Purpose of review
To provide an overview of the hematopoietic stem cell (HSC) niche in the bone marrow. In addition to highlighting recent advances in the field, we will also discuss components of the niche that may contribute to the development of cancer, or cancer metastases to the bone.
Much progress has been very recently made in the understanding of the cellular and molecular interactions in the HSC microenvironment. These recent findings point out the extraordinary complexity of the HSC microenvironment. Emerging data also suggest convergence of signals important for HSC and for leukemia or metastatic disease support.
The HSC niche comprises complex interactions between multiple cell types and molecules requiring cell-cell signaling as well as local secretion. These components can be thought of as therapeutic targets not only for HSC expansion, but also to modify behavior of hematopoietic malignancies and cancer metastases to the bone.
hematopoietic stem cells; niche; notch
Hematopoietic stem cells (HSCs), rare primitive cells capable of reconstituting all blood cell lineages, are the only stem cells currently routinely used for therapeutic purposes. Clinical experience has shown that HSC number is an important limiting factor in treatment success. Strategies to expand HSCs are of great clinical appeal, as they would improve therapeutic use of these cells in stem cell transplantation and in conditions of bone marrow failure. The microenvironment in which HSCs reside, known as the niche, has long been considered a critical regulator of HSCs. Data accumulated over the past decade strongly confirm the importance of the niche in HSC behavior. A number of niche components as well as signaling pathways, such as Notch, have been implicated in the interaction of the microenvironment with HSCs and continue to be genetically evaluated in the hope of defining the critical elements that are required and which, if modified, can initiate HSC behaviors. In this review, we highlight the known characteristics of HSCs, challenges in their expansion, the niche phenomenon, and explain why niche stimulated HSC expansion is of utmost interest in the field, while beginning to bring to the fore potential caveats of niche manipulation. Lastly, the potential pitfalls of avoiding malignancy and controlling self-renewal versus differentiation will be briefly reviewed.
The quiescence of hematopoietic stem cells (HSCs) is critical for preserving a lifelong steady pool of HSCs to sustain the highly regenerative hematopoietic system. It is thought that specialized niches in which HSCs reside control the balance between HSC quiescence and self-renewal, yet little is known about the extrinsic signals provided by the niche and how these niche signals regulate such a balance. We report that CXCL12 produced by bone marrow (BM) stromal cells is not only the major chemoattractant for HSCs but also a regulatory factor that controls the quiescence of primitive hematopoietic cells. Addition of CXCL12 into the culture inhibits entry of primitive hematopoietic cells into the cell cycle, and inactivation of its receptor CXCR4 in HSCs causes excessive HSC proliferation. Notably, the hyperproliferative Cxcr4−/− HSCs are able to maintain a stable stem cell compartment and sustain hematopoiesis. Thus, we propose that CXCR4/CXCL12 signaling is essential to confine HSCs in the proper niche and controls their proliferation.
Hematopoietic stem cells (HSCs) are quiescent cells with self-renewal capacity and the ability to generate all mature blood cells. HSCs normally reside in specialized niches in the bone marrow that help maintain their quiescence and long-term repopulating activity. There is emerging evidence that certain cytokines induced during inflammation have significant effects on HSCs in the bone marrow. Type I and II interferons, tumor necrosis factor, and lipopolysaccharide (LPS) directly stimulate HSC proliferation and differentiation, thereby increasing the short-term output of mature effector leukocytes. However, chronic inflammatory cytokine signaling can lead to HSC exhaustion and may contribute the development of hematopoietic malignancies. Pro-inflammatory cytokines such as G-CSF can also indirectly affect HSCs by altering the bone marrow microenvironment, disrupting the stem cell niche, and leading to HSC mobilization into the blood. Herein, we review our current understanding of the effects of inflammatory mediators on HSCs, and we discuss the potential clinical implications of these findings with respect to bone marrow failure and leukemogenesis.
inflammation; hematopoietic stem cells; toll-like receptors; tumor necrosis factor; interferon
The stem cell niche is composed of a specialized population of cells that plays an essential role in regulating adult stem cell self-renewal and differentiation. In adults, osteoblasts, responsible for osteogenesis, and hematopoietic cells, responsible for hematopoiesis, are closely associated in the bone marrow, suggesting a reciprocal relationship between the two. It was recently discovered that a subset of osteoblasts functions as a key component of the HSC niche (namely, the osteoblastic niche), controlling HSC numbers. HSCs interact not only with osteoblasts but also with other stromal cells, including endothelial cells. Sinusoidal endothelial cells in bone marrow have been revealed as an alternative HSC niche called the vascular niche. In this Review we compare the architecture of these 2 HSC niches in bone marrow. We also highlight the function of osteoblasts in maintaining a quiescent HSC microenvironment and the likely role of the vascular niche in regulating stem cell proliferation, differentiation, and mobilization. In addition, we focus on studies of animal models and in vitro assays that have provided direct insights into the actions of these osteoblastic and vascular niches, revealing central roles for numerous signaling and adhesion molecules. Many of the discoveries described herein may contribute to future clinical treatments for hematopoietic and bone-related disorders, including cancer.
Ample evidence indicated that hematopoietic stem cells (HSCs) receive signaling from infection or other immune responses to adjust their differentiation and self-renewal. More recent reports also suggested that, while the bone marrow microenvironment or niche may provide the immune privilege for HSCs, HSCs can present surface immune inhibitors per se to suppress innate immunity and adaptive immunity to evade potential immune surveillance and attack. These findings support the hypothesis that HSCs are capable of interacting with the immune system as signal “receivers” and signal “providers”. On the one hand, HSCs are capable of directly sensing the signals from the immune system through their surface receptors to modulate their self-renewal and differentiation (“in” signaling); on the other hand, HSCs display surface immune inhibitory molecules to evade the attack from the innate and adaptive immune systems (“out” signaling). The continuing investigation of the interplay between HSCs and immunity may lead to the open-up of a new research filed – the immunology of stem cells.
Hematopoietic stem cells; immunity; immune privilege; CD47; CD274; LILRB2; PIR-B; immune inhibitory receptors; infection; inflammation
Dynamic interactions between haematopoietic cells and their specialised bone marrow microenvironments, namely the vascular and osteoblastic ‘niches’ regulate haematopoiesis. The vascular niche is conducive for thrombopoiesis, and megakaryocytes may, in turn, regulate the vascular niche, especially in supporting vascular and haematopoietic regeneration following irradiation or chemotherapy. A role for platelets in tumour growth and metastasis is well established and, more recently, the vascular niche has also been implicated as an area for preferential homing and engraftment of malignant cells. This article aims to provide an overview of the dynamic interactions between cellular and molecular components of the bone marrow vascular niche and the potential role of megakaryocytes in bone marrow malignancy.
Maintenance of hematopoietic stem cells (HSCs) pool depends on fine balance between self-renewal and differentiation of HSCs. HSCs normally reside within the bone marrow niche of an adult mammal. The embryonic development of HSCs is a complex process that involves the migration of developing HSCs in multiple anatomical sites. Throughout the process, developing HSCs receive internal (transcriptional program) and external (HSC niche) signals, which direct them to maintain balance between self-renewal and differentiation, also to generate a pool of HSCs. In physiological condition HSCs differentiate into all mature cell types present in the blood. However, in pathological condition they may differentiate into non-hematological cells according to the need of the body. It was shown that HSCs can transdifferentiate into cell types that do not belong to the hematopoietic system suggests a complete paradigm shift of the hierarchical hematopoietic tree. This review describes the developmental origins and regulation of HSCs focusing on developmental signals that induce the adult hematopoietic stem cell program, as these informations are very critical for manipulating conditions for expansion of HSCs in ex vivo condition. This review also states clinical application and related patents using HSC.
Hematopoietic stem cells; embryonic development; regulation; self-renewal; differentiation; transdifferentiation; clinical application; patents
The hematopoietic stem cell (HSC) niche in the bone marrow has been studied extensively over the past few decades, yet the bone marrow microenvironment that supports the growth of metastatic prostate cancer (PCa) has only been recently considered to be a specialized “niche” as well. New evidence supports the fact that disseminated tumor cells (DTCs) of PCa actually target the HSC niche, displace the occupant HSCs, and take up residence in the pre-existing niche space. This review describes some of the evidence and mechanisms by which DTCs act as molecular parasites of the HSC niche. Furthermore, the interactions between DTCs, HSCs, and the niche may provide new targets for niche-directed therapy, as well as insight into the perplexing clinical manifestations of metastatic PCa disease.
Dormancy; Hematopoietic Stem Cell; Osteoblasts; Prostate Cancer; Metastasis; Niche
The hematopoietic stem cell (HSC) niche in the bone marrow has been studied extensively over the past few decades, yet the bone marrow microenvironment that supports the growth of metastatic prostate cancer (PCa) has only been recently considered to be a specialized ‘niche' as well. New evidence supports the fact that disseminated tumor cells (DTCs) of PCa actually target the HSC niche, displace the occupant HSCs and take up residence in the pre-existing niche space. This review describes some of the evidence and mechanisms by which DTCs act as molecular parasites of the HSC niche. Furthermore, the interactions between DTCs, HSCs and the niche may provide new targets for niche-directed therapy, as well as insight into the perplexing clinical manifestations of metastatic PCa disease.
dormancy; hematopoietic stem cell; metastasis; niche; osteoblasts; prostate cancer
The mechanism that regulates self-renewal and differentiation of hematopoietic stem cells (HSC) is a central question in stem cell biology that might ultimately lead to reliable protocols for in vitro expansion of HSC. Cellular fate is governed by cell-cell interaction with the microenvironment in the bone marrow, the stem cell niche. Mesenchymal stromal cells (MSC) are precursors of the cellular components, and they secrete extracellular matrix proteins of the bone marrow stroma. Therefore, MSC feeder layer might provide a suitable in vitro model system for the stem cell niche. In vitro assays demonstrate that MSC maintain the stem cell function of HSC and that MSC from bone marrow have a higher hematopoiesis supportive activity than MSC from adipose tissue. Co-cultivation with MSC might pave the way for expansion of long-term repopulating HSC, and various clinical trials indicate that co-transplantation of HSC and MSC might enhance engraftment. Thus, MSC are promising tools to elucidate the underlying mechanism of the cellular microenvironment. The large variety of preparative protocols for isolation and cultivation of MSC affects their stromal activity. Standardized isolation methods and molecular characterization of MSC are of utmost importance for reproducible isolation of hematopoiesis supportive stromal cells and for their potential clinical application.
Mesenchymal stem cell; Culture conditions; Microenvironment; Differentiation; Hematopoietic stem cells; Cell-cell interaction
Although the hematopoietic stem cell (HSC) niche has been an active area of study, the concept of the bone marrow microenvironment (BMM) harboring a niche for solid metastatic tumor cells has only recently been considered. The HSC niche and microenvironment that is thought to constitute the solid tumor niche share many of the same structural and functional components, suggesting the possibility that the HSC and tumor niche are one in the same. The osteoblast is a critical component for each of these niches, and is important for regulating cellular processes such homing and migration, growth and survival, and quiescence and dormancy. Current understanding of the HSC niche may provide more insight to better defining the solid tumor niche. As role of the niche in regulating these processes is better understood, new insights to the role of the BMM in metastatic disease may be gained, and provide more potential targets for therapy.
niche; bone marrow microenvironment; hematopoietic stem cell; metastasis; disseminated tumor cell
Hematopoietic stem cell (HSC) chemotaxis, adhesion, proliferation, quiescence and differentiation are regulated by interactions with bone marrow (BM) niches. Two niches have been identified in the adult BM: the endosteal (close to the bone) and the perivascular niche (close to blood vessels). A vast body of literature has revealed the molecular basis for the interaction of HSCs with the two niches. However, the signals that regulate the communication between the two niches have not been well defined. Taking in consideration several clinical and experimental arguments this review highlights the molecular cues, involved in the communication between the BM niches, which regulate the basic properties of HSCs in physiological and malignant conditions. As such, it aims at clarifying the most important advances in basic and clinical research focusing on the role of different factors in the regulation of the BM microenvironment.
bone marrow niches; hematopoietic stem cell properties; molecular signals.
Stem cell self-renewal is regulated by intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments called “niches.” The best-characterized stem cell is the hematopoietic stem cell (HSC). Self-renewal and differentiation ability of HSC are regulated by two major elements: endosteal and vascular regulatory elements. The osteoblastic niche localized at the inner surface of the bone cavity might serve as a reservoir for long-term HSC storage in a quiescent state. Whereas the vascular niche, which consists of sinusoidal endothelial cell lining blood vessel, provides an environment for short-term HSC proliferation and differentiation. Both niches act together to maintain hematopoietic homeostasis. In this paper, we provide some principles applying to the hematopoietic niches, which will be useful in the study and understanding of other stem cell niches. We will discuss altered microenvironment signaling leading to myeloid lineage disease. And finally, we will review some data on the development of acute myeloid leukemia from a subpopulation called leukemia-initiating cells (LIC), and we will discuss on the emerging evidences supporting the influence of the microenvironment on chemotherapy resistance.
Recently there has been increased interest in the regulatory interactions between osteoblasts and cells in the surrounding bone marrow microenvironment. The proximity of hematopoietic stem cells (HSCs) with osteoblastic cells first suggested regulatory interactions and recent data have highlighted the role of osteoblastic cells in providing a HSC niche. Reports have indicated that direct contact is necessary to mediate the osteoblastic effects and that these effects could be mediated through Notch activation. Notch signaling is important throughout development and also appears to play a critical role in cellular maturation and differentiation of osteoblastic cells and hematopoietic cells as disregulation can lead to bone loss and leukemias respectively. In this review we discuss the current understanding of Notch signaling and how it functions in hematopoiesis, osteoblastic cells, and the interactions between HSC and their osteoblastic niche.
Bone marrow (BM) cavities are utilized for hematopoiesis and to maintain hematopoietic stem cells (HSCs). HSCs have the ability to self-renew as well as to differentiate into multiple different hematopoietic lineage cells. HSCs produce their daughter cells throughout the lifespan of individuals and thus, maintaining HSCs is crucial for individual life. BM cavities provide a specialized microenvironment termed “niche” to support HSCs. Niches are composed of various types of cells such as osteoblasts, endothelial cells and reticular cells. Osteoclasts are unique cells which resorb bones and are required for BM cavity formation. Loss of osteoclast function or differentiation results in inhibition of BM cavity formation, an osteopetrotic phenotype. Osteoclasts are also reportedly required for hematopoietic stem and progenitor cell (HSPC) mobilization to the periphery from BM cavities. Thus, lack of osteoclasts likely results in inhibition of HSC maintenance and HSPC mobilization. However, we found that osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization by using three independent osteoclast-less animal models. In this review, I will discuss the roles of osteoclasts in hematopoietic stem cell maintenance and mobilization.
Osteoclasts; Hematopoietic stem and progenitor cell; Mobilization; Receptor activator of nuclear factor kappa B ligand; Osteomac; Osteopetrosis; op/op; C-Fos; Osteoprotegerin
Despite significant improvement in therapy, the prognosis of cancer with bone metastasis is generally poor. Therefore, there is a great need for new therapeutic approaches for metastatic disease. It has been appreciated that tumor cells metastasize to bone using similar mechanisms of hematopoietic stem cell (HSC) homing to bone marrow (e.g. CXCL12/CXCR4). It was recently found that prostate cancer (PCa) cells target the bone marrow microenvironment for HSCs, or HSC niche, during metastasis. Importantly, these disseminated PCa cells can be mobilized out of the niche using HSC mobilizing agents. These findings suggest that bone marrow HSC niche is a potential therapeutic target for metastatic disease. Therefore, the hypothesis worth considering is that agents that can disrupt the interactions between tumor cells and the HSC niche may prove efficacious when used in conjunction with standard chemotherapeutic agents. Although further understanding of the tumor-niche interactions is needed, the concept of targeting the niche in conjunction with chemotherapy could open up new windows to eradicate incurable metastatic diseases.
HSC homing, quiescence, and self-renewal depend on the bone marrow HSC niche. A large proportion of solid tumor metastases are bone metastases, known to usurp HSC homing pathways to establish footholds in the bone marrow. However, it is not clear whether tumors target the HSC niche during metastasis. Here we have shown in a mouse model of metastasis that human prostate cancer (PCa) cells directly compete with HSCs for occupancy of the mouse HSC niche. Importantly, increasing the niche size promoted metastasis, whereas decreasing the niche size compromised dissemination. Furthermore, disseminated PCa cells could be mobilized out of the niche and back into the circulation using HSC mobilization protocols. Finally, once in the niche, tumor cells reduced HSC numbers by driving their terminal differentiation. These data provide what we believe to be the first evidence that the HSC niche serves as a direct target for PCa during dissemination and plays a central role in bone metastases. Our work may lead to better understanding of the molecular events involved in bone metastases and new therapeutic avenues for an incurable disease.
Specific bone marrow (BM) niches are critical for hematopoietic stem cell (HSC) function during both normal hematopoiesis and in stem cell transplantation therapy. We demonstrate that the guidance molecule Robo4 functions to specifically anchor HSCs to BM niches. Robo4-deficient HSCs displayed poor localization to BM niches and drastically reduced long-term reconstitution capability while retaining multilineage potential. Cxcr4, a critical regulator of HSC location, is upregulated in Robo4−/− HSCs to compensate for Robo4 loss. Robo4 deletion led to altered HSC mobilization efficiency, revealing that inhibition of both Cxcr4- and Robo4-mediated niche interactions are necessary for efficient HSC mobilization. Surprisingly, we found that WT HSCs express very low levels of Cxcr4 and respond poorly to Cxcr4 manipulation relative to other hematopoietic cells. We conclude that Robo4 cooperates with Cxcr4 to endow HSCs with competitive access to limited stem cell niches, and we propose Robo4 as a therapeutic target in HSC transplantation therapy.
Hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are both adult stem cells residing in the bone marrow. MSCs interact with HSCs, they stimulate and enhance the proliferation of HSCs by secreting regulatory molecules and cytokines, providing a specialized microenvironment for controlling the process of hematopoiesis. In this paper we discuss how MSCs contribute to HSC niche, maintain the stemness and proliferation of HSCs, and support HSC transplantation.
Purpose: This paper reviews and reassesses the internationally accepted niches or ‘targets’ in bone marrow that are sensitive to the induction of leukaemia and primary bone cancer by radiation.
Conclusions: The hypoxic conditions of the 10 μm thick endosteal/osteoblastic niche where preleukemic stem cells and hematopoietic stem cells (HSC) reside provides a radioprotective microenvironment that is 2-to 3-fold less radiosensitive than vascular niches. This supports partitioning the whole marrow target between the low haematological cancer risk of irradiating HSC in the endosteum and the vascular niches within central marrow. There is a greater risk of induced bone cancer when irradiating a 50 μm thick peripheral marrow adjacent to the remodelling/reforming portion of the trabecular bone surface, rather than marrow next to the quiescent bone surface. This choice of partitioned bone cancer target is substantiated by the greater radiosensitivity of: (i) Bone with high remodelling rates, (ii) the young, (iii) individuals with hypermetabolic benign diseases of bone, and (iv) the epidemiology of alpha-emitting exposures. Evidence is given to show that the absence of excess bone-cancer in atomic-bomb survivors may be partially related to the extremely low prevalence among Japanese of Paget's disease of bone. Radiation-induced fibrosis and the wound healing response may be implicated in not only radiogenic bone cancers but also leukaemia. A novel biological mechanism for adaptive response, and possibility of dynamic targets, is advocated whereby stem cells migrate from vascular niches to stress-mitigated, hypoxic niches.
cancer predisposition; bone; stem cells; radiation-induced tumours
The skeletal system, while characterized by a hard tissue component, is in fact an extraordinarily dynamic system, with disparate functions ranging from structural support, movement and locomotion and soft-organ protection, to the maintenance of calcium homeostasis. Amongst these functions, it has long been known that mammalian bones house definitive hematopoiesis. In fact, several data demonstrate that the bone microenvironment provides essential regulatory cues to the hematopoietic system. In particular, interactions between the bone forming cells, or osteoblasts, and the most primitive hematopoietic stem cells (HSC) have recently been defined. This review will focus mainly on the role of osteoblasts as HSC regulatory cells, discussing the signaling mechanisms and molecules currently thought to be involved in their modulation of HSC behavior. We will then review additional cellular components of the HSC niche, including endothelial cells and osteoclasts. Finally, we will discuss the potential clinical implications of our emerging understanding of the complex HSC microenvironment.
The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin+ MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent ‘mesenspheres’ that can self-renew and expand in serial transplantations. Nestin+ MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or β3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin+ cells and favours their osteoblastic differentiation, in vivo nestin+ cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin+ MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin+ cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
The mechanisms that regulate hematopoietic stem cell (HSC) dormancy and self-renewal are well established and are largely dependent on signals emanating from the HSC niche. Recently, we found that prostate cancer (PCa) cells target the HSC niche in mouse bone marrow (BM) during metastasis. Little is known, however, as to how the HSC niche may regulate dormancy in cancer cells. In this study, we investigated the effects of TANK binding kinase 1 (TBK1) on PCa dormancy in the BM niche. We found that binding with niche osteoblasts induces the expression of TBK1 in PCa cells PC3 and C4-2B. Interestingly, TBK1 interacts with mammalian target of rapamycin (mTOR) and inhibits its function. Rapamycin, an mTOR inhibitor, induces cell cycle arrest of PCa cells and enhances chemotherapeutic resistance of PCa cells. As a result, the knockdown of TBK1 decreases PCa stem-like cells and drug resistance in vitro and in vivo. Taken together, these results strongly indicate that TBK1 plays an important role in the dormancy and drug resistance of PCa.
Ehninger and Trumpp discuss the role of monocytes/macrophages and other niche cells in the regulation of HSC mobilization and retention.
Stem cell niches are defined as the cellular and molecular microenvironments that regulate stem cell function together with stem cell autonomous mechanisms. This includes control of the balance between quiescence, self-renewal, and differentiation, as well as the engagement of specific programs in response to stress. In mammals, the best understood niche is that harboring bone marrow hematopoietic stem cells (HSCs). Recent studies have expanded the number of cell types contributing to the HSC niche. Perivascular mesenchymal stem cells and macrophages now join the previously identified sinusoidal endothelial cells, sympathetic nerve fibers, and cells of the osteoblastic lineage to form similar, but distinct, niches that harbor dormant and self-renewing HSCs during homeostasis and mediate stem cell mobilization in response to granulocyte colony-stimulating factor.