Hematopoietic stem cells (HSCs) reside and are maintained in specialized microenvironments within the bone marrow known as niches, which are comprised of various cell types. Among them, leptin ...receptor (LepR)-expressing CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells are known to create a niche for HSCs and at the same time to give rise to osteoblasts. These two functions of CAR/LepR
cells appear to be tightly but inversely regulated to ensure adequate physical space for HSCs. However, how osteogenesis is prevented in CAR cells to maintain spaces available for HSCs and hematopoiesis remains unclear. In this issue of
, Seike and colleagues (pp. 359-372) report that the transcription factor early B-cell factor (
) is preferentially expressed by CAR/LepR
cells and inhibits CAR cell differentiation into osteoblasts while at the same time maintaining self-renewal of CAR/LepR
cells. Using conditional knockout and retroviral systems, the investigators show that loss of
in CAR cells impairs HSC numbers and leads to osteosclerosis. This study provides novel insights into transcriptional requirements for CAR cell bone formation by identifying Ebf3 as a niche factor secreted from CAR/Lepr
cells that regulates the interplay between osteogenesis and hematopoiesis.
Hematopoietic stem cells (HSCs) interact dynamically with an intricate network of cells in the bone marrow (BM) microenvironment or niche. These interactions provide instructive cues that influence ...the production and lineage determination of different types of blood cells and maintenance of HSC quiescence. They also contribute to hematopoietic deregulation and hematological myeloid malignancies. Alterations in the BM niche are commonly observed in myeloid malignancies and contribute to the aberrant function of myelodysplastic and leukemia-initiating stem cells. In this work, we review how different components of the BM niche affect normal hematopoiesis, the molecular signals that govern this interaction, and how genetic changes in stromal cells or alterations in remodeled malignant BM niches contribute to myeloid malignancies. Understanding the intricacies between normal and malignant niches and their modulation may provide insights into developing novel therapeutics for blood disorders.
Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as β-glucan seems to be a mechanism that ...fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall β-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macrophage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with IκB degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in β-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target.
Candida albicans is a major cause of oropharyngeal, vulvovaginal and haematogenously disseminated candidiasis. Endocytosis of C. albicans hyphae by host cells is a prerequisite for tissue invasion. ...This internalization involves interactions between the fungal invasin Als3 and host E- or N-cadherin. Als3 shares some structural similarity with InlA, a major invasion protein of the bacterium Listeria monocytogenes. InlA mediates entry of L. monocytogenes into host cells through binding to E-cadherin. A role in internalization, for a non-classical stimulation of the clathrin-dependent endocytosis machinery, was recently highlighted. Based on the similarities between the C. albicans and L. monocytogenes invasion proteins, we studied the role of clathrin in the internalization of C. albicans. Using live-cell imaging and indirect immunofluorescence of epithelial cells infected with C. albicans, we observed that host E-cadherin, clathrin, dynamin and cortactin accumulated at sites of C. albicans internalization. Similarly, in endothelial cells, host N-cadherin, clathrin and cortactin accumulated at sites of fungal endocytosis. Furthermore, clathrin, dynamin or cortactin depletion strongly inhibited C. albicans internalization by epithelial cells. Finally, beads coated with Als3 were internalized in a clathrin-dependent manner. These data indicate that C. albicans, like L. monocytogenes, hijacks the clathrin-dependent endocytic machinery to invade host cells.
Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early ...during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.
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•Bone via the hormone osteocalcin improves muscle function during exercise•Circulating osteocalcin levels decrease in aging mice, monkeys, and humans•Osteocalcin promotes muscle uptake and utilization of glucose and fatty acids•Osteocalcin promotes muscle IL-6 secretion during exercise
Mera et al. show that the bone-derived hormone osteocalcin is necessary for optimum exercise capacity and that this hormone decreases with aging in mice, monkeys, and humans of both genders. Osteocalcin promotes muscle uptake and utilization of glucose and lipids during exercise and greatly improves the exercise capacity of old mice.
Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of β-catenin, instigate their appearance. The LDL receptor-related ...protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of β-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require β-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of β-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5A214V) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate β-catenin signaling in osteoblasts. Consistent with a lack of β-catenin activation in their osteoblasts, Lrp5A214V mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of β-catenin in osteoblasts (Ctnnb1CAosb), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5A214V mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate β-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
•Lrp5 gain-of-function mutations do not activate β-catenin signaling in osteoblasts.•Patients and mice with Lrp5-activating mutations have normal hematopoiesis.•Myeloid lineage differentiation is normal in Lrp5 high bone mass patients and mice.
Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a BCR-JAK2 fusion gene in fatal chronic and ...acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR) assays to describe a BCR-JAK2 fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR. BCR-JAK2 codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying BCR-JAK2 induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where Bcl-xL gene expression was elicited. Primary mouse progenitor cells transduced with BCR-JAK2 also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. Therefore, BCR-JAK2 is a novel tyrosine-kinase with transforming activity. It deregulates growth factor-dependent proliferation and cell survival, which can be abrogated by the TG101209 inhibitor. Moreover, transformed Ba/F3 cells developed tumors when injected subcutaneously into nude mice, thus proving the tumorigenic capacity of BCR-JAK2 in vivo. Together these findings suggest that adult and pediatric patients with BCR-ABL-negative leukemia and JAK2 overexpression may benefit from targeted therapies.
Dendritic cells (DCs) phagocytose, process, and present bacterial antigens to T lymphocytes to trigger adaptive immunity. In vivo, bacteria can also be found inside T lymphocytes. However, T cells ...are refractory to direct bacterial infection, leaving the mechanisms by which bacteria invade T cells unclear. We show that T cells take up bacteria from infected DCs by the process of transinfection, which requires direct contact between the two cells and is enhanced by antigen recognition. Prior to transfer, bacteria localize to the immunological synapse, an intimate DC/T cell contact structure that activates T cells. Strikingly, T cells efficiently eliminate the transinfecting bacteria within the first hours after infection. Transinfected T cells produced high levels of proinflammatory cytokines and were able to protect mice from bacterial challenge following adoptive transfer. Thus, T lymphocytes can capture and kill bacteria in a manner reminiscent of innate immunity.
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•Bacteria infecting DCs localize at the immunological synapse after T cell contact•T cells capture bacteria by transinfection from infected DCs•T cells kill transinfecting bacteria and produce proinflammatory cytokines•Adoptive transfer of transinfected T cells can protect mice from bacterial challenge
Although bacteria are found inside T cells, they are refractory to direct infection. Cruz et al. find that T cells take up bacteria from infected DCs by transinfection, a process remarkably enhanced by antigen recognition. Once transinfected, T cells efficiently eliminate bacteria, produce proinflammatory cytokines and confer protection in mice.
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