RESUMEN
Acute myeloid leukemia (AML) is a deadly form of leukemia with ineffective traditional treatment and frequent chemoresistance-associated relapse. Personalized drug screening holds promise in identifying optimal regimen, nevertheless, primary AML cells undergo spontaneous apoptosis during cultures, invalidating the drug screening results. Here, we reconstitute a 3D osteogenic niche (3DON) mimicking that in bone marrow to support primary AML cell survival and phenotype maintenance in cultures. Specifically, 3DON derived from osteogenically differentiated mesenchymal stem cells (MSC) from healthy and AML donors are co-cultured with primary AML cells. The AML cells under the AML_3DON niche showed enhanced viability, reduced apoptosis and maintained CD33+ CD34-phenotype, associating with elevated secretion of anti-apoptotic cytokines in the AML_3DON niche. Moreover, AML cells under the AML_3DON niche exhibited low sensitivity to two FDA-approved chemotherapeutic drugs, further suggesting the physiological resemblance of the AML_3DON niche. Most interestingly, AML cells co-cultured with the healthy_3DON niche are highly sensitive to the same sample drugs. This study demonstrates the differential responses of AML cells towards leukemic and healthy bone marrow niches, suggesting the impact of native cancer cell niche in drug screening, and the potential of re-engineering healthy bone marrow niche in AML patients as chemotherapeutic adjuvants overcoming chemoresistance, respectively.
Asunto(s)
Supervivencia Celular , Leucemia Mieloide Aguda , Células Madre Mesenquimatosas , Fenotipo , Microambiente Tumoral , Humanos , Leucemia Mieloide Aguda/patología , Microambiente Tumoral/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo/métodos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Médula Ósea/patología , Médula Ósea/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacos , Células de la Médula Ósea/citología , Masculino , Diferenciación Celular/efectos de los fármacos , FemeninoRESUMEN
The cardiac perivascular niche is a cellular microenvironment of a blood vessel. The principles of niche regulation are still poorly understood. We studied the effect of TGFß1 on cells forming the cardiac perivascular niche using 3D cell culture (cardiospheres). Cardiospheres contained progenitor (c-Kit), endothelial (CD31), and mural (αSMA) cells, basement membrane proteins (laminin) and extracellular matrix proteins (collagen I, fibronectin). TGFß1 treatment decreased the length of CD31+ microvasculature, VE cadherin protein level, and proportion of NG2+ cells, and increased proportion of αSMA+ cells and transgelin/SM22α protein level. We supposed that this effect is related to the stabilizing function of TGFß1 on vascular cells: decreased endothelial cell proliferation, as shown for HUVEC, and activation of mural cell differentiation.
Asunto(s)
Diferenciación Celular , Proliferación Celular , Factor de Crecimiento Transformador beta1 , Factor de Crecimiento Transformador beta1/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Diferenciación Celular/efectos de los fármacos , Humanos , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Animales , Proteínas de Microfilamentos/metabolismo , Proteínas de Microfilamentos/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Cadherinas/metabolismo , Laminina/metabolismo , Laminina/farmacología , Proteínas Musculares/metabolismo , Células Cultivadas , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/citología , Fibronectinas/metabolismo , Fibronectinas/farmacología , Antígenos CD/metabolismo , Miocardio/metabolismo , Miocardio/citología , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/fisiología , Colágeno Tipo I/metabolismo , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/citología , Técnicas de Cultivo Tridimensional de Células/métodosRESUMEN
BACKGROUND: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated. METHODS: C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. RESULTS: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. CONCLUSIONS: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.
Asunto(s)
Síndrome de Radiación Aguda , Médula Ósea , Ratones Endogámicos C57BL , Trombopoyetina , Animales , Masculino , Ratones , Síndrome de Radiación Aguda/tratamiento farmacológico , Síndrome de Radiación Aguda/patología , Médula Ósea/efectos de los fármacos , Médula Ósea/efectos de la radiación , Médula Ósea/metabolismo , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/efectos de la radiación , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/efectos de la radiación , Trombopoyetina/farmacología , Irradiación Corporal Total , Materiales Biomiméticos/farmacología , Materiales Biomiméticos/uso terapéuticoRESUMEN
Tamoxifen-inducible systems are widely used in research to control Cre-mediated gene deletion in genetically modified animals. Beyond Cre activation, tamoxifen also exerts off-target effects, whose consequences are still poorly addressed. Here, we investigated the impact of tamoxifen on lipopolysaccharide (LPS)-induced neuroinflammatory responses, focusing on the neurogenic activity in the adult mouse dentate gyrus. We demonstrated that a four-day LPS treatment led to an increase in microglia, astrocytes and radial glial cells with concomitant reduction of newborn neurons. These effects were counteracted by a two-day tamoxifen pre-treatment. Through selective microglia depletion, we elucidated that both LPS and tamoxifen influenced astrogliogenesis via microglia mediated mechanisms, while the effects on neurogenesis persisted even in a microglia-depleted environment. Notably, changes in radial glial cells resulted from a combination of microglia-dependent and -independent mechanisms. Overall, our data reveal that tamoxifen treatment per se does not alter the balance between adult neurogenesis and astrogliogenesis but does modulate cellular responses to inflammatory stimuli exerting a protective role within the adult hippocampal neurogenic niche.
Asunto(s)
Hipocampo , Microglía , Neurogénesis , Tamoxifeno , Animales , Tamoxifeno/farmacología , Microglía/efectos de los fármacos , Microglía/metabolismo , Hipocampo/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Ratones , Ratones Endogámicos C57BL , Lipopolisacáridos/farmacología , Enfermedades Neuroinflamatorias , Masculino , Ratones Transgénicos , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/fisiologíaRESUMEN
Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic alterations in oncogenic pathways such as Wnt/ß-catenin are the important triggers in HCC for primary refractoriness. T-cell exhaustion has been reported in various tumors and is likely to play a prominent role in the emergence of HCC due to chronic inflammation and cirrhosis-associated immune dysfunction. Immunosuppressive cells including regulatory T-cells and tumor-associated macrophages infiltrating the tumor are associated with hyperprogressive disease in the early stages of immune checkpoint inhibitor treatment. In addition, stellate cells and tumor-associated fibroblasts create an abundant desmoplastic environment by producing extracellular matrix. This strongly contributes to epithelial to mesenchymal transition via signaling activities including transforming growth factor beta, Wnt/ß-catenin, and Hippo pathway. The abundant desmoplastic environment has been demonstrated in pancreatic ductal adenocarcinoma and cholangiocarcinoma to suppress cytotoxic T-cell infiltration, PD-L1 expression, and neoantigen expression, resulting in a highly immunosuppressive niche. It is possible that a similar immunosuppressive environment is created in HCC with advanced fibrosis in the background liver. Although sufficient understanding is required for the establishment of immune therapies of HCC, further investigations are still required in this field.
Asunto(s)
Carcinoma Hepatocelular/terapia , Fibrosis/terapia , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia , Neoplasias Hepáticas/terapia , Nicho de Células Madre/efectos de los fármacos , Animales , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Fibrosis/inmunología , Fibrosis/patología , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Nicho de Células Madre/inmunologíaRESUMEN
Actinomycin D has been reported to selectively inhibit rRNA synthesis and ribosome biogenesis, induce G2 checkpoint of cell cycle arrest in HeLa cells. In Arabidopsis, actinomycin D was also used as agent to preferentially inhibit the ribosome biosynthesis and ribosomal function. However, the function of actinomycin D on Arabidopsis root development remains to be elucidated. In this study, we exposed Arabidopsis seedlings to actinomycin D with the aim of evaluating the effects of ribosome biogenesis on root development. The results demonstrated that actinomycin D inhibited Arabidopsis root growth by reduced meristematic activity in a dose dependent manner. Exposure to actinomycin D decreased the expression of WOX5 and key stem cell niche-defining transcription factors SHR and PLT1, thus the loss function of QC identity and stem cell niche maintenance. In addition, dead cells were observed after actinomycin D treatment in root stele initials and DNA damage response was constitutively activated. Collectively, we propose that ribosome biogenesis plays key role in primary root growth through maintenance of root stem cell niche and DNA damage response in Arabidopsis.
Asunto(s)
Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Dactinomicina/farmacología , Biogénesis de Organelos , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/metabolismo , Ribosomas/metabolismo , Arabidopsis/efectos de los fármacos , Proteínas de Arabidopsis/metabolismo , Muerte Celular/efectos de los fármacos , Daño del ADN , Ácidos Indolacéticos/metabolismo , Meristema/efectos de los fármacos , Meristema/crecimiento & desarrollo , Tamaño de los Órganos/efectos de los fármacos , Raíces de Plantas/efectos de los fármacos , Ribosomas/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacosRESUMEN
Multicellular spheroids show three-dimensional (3D) organization with extensive cell-cell and cell-extracellular matrix interactions. Owing to their native tissue-mimicking characteristics, mesenchymal stem cell (MSC) spheroids are considered promising as implantable therapeutics for stem cell therapy. Herein, we aim to further enhance their therapeutic potential by tuning the cultivation parameters and thus the inherent niche of 3D MSC spheroids. Significantly increased expression of multiple pro-regenerative paracrine signaling molecules and immunomodulatory factors by MSCs was observed after optimizing the conditions for spheroid culture. Moreover, these alterations in cellular behaviors may be associated with not only the hypoxic niche developed in the spheroid core but also with the metabolic reconfiguration of MSCs. The present study provides efficient methods for manipulating the therapeutic capacity of 3D MSC spheroids, thus laying solid foundations for future development and clinical application of spheroid-based MSC therapy for regenerative medicine.
Asunto(s)
Inmunomodulación , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Esferoides Celulares/citología , Esferoides Celulares/metabolismo , Nicho de Células Madre , Autofagia/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Hidrogeles/farmacología , Inmunomodulación/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Comunicación Paracrina/efectos de los fármacos , Esferoides Celulares/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacosRESUMEN
The bone marrow niche plays critical roles in hematopoietic recovery and hematopoietic stem cell (HSC) regeneration after myeloablative stress. However, it is not clear whether systemic factors beyond the local niche are required for these essential processes in vivo. Thrombopoietin (THPO) is a key cytokine promoting hematopoietic rebound after myeloablation and its transcripts are expressed by multiple cellular sources. The upregulation of bone marrow-derived THPO has been proposed to be crucial for hematopoietic recovery and HSC regeneration after stress. Nonetheless, the cellular source of THPO in myeloablative stress has never been investigated genetically. We assessed the functional sources of THPO following two common myeloablative perturbations: 5-fluorouracil (5-FU) administration and irradiation. Using a Thpo translational reporter, we found that the liver but not the bone marrow is the major source of THPO protein after myeloablation. Mice with conditional Thpo deletion from osteoblasts and/or bone marrow stromal cells showed normal recovery of HSCs and hematopoiesis after myeloablation. In contrast, mice with conditional Thpo deletion from hepatocytes showed significant defects in HSC regeneration and hematopoietic rebound after myeloablation. Thus, systemic THPO from the liver is necessary for HSC regeneration and hematopoietic recovery in myeloablative stress conditions.
Asunto(s)
Fluorouracilo/farmacología , Hematopoyesis/efectos de los fármacos , Hematopoyesis/efectos de la radiación , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de la radiación , Hepatocitos/metabolismo , Agonistas Mieloablativos/farmacología , Comunicación Paracrina , Trombopoyetina/metabolismo , Animales , Células Madre Hematopoyéticas/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/efectos de la radiación , Trombopoyetina/genética , Factores de TiempoRESUMEN
Bone marrow adipocytes (BMAs) have recently been recognized as a niche component with a suppressive function. Obese individuals with abundant BMAs exhibit impaired hematopoietic regeneration after hematopoietic stem cell transplantation (HSCT). We hypothesized that plasminogen activator inhibitor type-1 (PAI-1), an adipokine that regulates the fibrinolytic system, contributes to impaired hematopoiesis in bone marrow (BM) microenvironment with abundant BMAs. We demonstrated that BMAs differentiated in vitro could secrete PAI-1 and were positive for PAI-1 in vivo. In addition, the abundance of BMAs was associated with high levels of PAI-1 expression. The BMA-rich microenvironment exhibited impaired hematopoietic regeneration after HSCT when compared with a BMA-less microenvironment. The impaired hematopoietic regeneration in BMA-rich microenvironment was significantly alleviated by PAI-1 knockout or PAI-1 inhibitor treatment. Obese mice with abundant BMAs, compared with normal-weight mice, exhibited higher bone marrow PAI-1 concentrations, increased fibrinolytic system suppression, and lower stem cell factor (SCF) concentrations after HSCT. PAI-1 inhibitor administration significantly activated the fibrinolytic system in obese mice, contributing to the higher SCF concentration. Moreover, PAI-1 inhibitor treatment significantly alleviated the impaired hematopoietic regeneration in obese mice both after 5-fluorouracil injection and HSCT. These results indicate that PAI-1 hinders hematopoietic regeneration in BMA-rich microenvironments. The blockade of PAI-1 activity could be a novel therapeutic means of facilitating hematopoietic reconstitution in BMA-rich patients.
Asunto(s)
Adipocitos/metabolismo , Médula Ósea/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Obesidad/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/farmacología , Animales , Antimetabolitos/farmacología , Médula Ósea/metabolismo , Fluorouracilo/farmacología , Técnicas de Inactivación de Genes , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Ratones , Ratones Endogámicos C57BL , Obesidad/genética , Obesidad/terapia , Inhibidor 1 de Activador Plasminogénico/genética , Regeneración/efectos de los fármacos , Factor de Células Madre/metabolismo , Nicho de Células Madre/efectos de los fármacosRESUMEN
Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.
Asunto(s)
Glioblastoma/metabolismo , Glioma/metabolismo , Gosipol/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Encéfalo/patología , Neoplasias Encefálicas/metabolismo , Carcinogénesis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioma/tratamiento farmacológico , Glioma/patología , Gosipol/metabolismo , Gosipol/farmacología , Humanos , Células Madre Neoplásicas/metabolismo , Transducción de Señal/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacos , Temozolomida/farmacología , Microambiente Tumoral/efectos de los fármacosRESUMEN
Paneth cells and Lgr5+ intestinal stem cells (Lgr5+ ISCs) constitute the stem cell niche and maintain small intestinal epithelial integrity by recognizing various niche factors derived from subepithelial cells and external antigens. Although it has been known that interferon-γ (IFN-γ), a Th1 cytokine, is associated with intestinal epithelial disruption during inflammation as a niche factor, dynamics of Paneth cells and Lgr5+ ISCs in response to IFN-γ remain to be understood. Here we show that CAG-tdTomato;Lgr5-EGFP (CT-LE) mice generated in this study enable to identify Paneth cells and Lgr5+ ISCs separately by fluorescence signals. Lgr5+ ISCs underwent cell death a little earlier than Paneth cells in response to IFN-γ by simultaneous tracking using CT-LE mice. In addition, the timing of cell death in most Paneth cells overlapped with Lgr5+ ISCs, suggesting that Paneth cell depletion is induced directly by IFN-γ. Taken together, we established a novel simultaneous stem cell niche tracking method and clarified the involvement of both Paneth cells and Lgr5+ ISCs in stem cell niche damage induced by IFN-γ, further contribute to understanding the mechanism for maintaining intestinal homeostasis by stem cell niche.
Asunto(s)
Interferón gamma/farmacología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Células de Paneth/efectos de los fármacos , Células de Paneth/patología , Células Madre/efectos de los fármacos , Células Madre/patología , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Sistemas de Computación , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Interferón gamma/fisiología , Mucosa Intestinal/fisiología , Ratones , Ratones Transgénicos , Células de Paneth/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Interferón/metabolismo , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/fisiología , Células Madre/fisiología , Receptor de Interferón gammaRESUMEN
The autonomic nervous system (ANS), which consists of antagonistic sympathetic (adrenergic) and parasympathetic (cholinergic) arms, has emerged as an important regulator of neoplastic development, yet little is known about its role in multiple myeloma (MM). Clinical findings that anti-adrenergic ß-blocker intake reduces risk of disease-specific death and overall mortality in patients with MM have indicated that adrenergic input may worsen myeloma outcome. However, preclinical studies using ß-adrenergic receptor agonists or antagonists produced controversial results as to whether sympathetic pathways promote or inhibit myeloma. Retrospective outcome data demonstrating that high message levels of cholinergic receptor genes predict inferior survival in the Multiple Myeloma Research Foundation CoMMpass trial suggest that parasympathetic input may drive myeloma progression in a subset of patients. Here we review the ill-defined role of the ANS in MM, put myeloma in the context of other cancers, and discuss knowledge gaps that may afford exciting research opportunities going forward.
Asunto(s)
Sistema Nervioso Autónomo/metabolismo , Susceptibilidad a Enfermedades , Mieloma Múltiple/etiología , Mieloma Múltiple/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiopatología , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Médula Ósea/patología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Huesos/inervación , Huesos/metabolismo , Manejo de la Enfermedad , Progresión de la Enfermedad , Sinergismo Farmacológico , Humanos , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Pronóstico , Transducción de Señal/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacos , Resultado del TratamientoRESUMEN
Hematopoietic cell transplantation (HCT) has become a primary treatment for many cancers. Nowadays, the primary source of hematopoietic cells is by leukapheresis collection of these cells from peripheral blood, after a forced egress of hematopoietic cells from marrow into blood circulation, a process known as "mobilization". In this process, mobilizing agents disrupt binding interactions between hematopoietic cells and marrow microenvironment to facilitate collection. As the first essential step of HCT, poor mobilization, i.e. failure to obtain a desired or required number of hematopoietic cell, is one of the major factors affecting engraftment or even precluding transplantation. This review summarizes the available mobilization regimens using granulocyte-colony stimulating factor (G-CSF) and plerixafor, as well as the current understanding of the factors that are associated with poor mobilization. Strategies to mobilize patients or healthy donors who failed previous mobilization are discussed. Multiple novel agents are under investigation and some of them have shown the potential to enhance the mobilization response to G-CSF and/or plerixafor. Further investigation of the risk factors including genetic factors will offer an opportunity to better understand the molecular mechanism of mobilization and help develop new therapeutic strategies for successful mobilizations.
Asunto(s)
Bencilaminas/uso terapéutico , Ciclamas/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas , Nicho de Células Madre/efectos de los fármacos , Humanos , Factores de RiesgoRESUMEN
Bone marrow (BM) niche is a specific microenvironment for hematopoietic stem cells (HSCs) as well as non-hematopoietic cells. Evidence shows that chemo/radiotherapy can lead to the disruption of different properties of HSCs such as proliferation, differentiation, localization, self-renewa, and steady-state of cell populations. Investigations have shown that the deregulation of balance within the marrow cavity due to chemo/radiotherapy could lead to bone loss, abnormal hematopoiesis, and enhanced differentiation potential of mesenchymal stem cells towards the adipogenic lineage. Therefore, understanding the underlying mechanisms of chemo/radiotherapy induced BM niche changes may lead to the application of appropriate therapeutic agents to prevent BM niche defects. Highlights Chemo/radiotherapy disrupts the steady-state of bone marrow niche cells and result in deregulation of normal balance of stromal cell populations. Chemo/radiotherapy agents play a significant role in reducing of bone formation as well as fat accumulation in the bone marrow niche. Targeting molecular pathways may lead to recovery of bone marrow niches after chemo/radiotherapy.
Asunto(s)
Médula Ósea/efectos de los fármacos , Médula Ósea/efectos de la radiación , Neoplasias/terapia , Médula Ósea/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Redes Reguladoras de Genes/efectos de los fármacos , Redes Reguladoras de Genes/efectos de la radiación , Hematopoyesis/efectos de los fármacos , Hematopoyesis/efectos de la radiación , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de la radiación , Humanos , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/efectos de la radiaciónRESUMEN
Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a proposed strategy to target leukemia stem cells but this requires knowledge of the critical signals and may be subject to compensatory mechanisms. Signals from the niche require receptor-mediated endocytosis, a generic process dependent on the Dynamin family of large GTPases. Here, we show that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, can block transduction of key signalling pathways and overcome chemoresistance of leukemia stem cells. Our results provide a significant conceptual advance in therapeutic strategies for acute leukemia that may be applicable to other malignancies in which signals from the niche are involved in disease progression and chemoresistance.
Asunto(s)
Cianoacrilatos/farmacología , Dinaminas/antagonistas & inhibidores , Endocitosis/efectos de los fármacos , Indoles/farmacología , Leucemia Mieloide/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Enfermedad Aguda , Animales , Línea Celular Tumoral , Dinaminas/metabolismo , Humanos , Leucemia Mieloide/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Células Madre Neoplásicas/efectos de los fármacos , Nicho de Células Madre/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.
Asunto(s)
Glándulas Salivales/efectos de la radiación , Nicho de Células Madre/efectos de la radiación , Xerostomía/patología , Compuestos de Anilina/farmacología , Animales , Proliferación Celular/efectos de la radiación , Senescencia Celular/efectos de la radiación , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Traumatismos Experimentales por Radiación/patología , Glándulas Salivales/patología , Vías Secretoras/efectos de los fármacos , Vías Secretoras/efectos de la radiación , Nicho de Células Madre/efectos de los fármacos , Células Madre/efectos de los fármacos , Células Madre/patología , Células Madre/efectos de la radiación , Sulfonamidas/farmacología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/efectos de la radiación , Xerostomía/tratamiento farmacológico , Xerostomía/etiologíaRESUMEN
Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid (GC)-induced liver damage model of mice, found that GC stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells to break quiescence. We show that GC stress causes aging of the niche, which induces the up-regulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers focal adhesion kinase (FAK)/AMP-activated kinase (AMPK) signaling. This results in the loss of quiescence and leads to the eventual stemness exhaustion of progenitor cells. Conversely, blocking Gal-3 with the inhibitor TD139 prevents the loss of stemness and improves liver function. These experiments identify a stress-dependent change in progenitor cell niche that directly influence liver progenitor cell quiescence and function.
Asunto(s)
Dexametasona/farmacología , Galectina 3/metabolismo , Nicho de Células Madre/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Antígeno AC133/química , Antígeno AC133/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Cefalosporinas/farmacología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/antagonistas & inhibidores , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Galectina 3/antagonistas & inhibidores , Galectina 3/genética , Glicopéptidos/farmacología , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/citología , Células Madre/metabolismoRESUMEN
Erythropoiesis is one of the most demanding processes in the body, with more than 2 million red blood cells produced every second. Multiple hereditary and acquired red blood cell disorders arise from this complex system, with existing treatments effective in managing some of these conditions but few offering a long-term cure. Finding new treatments relies on the full understanding of the cellular and molecular interactions associated with the production and maturation of red blood cells, which take place within the erythroblastic island niche. The elucidation of processes associated within the erythroblastic island niche in health and during stress erythropoiesis has relied on in vivo modeling in mice, with complexities dissected using simple in vitro systems. Recent progress using state-of-the-art stem cell technology and gene editing has enabled a more detailed study of the human niche. Here, we review these different models and describe how they have been used to identify and characterize the cellular and molecular pathways associated with red blood cell production and maturation. We speculate that these systems could be applied to modeling red blood cell diseases and finding new druggable targets, which would prove especially useful for patients resistant to existing treatments. These models could also aid in research into the manufacture of red blood cells in vitro to replace donor blood transfusions, which is the most common treatment of blood disorders.
Asunto(s)
Modelos Animales de Enfermedad , Eritroblastos/citología , Eritropoyesis/fisiología , Modelos Biológicos , Nicho de Células Madre/fisiología , Estrés Fisiológico/fisiología , Animales , Moléculas de Adhesión Celular/deficiencia , Comunicación Celular , Células Cultivadas , Técnicas de Cocultivo , Evaluación Preclínica de Medicamentos , Eritropoyesis/efectos de los fármacos , Eritropoyesis/genética , Hematínicos/uso terapéutico , Enfermedades Hematológicas/tratamiento farmacológico , Enfermedades Hematológicas/fisiopatología , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Janus Quinasa 2/genética , Janus Quinasa 2/fisiología , Macrófagos/clasificación , Macrófagos/fisiología , Ratones , Ratones Transgénicos , Nicho de Células Madre/efectos de los fármacos , Estrés Fisiológico/genéticaRESUMEN
Hematopoiesis is a complex and intricate process that aims to replenish blood components in a constant fashion. It is orchestrated mostly by hematopoietic progenitor cells (hematopoietic stem cells (HSCs)) that are capable of self-renewal and differentiation. These cells can originate other cell subtypes that are responsible for maintaining vital functions, mediate innate and adaptive immune responses, provide tissues with oxygen, and control coagulation. Hematopoiesis in adults takes place in the bone marrow, which is endowed with an extensive vasculature conferring an intense flow of cells. A myriad of cell subtypes can be found in the bone marrow at different levels of activation, being also under constant action of an extensive amount of diverse chemical mediators and enzymatic systems. Bone marrow platelets, mature erythrocytes and leukocytes are delivered into the bloodstream readily available to meet body demands. Leukocytes circulate and reach different tissues, returning or not returning to the bloodstream. Senescent leukocytes, specially granulocytes, return to the bone marrow to be phagocytized by macrophages, restarting granulopoiesis. The constant high production and delivery of cells into the bloodstream, alongside the fact that blood cells can also circulate between tissues, makes the hematopoietic system a prime target for toxic agents to act upon, making the understanding of the bone marrow microenvironment vital for both toxicological sciences and risk assessment. Environmental and occupational pollutants, therapeutic molecules, drugs of abuse, and even nutritional status can directly affect progenitor cells at their differentiation and maturation stages, altering behavior and function of blood compounds and resulting in impaired immune responses, anemias, leukemias, and blood coagulation disturbances. This review aims to describe the most recently investigated molecular and cellular toxicity mechanisms of current major environmental pollutants on hematopoiesis in the bone marrow.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Nicho de Células Madre/efectos de los fármacos , Animales , Células Madre Hematopoyéticas/patología , HumanosRESUMEN
Intestinal epithelial barrier dysfunction is a risk factor in the pathogenesis of Crohn's disease (CD); however, no corrective FDA-approved therapies exist. We used an enteroid (EnO)-based system in two murine models of experimental CD, SAMP1/YitFc (SAMP) and TNFΔARE/+ (TNF). While severely inflamed SAMP mice do not generate EnOs, "inflammation-free" SAMP mice form EnO structures with impaired morphology and reduced intestinal stem cell (ISC) and Paneth cell viability. We validated these findings in TNF mice concluding that inflammation in intestinal tissues impedes EnO generation and suppressing inflammation by steroid administration partially rescues impaired formation in SAMP mice. We generated the first high-resolution transcriptional profile of the SAMP ISC niche demonstrating that alterations in multiple key pathways contribute to niche defect and targeting them may partially rescue the phenotype. Furthermore, we correlated the defects in formation and the rescue of EnO formation to reduced viability of ISCs and Paneth cells.