosophila male germline is renewed from a population of stem cells located in the apical tip of the adult testis. The morphological relationship between germline stem cells and their surrounding somatic cells is well understood but the factors that regulate stem cell proliferation and differentiation are still being uncovered. This study examined the effect of stimulating Dpp signalling directly in male germ cells. Ectopic Dpp or Activin signalling resulted in overproliferation of both stem cell-like and spermatogonial-like cells in the apical region of the testis. A third cell population that expressed stem cell markers was seen to proliferate in the distal testis when Dpp signalling was either stimulated or repressed in germline stem cells.     

Stem cell dynamics in response to nutrient availability

When nutrient availability becomes limited, animals must actively adjust their metabolism to allocate limited resources and maintain tissue homeostasis. However, it is poorly understood how tissues maintained by adult stem cells respond to chronic changes in metabolism. To begin to address this question, we fed flies a diet lacking protein (protein starvation) and assayed both germline and intestinal stem cells. Our results revealed a decrease in stem cell proliferation and a reduction in stem cell number; however, a small pool of active stem cells remained. Upon refeeding, stem cell number increased dramatically, indicating that the remaining stem cells are competent to respond quickly to changes in nutritional status. Stem cell maintenance is critically dependent upon intrinsic and extrinsic factors that act to regulate stem cell behavior. Activation of the insulin/IGF signaling pathway in stem cells and adjacent support cells in the germline was sufficient to suppress stem cell loss during starvation. Therefore, our data indicate that stem cells can directly sense changes in the systemic environment to coordinate their behavior with the nutritional status of the animal, providing a paradigm for maintaining tissue homeostasis under metabolic stress.     

Signals that regulate stem cell activity during plant development

Plant stem cells are used continuously to generate new structures during the entire life-span of the organism. In the adult plant, stem cells are found in specialized structures called meristems. The meristems contain the stem cell niche together with rapidly dividing daughter cells that will ultimately differentiate into specific cell types. Some of the master genes that orchestrate the establishment and maintenance of the stem cell niche have now been identified in both the root and the shoot. Recent results show that these genes also determine the fate of the stem cells and that feedback signals from differentiated cells are involved in stem cell specification. These advances have provided a framework to understand how short-range and long-range signals are integrated to specify and position the stem cell niche in the meristems, and how the differentiation potential of plant stem cells is controlled.     

果蝇干细胞研究进展

本文主要介绍了果蝇五种干细胞,包括生殖干细胞、神经干细胞、造血干细胞、小肠干细胞、肾干细胞及其微环境（niche）的组成成份;简述了五种干细胞系统对应的分子标记;最后重点介绍了调控每种干细胞系统的信号通路。     

Patterns of cell division and the risk of cancer

Epidermal and intestinal tissues divide throughout life to replace lost surface cells. These renewing tissues have long-lived basal stem cell lineages that divide many times, each division producing one stem cell and one transit cell. The transit cell divides a limited number of times, producing cells that move up from the basal layer and eventually slough off from the surface. If mutation rates are the same in stem and transit divisions, we show that minimal cancer risk is obtained by using the fewest possible stem divisions subject to the constraints imposed by the need to renew the tissue. In this case, stem cells are a necessary risk imposed by the constraints of tissue architecture. Cairns suggested that stem cells may have lower mutation rates than transit cells do. We develop a mathematical model to study the consequences of different stem and transit mutation rates. Our model shows that stem cell mutation rates two or three orders of magnitude less than transit mutation rates may favor relatively more stem divisions and fewer transit divisions, perhaps explaining how renewing tissues allocate cell divisions between long stem and short transit lineages.     

Effect of stem length to stem slender ratio of current-year twigs on the leaf display efficiency in evergreen and deciduous broadleaved trees

Aims Branches and leaves are the two main structural units of tree crown composition. Among the adaptive strategies of plants, the functional traits of branches and the relationships between branch traits and leaf traits determine the capacity of trees to access light and space. In this study, our objective is to test the hypothesis that leaf display efficiency is affected by the stem length to stem slender ratio within current-year twigs.Methods The stem length to stem slender ratios of current-year twigs were used as the proxy of stem structure traits. Leaf area ratio (total leaf area per stem mass), leaf density (leaf number per stem length) and leaf/stem mass ratio (total leaf mass per stem mass) were used as the proxies of leaf display efficiency. The relationship between stem structure traits and leaf display efficiency within current-year twigs were studied for 25 evergreen and 60 deciduous broadleaved woody species in Qingliang Mountain, Zhejiang, China. The standardized major axis estimation method was used to examine the scaling relationship between stem structural traits and leaf display efficiency within current-year twigs.Important findings The proxies of leaf display efficiency, measured by leaf area ratio, leaf density or leaf/stem mass ratio, were all significantly and negative correlated with stem length to stem slender ratio within current-year twigs in both evergreen and deciduous broadleaved woody species. This suggested that leaf display efficiency decreased with stem length to stem slender ratios within current-year twigs, which may reflect the role of mechanical safety and light within twigs. The slope of the relationship between leaf display efficiency and stem long-dimension structure traits in evergreen species was not significantly different from the one in deciduous species. In contrast, the y-intercept of the relationship between leaf density and stem long-dimension structure traits was significantly larger in evergreen species than in deciduous species, i.e. the leafing intensity of evergreen species was higher than that of deciduous species. Individual leaf area and specific leaf area were smaller in evergreen species than in deciduous species, which resulted in deciduous species have a larger leaf area per stem mass and leaf mass per stem mass at a given stem length to stem slender ratio compared to evergreen species. It may reflect the conservative adaptive strategy of high consumption and slow benefit in evergreen species. Our results demonstrated that leaf display efficiency could be affected by stem length, and would change with leaf life-span (deciduous versus evergreen).     

Relationships between stem cells and cancer stem cells

Stem cells have been shown to exist in a variety of tissues. Recent studies have characterized stem cell gene expression patterns, phenotypes, and potential therapeutic uses. One of the most important properties of stem cells is that of self renewal. This raises the possibility that some of the clinical properties of human tumors may be due to transformed stem cells. Similar signaling pathways may regulate self renewal in normal and transformed stem cells. These rare transformed stem cells may drive the process of tumorigenesis due to their potential for self renewal. There are important ramifications for clinical cancer treatment if the growth of solid tumors is at least partially dependent on a cancer stem cell population. In the cancer stem cell model, tumor recurrence may be due to the non-targeted stem cell compartment repopulating the tumor. If cancer stem cells can be prospectively identified and isolated, it should be possible to identify therapies that will selectively target these cells.     

Migration of multipotent interstitial stem cells in Hydra

Stem cells in Hydra represent one of the phylogenetically most ancient stem cell systems and, therefore, provide information for reconstructing the early history of stem cell control mechanisms. Hydra's interstitial stem cells are multipotent and differentiate into both somatic cell types and germ line cells. Although it is well accepted that cells of the interstitial cell lineage are migratory, the in vivo migratory potential of multipotent interstitial stem cells has never been explored. Combining in vivo tracing of genetically labeled interstitial stem cells and tissue transplantation, we show that in contrast to precursor cells, multipotent interstitial stem cells are stationary. Only when exposed to tissue depleted of the interstitial cell lineage, interstitial stem cells start to migrate and to repopulate emptied stem cell niches. We conclude that multipotent interstitial stem cells in Hydra are static and that microenvironmental cues including signals derived from the interstitial cell lineage or from niche cells can trigger a shift in collective stem cell behavior to start migration.     

Novel regulators revealed by profiling Drosophila testis stem cells within their niche

Stem cells are defined by the fact that they both self-renew, producing additional stem cells, and generate lineal descendants that differentiate into distinct functional cell types. In Drosophila, a small germline stem cell population is influenced by a complex microenvironment, the stem cell niche, which itself includes a somatic stem cell population. While stem cells are unique, their immediate descendants retain considerable stem cell character as they mitotically amplify prior to differentiation and can be induced to de-differentiate into stem cells. Despite their importance, very few genes are known that are expressed in the stem cells or their early amplifying daughters. We present here whole-genome microarray expression analysis of testes specifically enriched for stem cells, their amplifying daughters, and their niche. These studies have identified a number of loci with highly specific stem cell expression and provide candidate downstream targets of Jak/Stat self-renewal signaling. Furthermore, functional analysis for two genes predicted to be enriched has enabled us to define novel regulators of the germline lineage. The gene list generated in this study thus provides a potent resource for the investigation of stem cell identity and regulation from functional as well as evolutionary perspectives.     

Germ line stem cell competition in postnatal mouse testes

Niche is believed to affect stem cell behavior. In self-renewing systems for which functional transplantation assays are available, it has long been assumed that stem cells are fixed in the niche and that ablative treatments to remove endogenous stem cells are required for successful donor engraftment. Our results demonstrate that enriched populations of donor stem cells can produce long-lasting spermatogenic colonies in testes of immature and mature, nonablated mice, albeit at a lower frequency than in ablated mice. Colonization of nonablated recipient testes by neonate, pup, and cryptorchid adult donor spermatogonial stem cells demonstrates that competition for niche begins soon after birth and that endogenous stem cells influence the degree and pattern of donor cell colonization. Thus, a dynamic relationship between stem cell and niche exists in the testis, as has been suggested for hematopoiesis. Therefore, similar competitive properties of donor stem cells may be characteristic of all self-renewing systems.