RESUMO
PURPOSE OF THE REVIEW: In this review, we discuss the most recent scientific advances on the reciprocal regulatory interactions between the skeletal and hematopoietic stem cell niche, focusing on immunomodulation and its interplay with the cell's mitochondrial function, and how this impacts osteoimmune health during aging and disease. RECENT FINDINGS: Osteoimmunology investigates interactions between cells that make up the skeletal stem cell niche and immune system. Much work has investigated the complexity of the bone marrow microenvironment with respect to the skeletal and hematopoietic stem cells that regulate skeletal formation and immune health respectively. It has now become clear that these cellular components cooperate to maintain homeostasis and that dysfunction in their interaction can lead to aging and disease. Having a deeper, mechanistic appreciation for osteoimmune regulation will lead to better research perspective and therapeutics with the potential to improve the aging process, skeletal and hematologic regeneration, and disease targeting.
Assuntos
Envelhecimento , Medula Óssea , Células-Tronco Hematopoéticas , Homeostase , Nicho de Células-Tronco , Humanos , Envelhecimento/fisiologia , Envelhecimento/imunologia , Medula Óssea/imunologia , Nicho de Células-Tronco/fisiologia , Osso e Ossos/metabolismo , Osso e Ossos/imunologia , Mitocôndrias , Microambiente Celular/fisiologia , Células da Medula Óssea/imunologia , Animais , ImunomodulaçãoRESUMO
OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is rising in incidence, and at present, there are limited effective systemic therapies. iCCA tumours are infiltrated by stromal cells, with high prevalence of suppressive myeloid populations including tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Here, we show that tumour-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) and the host bone marrow is central for monopoiesis and potentiation of TAMs, and abrogation of this signalling axis facilitates antitumour immunity in a novel model of iCCA. METHODS: Blood and tumours were analysed from iCCA patients and controls. Treatment and correlative studies were performed in mice with autochthonous and established orthotopic iCCA tumours treated with anti-GM-CSF monoclonal antibody. RESULTS: Systemic elevation in circulating myeloid cells correlates with poor prognosis in patients with iCCA, and patients who undergo resection have a worse overall survival if tumours are more infiltrated with CD68+ TAMs. Mice with spontaneous iCCA demonstrate significant elevation of monocytic myeloid cells in the tumour microenvironment and immune compartments, and tumours overexpress GM-CSF. Blockade of GM-CSF with a monoclonal antibody decreased tumour growth and spread. Mice bearing orthotopic tumours treated with anti-GM-CSF demonstrate repolarisation of immunosuppressive TAMs and MDSCs, facilitating T cell response and tumour regression. GM-CSF blockade dampened inflammatory gene networks in tumours and TAMs. Human tumours with decreased GM-CSF expression exhibit improved overall survival after resection. CONCLUSIONS: iCCA uses the GM-CSF-bone marrow axis to establish an immunosuppressive tumour microenvironment. Blockade of the GM-CSF axis promotes antitumour T cell immunity.
Assuntos
Colangiocarcinoma , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Animais , Anticorpos Monoclonais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Camundongos , Mielopoese , Microambiente Tumoral , Macrófagos Associados a TumorRESUMO
Leukemias are challenging diseases to treat due, in part, to interactions between leukemia cells and the bone marrow microenvironment (BMME) that contribute significantly to disease progression. Studies have shown that leukemic cells secrete C-chemokine (C-C motif) ligand 3 (CCL3), to disrupt the BMME resulting in loss of hematopoiesis and support of leukemic cell survival and proliferation. In this study, a murine model of blast crisis chronic myelogenous leukemia (bcCML) that expresses the translocation products BCR/ABL and Nup98/HoxA9 was used to determine the role of CCL3 in BMME regulation. Leukemic cells derived from CCL3-/- mice were shown to minimally engraft in a normal BMME, thereby demonstrating that CCL3 signaling was necessary to recapitulate bcCML disease. Further analysis showed disruption in hematopoiesis within the BMME in the bcCML model. To rescue the altered BMME, therapeutic inhibition of CCL3 signaling was investigated using bone-targeted nanoparticles (NP) to deliver Maraviroc, an inhibitor of C-C chemokine receptor type 5 (CCR5), a CCL3 receptor. NP-mediated Maraviroc delivery partially restored the BMME, significantly reduced leukemic burden, and improved survival. Overall, our results demonstrate that inhibiting CCL3 via CCR5 antagonism is a potential therapeutic approach to restore normal hematopoiesis as well as reduce leukemic burden within the BMME.
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Leucemia/tratamento farmacológico , Animais , Proteínas de Bactérias , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Proteínas de Fluorescência Verde , Leucemia/etiologia , Leucemia Mieloide Aguda , Proteínas Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Doses de RadiaçãoRESUMO
In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival.
Assuntos
Medula Óssea/patologia , Microambiente Celular , Células-Tronco Hematopoéticas/patologia , Síndromes Mielodisplásicas/patologia , Animais , Medula Óssea/metabolismo , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Síndromes Mielodisplásicas/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , TransgenesRESUMO
The bone marrow microenvironment contains a heterogeneous population of stromal cells organized into niches that support hematopoietic stem cells (HSCs) and other lineage-committed hematopoietic progenitors. The stem cell niche generates signals that regulate HSC self-renewal, quiescence, and differentiation. Here, we review recent studies that highlight the heterogeneity of the stromal cells that comprise stem cell niches and the complexity of the signals that they generate. We highlight emerging data that stem cell niches in the bone marrow are not static but instead are responsive to environmental stimuli. Finally, we review recent data showing that hematopoietic niches are altered in certain hematopoietic malignancies, and we discuss how these alterations might contribute to disease pathogenesis.
Assuntos
Diferenciação Celular , Neoplasias Hematológicas/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Homeostase , Nicho de Células-Tronco , Animais , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/patologia , HumanosRESUMO
PURPOSE: Geography is known to affect cost of care in surgical procedures. Understanding the relationship between geography and hospital costs is pertinent in the effort to reduce healthcare costs. We studied the geographic variation in cost for transsphenoidal pituitary surgery in hospitals across New York State. METHODS: Using the Healthcare Cost and Utilization Project State Inpatient Database for New York from 2008 to 2011, we analyzed records of patients who underwent elective transsphenoidal pituitary tumor surgery and were discharged to home or self-care. N.Y. State was divided into five geographic regions: Buffalo, Rochester, Syracuse, Albany, and Downstate. These five regions were compared according to median charge and cost per day. RESULTS: From 2008 to 2011, 1803 transsphenoidal pituitary tumor surgeries were performed in New York State. Mean patient age was 50.7 years (54 % were female). Adjusting prices for length of stay, there was substantial variation in prices. Median charges per day ranged from $8485 to $13,321 and median costs per day ranged from $2962 to $6837 between the highest and lowest regions from 2008 to 2011. CONCLUSION: Within New York State, significant geographic variation exists in the cost for transsphenoidal pituitary surgery. The significance of and contributors to such variation is an important question for patients, providers, and policy makers. Transparency of hospital charges, costs, and average length of stay for procedures to the public provides useful information for informed decision-making, especially for a highly portable disease entity like pituitary tumors.
Assuntos
Procedimentos Neurocirúrgicos/economia , Neoplasias Hipofisárias/cirurgia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New YorkRESUMO
Estrogen deficiency expands hemopoietic stem and progenitor cells (HSPCs) and mature blood lineages, but the involved mechanism and the affected HSPC populations are mostly unknown. Here we show that ovariectomy (ovx) expands short-term HSPCs (ST-HSPCs) and improves blood cell engraftment and host survival after bone marrow (BM) transplantation through a dual role of the T-cell costimulatory molecule CD40 ligand (CD40L). This surface receptor is required for ovx to stimulate T-cell production of Wnt10b, a Wnt ligand that activates Wnt signaling in HSPCs and stromal cells (SCs). Moreover, CD40L is required for ovx to increase SC production of the hemopoietic cytokines interleukin (IL)-6, IL-7, and granulocyte macrophage-colony-stimulating factor. Attesting to the relevance of CD40L and Wnt10b, ovx fails to expand ST-HSPCs in CD40L-null mice and in animals lacking global or T-cell expression of Wnt10b. In summary, T cells expressed CD40L, and the resulting increased production of Wnt10b and hemopoietic cytokines by T cells and SCs, respectively, plays a pivotal role in the mechanism by which ovx regulates hemopoiesis. The data suggest that antiestrogens may represent pharmacological targets to improve ST-HSPC function through activation of the microenvironment.
Assuntos
Ligante de CD40/biossíntese , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Ovariectomia , Linfócitos T/metabolismo , Proteínas Wnt/biossíntese , Animais , Transplante de Medula Óssea/imunologia , Feminino , Citometria de Fluxo , Células-Tronco Hematopoéticas/imunologia , Camundongos , Camundongos Knockout , Linfócitos T/imunologia , Proteínas Wnt/imunologiaRESUMO
Pancytopenia is a major cause of morbidity in acute myeloid leukemia (AML), yet its cause is unclear. Normal osteoblastic cells have been shown to support hematopoiesis. To define the effects of leukemia on osteoblastic cells, we used an immunocompetent murine model of AML. Leukemic mice had inhibition of osteoblastic cells, with decreased serum levels of the bone formation marker osteocalcin. Osteoprogenitor cells and endosteal-lining osteopontin(+) cells were reduced, and osteocalcin mRNA in CD45(-) marrow cells was diminished. This resulted in severe loss of mineralized bone. Osteoclasts were only transiently increased without significant increases in bone resorption, and their inhibition only partially rescued leukemia-induced bone loss. In vitro data suggested that a leukemia-derived secreted factor inhibited osteoblastic cells. Because the chemokine CCL-3 was recently reported to inhibit osteoblastic function in myeloma, we tested its expression in our model and in AML patients. Consistent with its potential novel role in leukemic-dependent bone loss, CCL-3 mRNA was significantly increased in malignant marrow cells from leukemic mice and from samples from AML patients. Based on these results, we propose that therapeutic mitigation of leukemia-induced uncoupling of osteoblastic and osteoclastic cells may represent a novel approach to promote normal hematopoiesis in patients with myeloid neoplasms.
Assuntos
Quimiocina CCL3/metabolismo , Modelos Animais de Doenças , Hematopoese , Leucemia Mieloide/patologia , Osteoblastos/patologia , Osteoclastos/patologia , Animais , Western Blotting , Conservadores da Densidade Óssea/farmacologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Quimiocina CCL3/genética , Difosfonatos/farmacologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imidazóis/farmacologia , Imunocompetência , Técnicas Imunoenzimáticas , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Baço/patologia , Ácido ZoledrônicoRESUMO
Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment. Controversy exists on N-cadherin's role in support of HSCs. Specifically, it is unknown whether microenvironmental N-cadherin is required for normal marrow microarchitecture and for hematopoiesis. To determine whether osteoblastic N-cadherin is required for HSC regulation, we used a genetic murine model in which deletion of Cdh2, the gene encoding N-cadherin, has been targeted to cells of the osteoblastic lineage. Targeted deletion of N-cadherin resulted in an age-dependent bone phenotype, ultimately characterized by decreased mineralized bone, but no difference in steady-state HSC numbers or function at any time tested, and normal recovery from myeloablative injury. Intermittent parathyroid hormone (PTH) treatment is well established as anabolic to bone and to increase marrow HSCs through microenvironmental interactions. Lack of osteoblastic N-cadherin did not block the bone anabolic or the HSC effects of PTH treatment. This report demonstrates that osteoblastic N-cadherin is not required for regulation of steady-state hematopoiesis, HSC response to myeloablation, or for rapid expansion of HSCs through intermittent treatment with PTH.
Assuntos
Caderinas/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Osteoblastos/citologia , Osteoblastos/fisiologia , Envelhecimento/genética , Envelhecimento/patologia , Animais , Sequência de Bases , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Densidade Óssea/fisiologia , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/genética , Remodelação Óssea/fisiologia , Osso e Ossos/anatomia & histologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Caderinas/deficiência , Caderinas/genética , Microambiente Celular/fisiologia , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoblastos/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Microenvironmental expansion of hematopoietic stem cells (HSCs) is induced by treatment with parathyroid hormone (PTH) or activation of the PTH receptor (PTH1R) in osteoblastic cells; however, the osteoblastic subset mediating this action of PTH is unknown. Osteocytes are terminally differentiated osteoblasts embedded in mineralized bone matrix but are connected with the BM. Activation of PTH1R in osteocytes increases osteoblastic number and bone mass. To establish whether osteocyte-mediated PTH1R signaling expands HSCs, we studied mice expressing a constitutively active PTH1R in osteocytes (TG mice). Osteoblasts, osteoclasts, and trabecular bone were increased in TG mice without changes in BM phenotypic HSCs or HSC function. TG mice had progressively increased trabecular bone but decreased HSC function. In severely affected TG mice, phenotypic HSCs were decreased in the BM but increased in the spleen. TG osteocytes had no increase in signals associated with microenvironmental HSC support, and the spindle-shaped osteoblastic cells that increased with PTH treatment were not present in TG bones. These findings demonstrate that activation of PTH1R signaling in osteocytes does not expand BM HSCs, which are instead decreased in TG mice. Therefore, osteocytes do not mediate the HSC expansion induced by PTH1R signaling. Further, osteoblastic expansion is not sufficient to increase HSCs.
Assuntos
Remodelação Óssea , Células-Tronco Hematopoéticas/citologia , Osteoblastos/citologia , Osteócitos/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/fisiologia , Animais , Citometria de Fluxo , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Transgênicos , Mutação/genética , Osteoblastos/metabolismo , Osteócitos/citologia , Hormônio Paratireóideo/metabolismo , Ratos , Transdução de SinaisRESUMO
Intermittent parathyroid hormone (iPTH) treatment expands hemopoietic stem and progenitor cells (HSPCs), but the involved mechanisms and the affected HSPC populations are mostly unknown. Here we show that T cells are required for iPTH to expand short-term HSPCs (ST-HSPCs) and improve blood cell engraftment and host survival after BM transplantation. Silencing of PTH/PTH-related protein receptor (PPR) in T cells abrogates the effects of iPTH, thus demonstrating a requirement for direct PPR signaling in T cells. Mechanistically, iPTH expands ST-HSPCs by activating Wnt signaling in HSPCs and stromal cells (SCs) through T-cell production of the Wnt ligand Wnt10b. Attesting to the relevance of Wnt10b, iPTH fails to expand ST-HSPCs in mice with Wnt10b(-/-) T cells. Moreover, iPTH fails to promote engraftment and survival after BM transplantation in Wnt10b null mice. In summary, direct PPR signaling in T cells and the resulting production of Wnt10b play a pivotal role in the mechanism by which iPTH expands ST-HSPCs. The data suggest that T cells may provide pharmacologic targets for HSPC expansion.
Assuntos
Proliferação de Células/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , Linfócitos T/fisiologia , Animais , Transplante de Medula Óssea , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Feminino , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/fisiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/efeitos dos fármacos , Fatores de Tempo , Proteínas Wnt/genéticaRESUMO
Hematopoietic stem cell (HSC) behavior is governed in large part by interactions of the blood system with the bone microenvironment. Increasing evidence demonstrates the profound role the local HSC microenvironment or niche plays in normal stem cell function, in therapeutic activation and in the setting of malignancy. A number of cellular and molecular components of the microenvironment have been identified thus far, several of which are likely to provide exciting therapeutic targets in the near future. Clinically effective strategies for niche manipulation, however, require careful study of the interaction of these niche components. Some of the key findings defining these regulatory interactions are explored in this concise review, with special emphasis on potential translational applications.
Assuntos
Células da Medula Óssea/citologia , Medula Óssea/fisiologia , Células-Tronco Hematopoéticas/citologia , Nicho de Células-Tronco/fisiologia , Animais , Osso e Ossos/fisiologia , HumanosRESUMO
Hematopoietic stem and progenitor cells (HSPCs), which continuously maintain all mature blood cells, are regulated within the marrow microenvironment. We previously reported that pharmacologic treatment of naïve mice with prostaglandin E2 (PGE2) expands HSPCs. However, the cellular mechanisms mediating this expansion remain unknown. Here, we demonstrate that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate. In a murine model of sublethal total body irradiation (TBI), in which HSPCs are rapidly lost, treatment with a long-acting PGE2 analog (dmPGE2) reversed the apoptotic program initiated by TBI. dmPGE2 treatment in vivo decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity. The antiapoptotic effect of dmPGE2 on HSPCs did not impair their ability to differentiate in vivo, resulting instead in improved hematopoietic recovery after TBI. dmPGE2 also increased microenvironmental cyclooxygenase-2 expression and expanded the α-smooth muscle actin-expressing subset of marrow macrophages, thus enhancing the bone marrow microenvironmental response to TBI. Therefore, in vivo treatment with PGE2 analogs may be particularly beneficial to HSPCs in the setting of injury by targeting them both directly and also through their niche. The current data provide rationale for in vivo manipulation of the HSPC pool as a strategy to improve recovery after myelosuppression.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Dinoprostona/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Actinas/genética , Actinas/imunologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Células da Medula Óssea/patologia , Células da Medula Óssea/efeitos da radiação , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/efeitos da radiação , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Dinoprostona/análogos & derivados , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/efeitos da radiação , Macrófagos/patologia , Macrófagos/efeitos da radiação , Masculino , Camundongos , Camundongos Transgênicos , Lesões Experimentais por Radiação/imunologia , Lesões Experimentais por Radiação/patologia , Irradiação Corporal TotalRESUMO
The skeleton serves as the principal site for hematopoiesis in adult terrestrial vertebrates. The function of the hematopoietic system is to maintain homeostatic levels of all circulating blood cells, including myeloid cells, lymphoid cells, red blood cells, and platelets. This action requires the daily production of more than 500 billion blood cells. The vast majority of these cells are synthesized in the bone marrow, where they arise from a limited number of hematopoietic stem cells (HSCs) that are multipotent and capable of extensive self-renewal. These attributes of HSCs are best demonstrated by marrow transplantation, where even a single HSC can repopulate the entire hematopoietic system. HSCs are therefore adult stem cells capable of multilineage repopulation, poised between cell fate choices which include quiescence, self-renewal, differentiation, and apoptosis. While HSC fate choices are in part determined by multiple stochastic fluctuations of cell autonomous processes, according to the niche hypothesis, signals from the microenvironment are also likely to determine stem cell fate. While it had long been postulated that signals within the bone marrow could provide regulation of hematopoietic cells, it is only in the past decade that advances in flow cytometry and genetic models have allowed for a deeper understanding of the microenvironmental regulation of HSCs. In this review, we will highlight the cellular regulatory components of the HSC niche.
Assuntos
Medula Óssea/metabolismo , Osso e Ossos/citologia , Diferenciação Celular/fisiologia , Células-Tronco Hematopoéticas/citologia , Nicho de Células-Tronco/fisiologia , Animais , Linhagem da Célula/fisiologia , Células-Tronco Hematopoéticas/metabolismo , HumanosRESUMO
Signals from the microenvironment are known to be critical for development, sustaining adult stem cells, and for oncogenic progression. While candidate niche-driven signals that can promote cancer progression have been identified1-6, concerted efforts to comprehensively map microenvironmental ligands for cancer stem cell specific surface receptors have been lacking. Here, we use temporal single cell RNA-sequencing to identify molecular cues from the bone marrow stromal niche that engage leukemia stem cells (LSC) during oncogenic progression. We integrate these data with our RNA-seq analysis of human LSCs from distinct aggressive myeloid cancer subtypes and our CRISPR based in vivo LSC dependency map7 to develop a temporal receptor-ligand interactome essential for disease progression. These analyses identify the taurine transporter (TauT)-taurine axis as a critical dependency of myeloid malignancies. We show that taurine production is restricted to the osteolineage population during cancer initiation and expansion. Inhibiting taurine synthesis in osteolineage cells impairs LSC growth and survival. Our experiments with the TauT genetic loss of function murine model indicate that its loss significantly impairs the progression of aggressive myeloid leukemias in vivo by downregulating glycolysis. Further, TauT inhibition using a small molecule strongly impairs the growth and survival of patient derived myeloid leukemia cells. Finally, we show that TauT inhibition can synergize with the clinically approved oxidative phosphorylation inhibitor venetoclax8, 9 to block the growth of primary human leukemia cells. Given that aggressive myeloid leukemias continue to be refractory to current therapies and have poor prognosis, our work indicates targeting the taurine transporter may be of therapeutic significance. Collectively, our data establishes a temporal landscape of stromal signals during cancer progression and identifies taurine-taurine transporter signaling as an important new regulator of myeloid malignancies.
RESUMO
Histologically, malignant struma ovarii metastasizes rarely, and only a few cases reported bone metastasis. Here, we describe 2 cases of biologically malignant struma ovarii with pelvic bone metastasis. Case 1 is a 22-year-old female who was found to have a large left ovarian mass during routine prenatal ultrasound. Papillary thyroid cancer arising in struma ovarii was identified after laparoscopic salpingo-oophorectomy. After total thyroidectomy, radioactive iodine whole-body scan revealed extrathyroidal iodine uptake in left anterior pelvis. Subsequent I-131 treatment resolved the pelvic metastasis. Case 2 is a 49-year-old female who was diagnosed with malignant struma ovarii in 1996 and presented in 2007 with pelvic recurrence and extensive left hip metastasis. Treatment with resection of the pelvic tumor, total thyroidectomy, and multiple I-131 ablation led to eventual resolution of the abdominal and left hip foci. In conclusion, we present 2 rare cases of malignant struma ovarii, both with metastasis to the pelvic bone. This report makes pelvic bone the most frequent site for bone metastasis in malignant struma ovarii. It also emphasizes the importance of total thyroidectomy in allowing identification and treatment of bony metastasis with radioactive iodine.
Assuntos
Neoplasias Ósseas/secundário , Neoplasias Ovarianas/patologia , Ossos Pélvicos/patologia , Estruma Ovariano/patologia , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/cirurgia , Feminino , Humanos , Histerectomia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Imagem Multimodal , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/cirurgia , Ovariectomia , Ossos Pélvicos/diagnóstico por imagem , Ossos Pélvicos/cirurgia , Tomografia por Emissão de Pósitrons , Salpingectomia , Estruma Ovariano/diagnóstico , Estruma Ovariano/cirurgia , Tireoidectomia , Tomografia Computadorizada por Raios X , Imagem Corporal Total , Adulto JovemRESUMO
Prior research establishing that bone interacts in coordination with the bone marrow microenvironment (BMME) to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations. Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells (HSCs) and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling. These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses. A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions. To advance this understanding, herein, we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment. Specifically, we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches. We then discuss unresolved questions and ambiguities that remain in the field.
RESUMO
The bone marrow microenvironment consists of distinct cell populations, such as mesenchymal stromal cells, endothelial cells, osteolineage cells, and fibroblasts, which provide support for hematopoietic stem cells (HSCs). In addition to supporting normal HSCs, the bone marrow microenvironment also plays a role in the development of hematopoietic stem cell disorders, such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). MDS-associated mutations in HSCs lead to a block in differentiation and progressive bone marrow failure, especially in the elderly. MDS can often progress to therapy-resistant AML, a disease characterized by a rapid accumulation of immature myeloid blasts. The bone marrow microenvironment is known to be altered in patients with these myeloid neoplasms. Here, a comprehensive protocol to isolate and phenotypically characterize bone marrow microenvironmental cells from murine models of myelodysplastic syndrome and acute myeloid leukemia is described. Isolating and characterizing changes in the bone marrow niche populations can help determine their role in disease initiation and progression and may lead to the development of novel therapeutics targeting cancer-promoting alterations in the bone marrow stromal populations.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Animais , Camundongos , Idoso , Medula Óssea , Células Endoteliais , Células-Tronco Hematopoéticas , Microambiente TumoralRESUMO
The efficient clearance of dead and dying cells, efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs and on their function. To investigate, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including bone marrow remodeling and bone loss in the setting of aging, cancer and other diseases.