The hematopoietic stem-cell niche in health and leukemia

Research in the last decade has shown that hematopoietic stem cells (HSCs) interact with and are modulated by a complex multicellular microenvironment in the bone marrow, which includes both the HSC progeny and multiple non-hematopoietic cell types. Intense work is gradually throwing light on the composition of the HSC niche and the molecular cues exchanged between its components, which has implications for HSC production, maintenance and expansion. In addition, it has become apparent that bidirectional interactions between leukemic cells and their niche play a previously unrecognized role in the initiation and development of hematological malignancies. Consequently, targeting of the malignant niche holds considerable promise for more specific antileukemic therapies. Here we summarize the latest insights into HSC niche biology and recent work showing multiple connections between hematological malignancy and alterations in the bone marrow microenvironment.     

Regulation of myelopoiesis by proinflammatory cytokines in infectious diseases

Hematopoiesis is hierarchically orchestrated by a very small population of hematopoietic stem cells (HSCs) that reside in the bone-marrow niche and are tightly regulated to maintain homeostatic blood production. HSCs are predominantly quiescent, but they enter the cell cycle in response to inflammatory signals evoked by severe systemic infection or injury. Thus, hematopoietic stem and progenitor cells (HSPCs) can be activated by pathogen recognition receptors and proinflammatory cytokines to induce emergency myelopoiesis during infection. This emergency myelopoiesis counterbalances the loss of cells and generates lineage-restricted hematopoietic progenitors, eventually replenishing mature myeloid cells to control the infection. Controlled generation of such signals effectively augments host defense, but dysregulated stimulation by these signals is harmful to HSPCs. Such hematopoietic failure often results in blood disorders including chronic inflammatory diseases and hematological malignancies. Recently, we found that interleukin (IL)-27, one of the IL-6/IL-12 family cytokines, has a unique ability to directly act on HSCs and promote their expansion and differentiation into myeloid progenitors. This process resulted in enhanced production of neutrophils by emergency myelopoiesis during the blood-stage mouse malaria infection. In this review, we summarize recent advances in the regulation of myelopoiesis by proinflammatory cytokines including type I and II interferons, IL-6, IL-27, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in infectious diseases.     

Oncogenic protein tyrosine kinases

Platelet-derived growth factor receptors (PDGFRs) and their ligands, platelet-derived growth factors (PDGFs) play critical roles in mesenchymal cell migration and proliferation. In embryogenesis the PDGFR/PDGF system is essential for the correct development of the kidney, cardiovascular system, brain, lung and connective tissue. In adults, PDGFR/PDGF is important in wound healing, inflammation and angiogenesis. Abnormalities of PDGFR/PDGF are thought to contribute to a number of human diseases, and especially malignancy. Constitutive activation of the PDGFRalpha or PDGFRbeta receptor tyrosine kinases is seen in myeloid malignancies as a consequence of fusion to diverse partner genes, and activating mutations of PDGFRalpha are seen in gastrointestinal tumours (GISTs). Autocrine signalling as a consequence of PDGF-B overexpression is clearly implicated in the pathogenesis of dermatofibrosarcoma protruberans (DFSP) and overexpression of PDGFRs and/or their ligands has been described in many solid tumours. PDGFR signalling is inhibited by imatinib mesylate, and this compound has clear clinical activity in patients with myeloid malignancies, GIST and DFSP.     

Oncogenic mechanisms in myeloproliferative disorders

Myeloproliferative disorders (MPDs) are clonal haematopoietic malignancies involving the abnormal proliferation of myeloid lineages. The World Health Organisation (WHO) classification of haematopoietic malignancies distinguishes MPDs from myelodysplastic/ myeloproliferative disorders and systemic mastocytosis. These malignancies frequently involve constitutive tyrosine kinase activity, resulting from either oncogenic fusion protein production or from point mutations. Chronic myelogenous leukaemia is the model used for studies of the consequences of such molecular defects. However, the heterogeneity of the clinical course of MPDs should be seen in a more rationale conceptual framework, including the many molecular events associated with these diseases. This review focuses on the various tyrosine kinase-related molecular mechanisms underlying both MPDs and rare diseases with myeloproliferative features. We pay particular attention to the newly identified JAK2 V617F mutation in polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional molecular mechanisms. Received 9 June 2006; received after revision 28 July 2006; accepted 11 September 2006     

Regulation of self-renewal and differentiation by the intestinal stem cell niche

The gastrointestinal epithelium is a highly organised tissue that is constantly being renewed. In order to maintain homeostasis, the balance between intestinal stem cell (ISC) self-renewal and differentiation must be carefully regulated. In this review, we describe how the intestinal stem cell niche provides a unique environment to regulate self-renewal and differentiation of ISCs. It has traditionally been believed that the mesenchymal myofibroblasts play an important role in the crosstalk between ISCs and the niche. However, recent evidence in Drosophila and in vertebrates suggests that epithelial cells also contribute to the niche. We discuss the multiple signalling pathways that are utilised to regulate stemness within the niche, including members of the Wnt, BMP and Hedgehog pathways, and how aberrations in these signals lead to disruption of the normal crypt–villus axis. Finally, we also discuss how CDX1 and inhibition of the Notch pathway are important in specifying enterocyte and goblet cell differentiation respectively.     

The multifaceted role of periostin in priming the tumor microenvironments for tumor progression

Tumor microenvironment consists of tumor cells, stromal cells, extracellular matrix and a plethora of soluble components. The complex array of interactions between tumor cells and their surrounding tumor microenvironments contribute to the determination of the fate of tumor cells during tumorigenesis and metastasis. Matricellular protein periostin is generally absent in most adult tissues but is highly expressed in tumor microenvironments. Current evidence reveals that periostin plays a critical role in establishing and remodeling tumor microenvironments such as the metastatic niche, cancer stem cell niche, perivascular niche, pre-metastatic niche, fibrotic microenvironment and bone marrow microenvironment. Here, we summarize the current knowledge of the multifaceted role of periostin in the tumor microenvironments.     

Antizyme inhibitor: mysterious modulator of cell proliferation

In contrast to the considerable interest in the oncogene ornithine decarboxylase (ODC) and in the family of antizymes with regard to cell proliferation and tumorigenesis, the endogenous antizyme inhibitor (AZI) has been less well studied. AZI is highly homologous to the enzyme ODC but does not possess any decarboxylase activity. Elevated ODC activity is associated with most forms of human malignancies. Antizymes bind ODC, inhibit ODC activity and promote the ubiquitin-independent degradation of ODC. Consequently they are proposed as tumor suppressors. In particular, the most studied member of the antizyme family, antizyme 1, has been demonstrated to play a role in tumor suppression. AZI inactivates all members of the antizyme family, reactivates ODC and prevents the proteolytic degradation of ODC, which may suggest a role for AZI in tumor progression. Received 9 December 2005; received after revision 13 April 2006; accepted 1 June 2006     

Retinoic acid signaling and neurogenic niche regulation in the developing peripheral nervous system of the cephalochordate amphioxus

The retinoic acid (RA) signaling pathway regulates axial patterning and neurogenesis in the developing central nervous system (CNS) of chordates, but little is known about its roles during peripheral nervous system (PNS) formation and about how these roles might have evolved. This study assesses the requirement of RA signaling for establishing a functional PNS in the cephalochordate amphioxus, the best available stand-in for the ancestral chordate condition. Pharmacological manipulation of RA signaling levels during embryogenesis reduces the ability of amphioxus larvae to respond to sensory stimulation and alters the number and distribution of ectodermal sensory neurons (ESNs) in a stage- and context-dependent manner. Using gene expression assays combined with immunohistochemistry, we show that this is because RA signaling specifically acts on a small population of soxb1c-expressing ESN progenitors, which form a neurogenic niche in the trunk ectoderm, to modulate ESN production during elongation of the larval body. Our findings reveal an important role for RA signaling in regulating neurogenic niche activity in the larval amphioxus PNS. Although only few studies have addressed this issue so far, comparable RA signaling functions have been reported for neurogenic niches in the CNS and in certain neurogenic placode derivatives of vertebrates. Accordingly, the here-described mechanism is likely a conserved feature of chordate embryonic and adult neural development.     

Invariant natural killer T cells in adipose tissue: novel regulators of immune-mediated metabolic disease

Adipose tissue (AT) represents a microenvironment where intersection takes place between immune processes and metabolic pathways. A variety of immune cells have been characterized in AT over the past decades, with the most recent addition of invariant natural killer T (iNKT) cells. As members of the T cell family, iNKT cells represent a subset that exhibits both innate and adaptive characteristics and directs ensuing immune responses. In disease conditions, iNKT cells have established roles that include disorders in the autoimmune spectrum in malignancies and infectious diseases. Recent work supports a role for iNKT cells in the maintenance of AT homeostasis through both immune and metabolic pathways. The deficiency of iNKT cells can result in AT metabolic disruptions and insulin resistance. In this review, we summarize recent work on iNKT cells in immune regulation, with an emphasis on AT-resident iNKT cells, and identify the potential mechanisms by which adipocytes can mediate iNKT cell activity.     

Peripheral B cell survival

Recent findings suggest that lymphocyte survival is a continuous active process and support the role of B cell receptor engagement in B cell survival. In this context the conflict of survival interests between the diverse B cells gives rise to a pattern of interactions which mimics the behavior of complex ecological systems. In response to competition lymphocytes modify their survival requirements and diverge to occupy different immunological niches through differentiation. Thus naive and memory-activated B cell populations show independent homeostatic regulation. We discuss how niche differentiation allows the coexistence of different cell types and guarantees both repertoire diversity and efficient immune responses.     

The potential importance of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of Alzheimer’s disease

The exact cause of Alzheimer’s disease (AD) is still unknown, but the deposition of amyloid-β (Aβ) plaques and chronic inflammation indicates that immune disturbances are involved in AD pathogenesis. Recent genetic studies have revealed that many candidate genes are expressed in both microglia and myeloid cells which infiltrate into the AD brains. Invading myeloid cells controls the functions of resident microglia in pathological conditions, such as AD pathology. AD is a neurologic disease with inflammatory component where the immune system is not able to eliminate the perpetrator, while, concurrently, it should prevent neuronal injuries induced by inflammation. Recent studies have indicated that AD brains are an immunosuppressive microenvironment, e.g., microglial cells are hyporesponsive to Aβ deposits and anti-inflammatory cytokines enhance Aβ deposition. Immunosuppression is a common element in pathological disorders involving chronic inflammation. Studies on cancer-associated inflammation have demonstrated that myeloid-derived suppressor cells (MDSCs) have a crucial role in the immune escape of tumor cells. Immunosuppression is not limited to tumors, since MDSCs can be recruited into chronically inflamed tissues where inflammatory mediators enhance the proliferation and activation of MDSCs. AD brains express a range of chemokines and cytokines which could recruit and expand MDSCs in inflamed AD brains and thus generate an immunosuppressive microenvironment. Several neuroinflammatory disorders, e.g., the early phase of AD pathology, have been associated with an increase in the level of circulating MDSCs. We will elucidate the immunosuppressive armament of MDSCs and present evidences in support of the crucial role of MDSCs in the pathogenesis of AD.     

The impact of phosphatases on proliferative and survival signaling in cancer

The dynamic and stringent coordination of kinase and phosphatase activity controls a myriad of physiologic processes. Aberrations that disrupt the balance of this interplay represent the basis of numerous diseases. For a variety of reasons, early work in this area portrayed kinases as the dominant actors in these signaling events with phosphatases playing a secondary role. In oncology, these efforts led to breakthroughs that have dramatically altered the course of certain diseases and directed vast resources toward the development of additional kinase-targeted therapies. Yet, more recent scientific efforts have demonstrated a prominent and sometimes driving role for phosphatases across numerous malignancies. This maturation of the phosphatase field has brought with it the promise of further therapeutic advances in the field of oncology. In this review, we discuss the role of phosphatases in the regulation of cellular proliferation and survival signaling using the examples of the MAPK and PI3K/AKT pathways, c-Myc and the apoptosis machinery. Emphasis is placed on instances where these signaling networks are perturbed by dysregulation of specific phosphatases to favor growth and persistence of human cancer.     

Home sweet home: skin stem cell niches

The epidermis and its appendages, such as the hair follicle (HF), continually regenerate throughout postnatal mammalian life due to the activity of resident epithelial stem cells (SCs). The follicular SC niche, or the bulge, is composed of a heterogeneous population of self-renewing multipotent cells. Multiple intrinsic molecular mechanisms promote the transition of follicular SCs from quiescence to activation. In addition, numerous extrinsic cell types influence the activity and characteristics of bulge cells. Ultimately, the balance between these intrinsic and extrinsic mechanisms influences the function of bulge cells during homeostasis and tissue regeneration and likely contributes to skin tumorigenesis. Here, we review both the intrinsic and extrinsic factors that contribute to the skin SC niche.     

Oncogenic protein tyrosine kinases

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, the normal role of which remains to be completely elucidated. Although work carried out in mammals suggests a function in neural development, results from studies in Drosophila indicate an additional role in visceral muscle differentiation. The aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas, while the occurrence of ALK fusion proteins in anaplastic large cell lymphoma (ALCL) has resulted in the identification of the new tumor entity, ALK-positive ALCL. ALK represents one of few examples of a receptor tyrosine kinase implicated in oncogenesis in both haematopoietic and non-haematopoietic tumors, given that ALK fusions also occur in the mesenchymal tumor known as inflammatory myofibroblastic tumor (IMT). The study of ALK fusion proteins, besides demonstrating their importance in tumor development, has also raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies.     

Oncogenic protein tyrosine kinases

FLT3, a member of the class III receptor tyrosine kinases (RTKs), is preferentially expressed on the cell surface of hematopoietic progenitors, and the ligand of FLT3 (FL) is expressed as a membrane-bound or soluble form by bone marrow stroma cells. It has been disclosed that FL-FLT3 interaction plays an important role in the maintenance, proliferation and differentiation of hematopoiesis. FLT3 is also expressed in a high proportion of acute myeloid leukemia (AML) and B-lineage acute lymphoblastic leukemia cells. Activating mutations of FLT3 are the most frequent genetic lesions in AML, and AML patients with FLT3 mutations have a worse prognosis than those with normal FLT3. Exploring the mechanism by which FLT3 mutations cause autoactivation and uncontrolled signaling might lead to a better understanding of how FLT3 becomes oncogenic and provide insights for the development of new drugs.     

Hypoxia in the regulation of neural stem cells

In aerobic organisms, oxygen is a critical factor in tissue and organ morphogenesis from embryonic development throughout post-natal life, as it regulates various intracellular pathways involved in cellular metabolism, proliferation, survival and fate. In the mammalian central nervous system, oxygen plays a critical role in regulating the growth and differentiation state of neural stem cells (NSCs), multipotent neuronal precursor cells that reside in a particular microenvironment called the neural stem cell niche and that, under certain physiological and pathological conditions, differentiate into fully functional mature neurons, even in adults. In both experimental and clinical settings, oxygen is one of the main factors influencing NSCs. In particular, the physiological condition of mild hypoxia (2.5–5.0% O₂) typical of neural tissues promotes NSC self-renewal; it also favors the success of engraftment when in vitro-expanded NSCs are transplanted into brain of experimental animals. In this review, we analyze how O₂ and specifically hypoxia impact on NSC self-renewal, differentiation, maturation, and homing in various in vitro and in vivo settings, including cerebral ischemia, so as to define the O₂ conditions for successful cell replacement therapy in the treatment of brain injury and neurodegenerative diseases.