Transcriptional regulation of Rex1 (zfp42) in normal prostate epithelial cells and prostate cancer cells

The enormous regenerative capacity of the blood system to sustain functionally mature cells are generated from highly proliferative, short‐lived progenitors, which in turn arise from a rare population of pluripotent and self‐renewing hematopoietic stem cells (HSC). In the bone marrow, these stem cells are kept in a low proliferative, relatively quiescent state in close proximity to stromal cells and osteoblasts, forming specialized niches. The interaction in particular to bone is crucial to prevent exhaustion of HSCs from uncontrolled cell‐cycle entry and to excessive proliferation. In addition, the niche and its components protect stem cells from stress, such as accumulation of reactive oxygen species and DNA damage. One of the key issues is to identify conditions to increase the number of HSCs, either in vivo or during ex vivo growth cultures. This task has been very difficult to resolve and most attempts have been unsuccessful. However, the mechanistic insights to HSC self‐renewal and preservation are gradually increasing and there is now hope that future research will enable scientists and clinicians to modulate the process. In this review, we will focus on the molecular mechanisms of self‐renewal and HSC maintenance in the light of novel findings that HSCs reside at the lowest end of an oxygen gradient. Hypoxia appears to regulate hematopoiesis in the bone marrow by maintaining important HSC functions, such as cell cycle control, survival, metabolism, and protection against oxidative stress. To improve the therapeutic expansion of HSCs we need to learn more about the molecular mechanisms of hypoxia‐mediated regulation. J. Cell. Physiol. 222:17–22, 2010. © 2009 Wiley‐Liss, Inc.     

Cell cycle regulation in hematopoietic stem cells

Hematopoietic stem cells (HSCs) give rise to all lineages of blood cells. Because HSCs must persist for a lifetime, the balance between their proliferation and quiescence is carefully regulated to ensure blood homeostasis while limiting cellular damage. Cell cycle regulation therefore plays a critical role in controlling HSC function during both fetal life and in the adult. The cell cycle activity of HSCs is carefully modulated by a complex interplay between cell-intrinsic mechanisms and cell-extrinsic factors produced by the microenvironment. This fine-tuned regulatory network may become altered with age, leading to aberrant HSC cell cycle regulation, degraded HSC function, and hematological malignancy.     

Hematopoietic stem cells

Considerable effort has been made in recent years in defining the embryonic origin of the hematopoietic stem cell (HSC). Using transgenic mouse models, a number of genes that regulate the formation, self-renewal, or differentiation of HSCs have been identified. Of particular interest, it has recently been shown that key regulators of definitive blood formation played a crucial role in adult HSC development. Specifically, the use of some of these regulatory molecules has dramatically improved the potential of adult HSC expansion. Furthermore, the elucidation of the molecular phenotype of the HSC has just begun. Finally, unexpected degrees of HSC developmental or differentiation plasticity have emerged. In this review, we will summarize the recent advances made in the human HSC field, and we will examine the impacts these discoveries may have clinically and on our understanding of the organization of the human hematopoietic system.     

Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways

Hematopoietic stem cells （HSCs） are a rare population of cells that are responsible for life-long generation of blood cells of all lineages. In order to maintain their numbers, HSCs must establish a balance between the opposing cell fates of self-renewal （in which the ability to function as HSCs is retained） and initiation of hematopoietic differentiation. Multiple signaling pathways have been implicated in the regulation of HSC cell fate. One such set of pathways are those activated by the Wnt family of ligands. Wnt signaling pathways play a crucial role during embryogenesis and deregulation of these pathways has been implicated in the formation of solid tumors. Wnt signaling also plays a role in the regulation of stem cells from multiple tissues, such as embryonic, epidermal, and intestinal stem cells. However, the function of Wnt signaling in HSC biology is still controversial. In this review, we will discuss the basic characteristics of the adult HSC and its regulatory microenvironment, the ＂niche＂, focusing on the regulation of the HSC and its niche by the Wnt signaling pathways.     

Mapping bone marrow niches of disseminated tumor cells

Breast cancer cells may disseminate early, before tumor diagnosis. Disseminated tumor cells, or DTCs, reside in the bone marrow, and may persist for years or even decades. Some of these cells may be re-activated to resume aggressive growth, and eventually become overt bone metastases. Recent studies have begun to shed light on this complicated process and revealed multiple steps and intermediate states of colonizing DTCs. However, how cancer-host interactions evolve during this process needs to be further understood. Most of our current knowledge of the bone microenvironment is obtained through studies looking for the hematopoietic stem cell (HSC) niche. Although this long-standing question has not yet been resolved, our search for the HSC niche has resulted in a detailed map of various cell types in the bone marrow. Furthermore, various techniques used to find the HSC niche may also be adapted for finding the cancer cell niche. In this article, we will review the recent progress in both the DTC and HSC areas with a focus on their potential microenvironment niches. We will also discuss how to apply what we have learned from HSC studies to map DTCs in the bone context. We hope to stimulate thoughts and ideas to further elucidate the bone colonization process, and develop potential therapeutic interventions.     

Establishment and regulation of the HSC niche: Roles of osteoblastic and vascular compartments

Hematopoietic stem cells (HSC) are multi-potent cells that function to generate a lifelong supply of all blood cell types. During mammalian embryogenesis, sites of hematopoiesis change over the course of gestation: from extraembryonic yolk sac and placenta, to embryonic aorta-gonad-mesonephros region, fetal liver, and finally fetal bond marrow where HSC reside postnatally. These tissues provide microenviroments for de novo HSC formation, as well as HSC maturation and expansion. Within adult bone marrow, HSC self-renewal and differentiation are thought to be regulated by two major cellular components within their so-called niche: osteoblasts and vascular endothelial cells. This review focuses on HSC generation within, and migration to, different tissues during development, and also provides a summary of major regulatory factors provided by osteoblasts and vascular endothelial cells within the adult bone marrow niche.     

A novel purification method for multipotential skeletal stem cells

At least some cells within bone marrow stromal populations are multipotential (i.e., differentiate in vitro into osteoblasts, chondrocytes, and adipocytes) and thus designated skeletal stem cells (SSCs) or mesenchymal stem cells (MSCs) amongst other names. Recently, a subpopulation of stromal cells, notably osteoblasts or their progenitors, has been identified as a definitive regulatory component of the hematopoietic stem cell (HSC) niche. Thus, the development of methods for purifying not only SSCs but cells comprising the HSC niche is of interest. Here, we report a method for purifying a novel bone marrow‐derived population with a high frequency of osteoprogenitors and high expression levels of osteoblast differentiation markers (highly purified osteoprogenitors (HipOPs)) as well as markers of the bone niche for HSCs. In vivo transplantation experiments demonstrated that donor HipOPs differentiated into not only osteoblasts, osteocytes and cells around sinusoids but also hematopoietic cells. Thus, HipOPs represent a novel population for simultaneous reconstruction of bone and bone marrow microenvironments. J. Cell. Biochem. 108: 368–377, 2009. © 2009 Wiley‐Liss, Inc.     

A new bone to pick: osteoblasts and the haematopoietic stem-cell niche

Two recent publications highlight the role of bone-forming cells, the osteoblasts, in controlling the development of neighboring haematopoietic stem cells (HSCs).1,2 Using two distinct transgenic mouse models, one using the conditional deletion of the Bone Morphogenetic Protein Receptor 1A (BMPR1A) gene, the other using over-expression of an active PTH/PTHrP receptor (PPR) mutant within osteoblasts, the authors show parallel, concordant increases in the generation of trabecular osteoblasts and the number of HSCs. In situ staining showed that rarely cycling HSCs sporadically attach to endosteal osteoblasts, while in vitro assays indicated that ligation of Jag1 on osteoblasts by Notch1 on HSCs promotes HSC proliferation. These two independent works have revived and revitalized the notion that osteoblasts are a major, defining component of the HSC niche within the bone marrow (BM). This minireview discusses these results in the context of other recent studies of mesenchymal cells within the BM microenvironment, presents one potential unified model of the functional anatomy of the BM HSC niche, and highlights new questions raised by these and other studies of osteoblasts and HSCs.     

Stem Cell Regulation by the Haemopoietic Stem Cell Niche

Both cellular as well as extracellular matrix components of the stem cell microenvironment, or niche, are critical in stem cell regulation. Recent data highlight a central role for osteoblasts and their by product osteopontin as a key part of the hematopoietic stem cell (HSC) niche. Herein we describe a model for the yin and yang of HSC regulation mediated by osteoblasts. In this respect, osteoblasts synthesise proteins with opposing effects on HSC proliferation and differentiation highlighting their pivotal role in adult hematopoiesis. Although osteoblasts play a central role in HSC regulation other stromal and microenvironmental cell types and their extracellular matrix proteins also contribute to this biology. For example, the glycosaminoglycan hyaluronic acid as well as the membrane bound form of stem cell factor are also key regulators of HSC. Osteopontin and these “niche” molecules are not only involved in regulation of HSC quiescence but also effect HSC homing, trans-marrow migration and lodgement. Accordingly this leads us to expand upon Schofield’s niche hypothesis: we propose that the HSC niche is critical for attraction of primitive hematopoietic progenitors to the endosteal region and tightly tethering them within this location, and by doing so placing them into intimate contact with cells such as osteoblasts whose extracellular products are able to exquisitely regulate their fate.     

Telomere dynamics in hematopoietic stem cells

The hematopoietic system has an outstanding regenerative capacity which depends on a relatively small population of hematopoietic stem cells (HSC). In contrast to normal human cells, blood-forming stem cells, like most of their counterparts from other adult tissues, exhibit telomerase activity to a certain level. Nevertheless, this telomerase activity does not prevent telomere shortening in HSC, suggesting a restriction of their proliferative capacity. Here, we review recent studies on telomere dynamics in HSC of humans and mice. Furthermore, we discuss the impact of telomere manipulation in HSC for possible clinical applications and speculate on functions of telomerase beyond telomere lengthening.     

Defining the hematopoietic stem cell niche: the chicken and the egg conundrum

Understanding the in vivo regulation of hematopoietic stem cells (HSCs) will be critical to identifying key factors involved in the regulation of HSC self‐renewal and differentiation. The niche (microenvironment) in which HSCs reside has recently regained attention accompanied by a dramatic increase in the understanding of the cellular constituents of the bone marrow HSC niche. The use of sophisticated genetic models allowing modulation of specific lineages has demonstrated roles for mesenchymal‐derived elements such as osteoblasts and adipocytes, vasculature, nerves, and a range of hematopoietic progeny of the HSC as being participants in the regulation of the bone marrow microenvironment. Whilst providing significant insight into the cellular composition of the niche, is it possible to manipulate any given cell lineage in vivo without impacting, knowingly or unknowingly, on those that remain? J. Cell. Biochem. 112: 1486–1490, 2011. © 2011 Wiley‐Liss, Inc.     

The role of the CCN family of proteins in blood cancers

Haematopoiesis is the term used to describe the production of blood cells. This is a tightly regulated hierarchical system in which mature circulating blood cells develop from a small population of haematopoietic stem (HSC) and progenitor cells within the microenvironment of the bone marrow. Molecular and genetic abnormalities arising in these stem cells lead to a block in the normal programme of proliferation and differentiation and result in the development of the blood cancers known as the leukaemias and lymphomas. Recently the regulatory role of the bone marrow microenvironment or niche has also become increasingly recognised. The interface between the bone and bone marrow (endosteum) and the region surrounding the blood vessels (perivascular) provide distinct niches harbouring quiescent HSC or proliferative HSC respectively. Current chemotherapeutic regimes can often successfully target the proliferative HSC but disease relapse occurs due to residual quiescent HSC. Understanding these developmental and regulatory processes and the associated cell communication mechanisms are thus crucial to the development of new treatment strategies. The CCN family of proteins have been recognised to play a key role in all aspects of haematopoiesis.     

Regulation of hematopoietic and leukemic stem cells by the immune system

Hematopoietic stem cells (HSCs) are rare, multipotent cells that generate via progenitor and precursor cells of all blood lineages. Similar to normal hematopoiesis, leukemia is also hierarchically organized and a subpopulation of leukemic cells, the leukemic stem cells (LSCs), is responsible for disease initiation and maintenance and gives rise to more differentiated malignant cells. Although genetically abnormal, LSCs share many characteristics with normal HSCs, including quiescence, multipotency and self-renewal. Normal HSCs reside in a specialized microenvironment in the bone marrow (BM), the so-called HSC niche that crucially regulates HSC survival and function. Many cell types including osteoblastic, perivascular, endothelial and mesenchymal cells contribute to the HSC niche. In addition, the BM functions as primary and secondary lymphoid organ and hosts various mature immune cell types, including T and B cells, dendritic cells and macrophages that contribute to the HSC niche. Signals derived from the HSC niche are necessary to regulate demand-adapted responses of HSCs and progenitor cells after BM stress or during infection. LSCs occupy similar niches and depend on signals from the BM microenvironment. However, in addition to the cell types that constitute the HSC niche during homeostasis, in leukemia the BM is infiltrated by activated leukemia-specific immune cells. Leukemic cells express different antigens that are able to activate CD4⁺ and CD8⁺ T cells. It is well documented that activated T cells can contribute to the control of leukemic cells and it was hoped that these cells may be able to target and eliminate the therapy-resistant LSCs. However, the actual interaction of leukemia-specific T cells with LSCs remains ill-defined. Paradoxically, many immune mechanisms that evolved to activate emergency hematopoiesis during infection may actually contribute to the expansion and differentiation of LSCs, promoting leukemia progression. In this review, we summarize mechanisms by which the immune system regulates HSCs and LSCs.     

Bone-marrow haematopoietic-stem-cell niches

Adult stem cells hold many promises for future clinical applications and regenerative medicine. The haematopoietic stem cell (HSC) is the best-characterized somatic stem cell so far, but in vitro expansion has been unsuccessful, limiting the future therapeutic potential of these cells. Here we review recent progress in characterizing the composition of the HSC bone-marrow microenvironment, known as the HSC niche. During homeostasis, HSCs, and therefore putative bone-marrow HSC niches, are located near bone surfaces or are associated with the sinusoidal endothelium. The molecular crosstalk between HSCs and the cellular constituents of these niches is thought to control the balance between HSC self-renewal and differentiation, indicating that future successful expansion of HSCs for therapeutic use will require three-dimensional reconstruction of a stem-cell-niche unit.     

Hematopoietic stem cell niche: An interplay among a repertoire of multiple functional niches

Background

Hematopoietic stem cell (HSC) niche of the BM provides a specialized microenvironment for the regulation of HSCs. The strict control of HSCs by the niche coordinates the balance between the proliferation and the differentiation of HSCs for the homeostasis of the blood system in steady states and during stress hematopoiesis. The osteoblastic and vascular niches are the classically identified constituents of the BM niche.

Scope of review

Recent research broadens our understanding of the BM niche as an assembly of multiple niche cells within the BM. We provide an overview of the HSC niche aiming to delineate the defined and possible niche cell interactions which collectively modulate the HSC integrity.

Major conclusions

Multiple cells in the BM, including osteoblasts, vascular endothelia, perivascular mesenchymal cells and HSC progeny cells, function conjunctively as niche cells to regulate HSCs.

General significance

The study of HSC niche cells and their functions provides insights into stem cell biology and also may be extrapolated into the study of cancer stem cells. This article is part of a Special Issue entitled Biochemistry of Stem Cells.     

Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance

Recent studies have proposed that bone marrow hematopoietic stem cells (HSCs) are maintained via N-cadherin-mediated homophilic adhesion with osteoblasts. However, there is not yet any evidence that N-cadherin-expressing cells have HSC activity or that osteoblasts are required for HSC maintenance. We were unable to detect N-cadherin expression in highly purified HSCs by polymerase chain reaction, by using commercial anti-N-cadherin antibodies, or by beta-galactosidase staining of N-cadherin gene trap mice. Only N-cadherin-negative bone marrow cells exhibited HSC activity in irradiated mice. Finally, biglycan-deficient mice had significant reductions in trabecular bone and osteoblasts but showed no defects in hematopoiesis, HSC frequency, or function. Thus, reductions in osteoblasts do not necessarily lead to reductions in HSCs. Most bone marrow HSCs in wild-type and biglycan-deficient mice localized to sinusoids, and few localized within five cell diameters of the endosteum. These results question whether significant numbers of HSCs depend on N-cadherin-mediated adhesion to osteoblasts.     

Regulation of differentiation of mesenchymal stem cells into musculoskeletal cells

Mesenchymal stem cells (MSCs) are multipotent cells that have the capability of differentiating into several different cells such as osteoblasts (bone), chondrocytes (cartilage), adipocytes (fat), myocytes (muscle) and tenocytes (tendon). In this review we highlight the different regulators which determine the lineage a particular MSC will differentiate into. Mesenchymal stem cells are increasingly being used in tissue regeneration and repair. Strict regulation of differentiation of MSCs is essential for a positive outcome of the particular tissue treated with MSCs, especially due to the fact that capacity to differentiate decreases with increasing age of the donor.