Hematopoietic stem cell (HSC) research took hold in the 1950s with the demonstration that intravenously injected bone marrow cells can rescue irradiated mice from lethality by reestablishing blood ...cell production. Attempts to quantify the cells responsible led to the discovery of serially transplantable, donor-derived, macroscopic, multilineage colonies detectable on the spleen surface 1 to 2 weeks posttransplant. The concept of self-renewing multipotent HSCs was born, but accompanied by perplexing evidence of great variability in the outcomes of HSC self-renewal divisions. The next 60 years saw an explosion in the development and use of more refined tools for assessing the behavior of prospectively purified subsets of hematopoietic cells with blood cell–producing capacity. These developments have led to the formulation of increasingly complex hierarchical models of hematopoiesis and a growing list of intrinsic and extrinsic elements that regulate HSC cycling status, viability, self-renewal, and lineage outputs. More recent examination of these properties in individual, highly purified HSCs and analyses of their perpetuation in clonally generated progeny HSCs have now provided definitive evidence of linearly transmitted heterogeneity in HSC states. These results anticipate the need and use of emerging new technologies to establish models that will accommodate such pluralistic features of HSCs and their control mechanisms.
Caspase-3 is a widely expressed member of a conserved family of proteins, generally recognized for their activated proteolytic roles in the execution of apoptosis in cells responding to specific ...extrinsic or intrinsic inducers of this mode of cell death. However, accumulating evidence indicates that caspase-3 also plays key roles in regulating the growth and homeostatic maintenance of both normal and malignant cells and tissues in multicellular organisms. Given that yeast possess an ancestral caspase-like gene suggests that the caspase-3 protein may have acquired different functions later during evolution to better meet the needs of more complex multicellular organisms, but without necessarily losing all of the functions of its ancestral yeast precursor. This review provides an update on what has been learned about these interesting dichotomous roles of caspase-3, their evolution, and their potential relevance to malignant as well as normal cell biology.
Cancer stem cells: an evolving concept Nguyen, Long V; Vanner, Robert; Dirks, Peter ...
Nature reviews. Cancer,
02/2012, Letnik:
12, Številka:
2
Journal Article
Recenzirano
The cancer stem cell (CSC) concept derives from the fact that cancers are dysregulated tissue clones whose continued propagation is vested in a biologically distinct subset of cells that are ...typically rare. This idea is not new, but has recently gained prominence because of advances in defining normal tissue hierarchies, a greater appreciation of the multistep nature of oncogenesis and improved methods to propagate primary human cancers in immunodeficient mice. As a result we have obtained new insights into why the CSC concept is not universally applicable, as well as a new basis for understanding the complex evolution, phenotypic heterogeneity and therapeutic challenges of many human cancers.
Hematopoietic stem cells (HSCs) sustain long-term reconstitution of hematopoiesis in transplantation recipients, yet their role in the endogenous steady-state hematopoiesis remains unclear. In ...particular, recent studies suggested that HSCs provide a relatively minor contribution to immune cell development in adults. We directed transgene expression in a fraction of HSCs that maintained reconstituting activity during serial transplantations. Inducible genetic labeling showed that transgene-expressing HSCs gave rise to other phenotypic HSCs, confirming their top position in the differentiation hierarchy. The labeled HSCs rapidly contributed to committed progenitors of all lineages and to mature myeloid cells and lymphocytes, but not to B-1a cells or tissue macrophages. Importantly, labeled HSCs gave rise to more than two-thirds of all myeloid cells and platelets in adult mice, and this contribution could be accelerated by an induced interferon response. Thus, classically defined HSCs maintain immune cell development in the steady state and during systemic cytokine responses.
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•A subset of self-renewing HSCs in adult bone marrow was genetically marked•HSCs provide a major sustained contribution to endogenous hematopoiesis•HSCs give rise to all immune cell types except B-1a cells and tissue macrophages•Multilineage contribution of HSCs is accelerated by interferon response
The role of hematopoietic stem cells (HSCs) in steady-state hematopoiesis remains controversial. Here, Sawai et al. use lineage tracing to reveal a major contribution of HSCs to all blood cell lineages, including myeloid cells and lymphocytes, throughout adult life.
To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast ...identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity.
► Inhibition of mitochondrial translation has antileukemia activity ► AML cells have higher mitochondrial biogenesis than normal hematopoietic cells ► Mitochondrial translation inhibition is a therapeutic strategy for AML ► Tigecycline is a potential therapeutic agent for AML therapy
Mammalian hematopoiesis is a hierarchically organized process in which all types of mature blood cells are continuously generated from more primitive cells that lack any morphological evidence of ...differentiation. However, it is now accepted that this morphologically homogeneous precursor population consists of multiple distinct subsets of cells. The most primitive of these are defined by their ability to produce similarly undifferentiated progeny through many cell divisions, in addition to generating cells with activated differentiation programs. The term hematopoietic stem cell (HSC) is now conventionally restricted to cells with this long-term self-sustaining ability. Nevertheless, clonal tracking studies have revealed significant heterogeneity in the behavior of such stringently defined HSCs. Moreover, superimposed on the heterogeneous behavior that can be elicited from the HSCs present at any given time during development are additional differences that distinguish HSCs at different times both before and after birth. The latter include changes in the representation of HSCs that display specific differentiation programs, as well as changes in their turnover and self-renewal control. Here, we summarize recent studies characterizing these developmental changes, some of the mechanisms that control them, and their potential relevance to understanding age-associated differences in leukemia as well as normal hematopoiesis.
Adult hematopoietic stem cells (HSCs) with serially transplantable activity comprise two subtypes. One shows a balanced output of mature lymphoid and myeloid cells; the other appears selectively ...lymphoid deficient. We now show that both of these HSC subtypes are present in the fetal liver (at a 1:10 ratio) with the rarer, lymphoid-deficient HSCs immediately gaining an increased representation in the fetal bone marrow, suggesting that the marrow niche plays a key role in regulating their ensuing preferential amplification. Clonal analysis of HSC expansion posttransplant showed that both subtypes display an extensive but variable self-renewal activity with occasional interconversion. Clonal analysis of their differentiation programs demonstrated functional and molecular as well as quantitative HSC subtype-specific differences in the lymphoid progenitors they generate but an indistinguishable production of multipotent and myeloid-restricted progenitors. These findings establish a level of heterogeneity in HSC differentiation and expansion control that may have relevance to stem cell populations in other hierarchically organized tissues.
► HSC subtypes differ in their ability to complete lymphoid differentiation programs ► All HSC subtypes appear early in development but later expand at different rates ► Lymphoid-deficient HSCs expand preferentially after the fetal marrow is colonized ► Individual HSCs can generate different HSC subtypes
The mammary gland in adult women consists of biologically distinct cell types that differ in their surface phenotypes. Isolation and molecular characterization of these subpopulations of mammary ...cells have provided extensive insights into their different transcriptional programs and regulation. This information is now serving as a baseline for interpreting the heterogeneous features of human breast cancers. Examination of breast cancer mutational profiles further indicates that most have undergone a complex evolutionary process even before being detected. The consequent intra-tumoral as well as inter-tumoral heterogeneity of these cancers thus poses major challenges to deriving information from early and hence likely pervasive changes in potential therapeutic interest. Recently described reproducible and efficient methods for generating human breast cancers de novo in immunodeficient mice transplanted with genetically altered primary cells now offer a promising alternative to investigate initial stages of human breast cancer development. In this review, we summarize current knowledge about key transcriptional regulatory processes operative in these partially characterized subpopulations of normal human mammary cells and effects of disrupting these processes in experimentally produced human breast cancers.
Modelling the genesis of human cancers is at a scientific turning point. Starting from primary sources of normal human cells, it is now possible to reproducibly generate several types of malignant ...cell populations. Powerful methods for clonally tracking and manipulating their appearance and progression in serially transplanted immunodeficient mice are also in place. These developments circumvent historic drawbacks inherent in analyses of cancers produced in model organisms, established human malignant cell lines, or highly heterogeneous patient samples. In this review, we survey the advantages, contributions and limitations of current
de novo
human tumorigenesis strategies and note several exciting prospects on the horizon.
A better understanding of the earliest stages of human cancer formation can enable future improvements in early detection, diagnosis and treatment. In this review, the authors summarize the methods enabling
de novo
tumorigenesis protocols to be applied to human cells and the insights derived from them to date, as well as the exciting and relevant technical developments anticipated to extend even further the utility of these strategies.
The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules ...that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.
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