RESUMO
Neutrophils play important roles in inflammatory airway diseases. In this study, we assessed whether apolipoprotein A-I modifies neutrophil heterogeneity as part of the mechanism by which it attenuates acute airway inflammation. Neutrophilic airway inflammation was induced by daily intranasal administration of LPS plus house dust mite (LPS+HDM) to Apoa1-/- and Apoa1+/+ mice for 3 d. Single-cell RNA sequencing was performed on cells recovered from bronchoalveolar lavage fluid on day 4. Unsupervised profiling identified 10 clusters of neutrophils in bronchoalveolar lavage fluid from Apoa1-/- and Apoa1+/+ mice. LPS+HDM-challenged Apoa1-/- mice had an increased proportion of the Neu4 neutrophil cluster that expressed S100a8, S100a9, and Mmp8 and had high maturation, aggregation, and TLR4 binding scores. There was also an increase in the Neu6 cluster of immature neutrophils, whereas neutrophil clusters expressing IFN-stimulated genes were decreased. An unsupervised trajectory analysis showed that Neu4 represented a distinct lineage in Apoa1-/- mice. LPS+HDM-challenged Apoa1-/- mice also had an increased proportion of recruited airspace macrophages, which was associated with a reciprocal reduction in resident airspace macrophages. Increased expression of a common set of proinflammatory genes, S100a8, S100a9, and Lcn2, was present in all neutrophils and airspace macrophages from LPS+HDM-challenged Apoa1-/- mice. These findings show that Apoa1-/- mice have increases in specific neutrophil and macrophage clusters in the lung during acute inflammation mediated by LPS+HDM, as well as enhanced expression of a common set of proinflammatory genes. This suggests that modifications in neutrophil and macrophage heterogeneity contribute to the mechanism by which apolipoprotein A-I attenuates acute airway inflammation.
Assuntos
Apolipoproteína A-I , Camundongos Knockout , Neutrófilos , Pneumonia , Animais , Camundongos , Neutrófilos/imunologia , Pneumonia/imunologia , Pneumonia/genética , Apolipoproteína A-I/genética , Camundongos Endogâmicos C57BL , Lipopolissacarídeos/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Pulmão/imunologia , Pulmão/patologia , Calgranulina A , Calgranulina BRESUMO
Allogeneic hematopoietic cell transplantation (allo-HCT) offers a curative option for patients with certain non-malignant hematological diseases. High-dose post-transplant cyclophosphamide (PT-Cy) (200 mg/kg) and sirolimus (3 mg/kg), (HiC) synergistically induce stable mixed chimerism. Further, sirolimus and cytotoxic T lymphocyte-associated antigen-4 immunoglobulin (CTLA4-Ig), also known as Abatacept (Aba), promote immune tolerance and allograft survival. Here, in a major histocompatibility complex (MHC)-mismatched allo-HCT murine model, we combined Aba and/or T-cell depleting anti-Thy1.2 (Thy) with a lower dose of PT-Cy (50 mg/kg) and Sirolimus (3 mg/kg), (LoC). While mice in the LoC group showed graft rejection, the addition of Thy to LoC induced similar donor chimerism levels when compared to the HiC group. However, the addition of Aba to LoC led to graft acceptance only in younger mice. When Thy was added to the LoC+Aba setting, graft acceptance was restored in both age groups. Engrafted groups displayed significantly reduced frequencies of recipient-specific interferon-γ-producing T cells as well as an increased frequency in regulatory T cells (Tregs) except in the LoC+Aba group. Splenocytes from engrafted mice showed no proliferation upon restimulation with Balb/c stimulators. Collectively, in combination with Aba or Thy, LoC may be considered to reduce graft rejection in patients who undergo allo-HCT.
Assuntos
Abatacepte , Ciclofosfamida , Depleção Linfocítica , Sirolimo , Animais , Ciclofosfamida/farmacologia , Sirolimo/farmacologia , Camundongos , Abatacepte/farmacologia , Abatacepte/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Camundongos Endogâmicos BALB C , Quimeras de Transplante , Transplante Homólogo/métodos , AloenxertosRESUMO
Background: The high-intensity focused electromagnetic field (HIFEM) procedure is an effective method for noninvasive toning and shaping of buttocks. Objectives: To investigate and compare the efficacy of simultaneous application of HIFEM procedure with radiofrequency (RF) heating vs HIFEM standalone procedure on the buttocks. Methods: Sixty-seven subjects (21-67 years, BMI 16-34â kg/m2) were recruited and divided into two groups. Group A received simultaneous HIFEM + RF therapy, and group B received standalone HIFEM treatments. All participants underwent four 30-minute bilateral treatments on the buttocks. The MRI was used to evaluate the changes in muscle and fat thickness. Results: Data of 32 subjects from group A and 31 subjects from group B were reviewed at 1-month follow-up. On average, subjects from group A showed a 31.3% higher increase in muscle thickness, as shown in the MRI evaluation. The gluteal muscle thickness continued to grow and peaked at a 3-month follow-up, wherein 27 patients were evaluated in each group (n = 54). Group A showed on average +24.7% increase (gluteus maximus +8.5 ± 1.9â mm, medius +6.0 ± 1.1â mm, minimus +2.9 ± 0.8â mm), while group B exhibited only +15.9% increase in muscle thickness (gluteus maximus +5.2 ± 1.1â mm, medius +3.6 ± 1.0â mm, minimus +1.6 ± 0.4â mm). On average, group A showed a 35.6% higher growth in muscle thickness. Treatments were safe and comfortable with high satisfaction rates. No adverse event was reported throughout the study. Conclusions: Our results suggest that simultaneous use of HIFEM + RF is safe and significantly more effective for gluteal contouring than the HIFEM procedure alone.
RESUMO
Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Here, we examined whether the gain of Myc and the loss of RB1 and Trp53 function in EC cells result in SI-NET using tryptophan hydroxylase 1 (TPH1) Cre-ERT2-driven RB1fl Trp53fl MycLSL (RPM) mice. TPH1-Cre-induced gain of Myc and loss of RB1 and Trp53 function resulted in endocrine or neuronal tumors in pancreas, lung, enteric neurons, and brain. Lineage tracing indicated that the cellular origin for these tumors was TPH1-expressing neuroendocrine, neuronal, or their precursor cells in these organs. However, despite that TPH1 is most highly expressed in EC cells of the small intestine, we observed no incidence of EC cell tumors. Instead, the tumor of epithelial cell origin in the intestine was exclusively nonendocrine adenocarcinoma, suggesting dedifferentiation of EC cells into intestinal stem cells (ISCs) as a cellular mechanism. Furthermore, ex vivo organoid studies indicated that loss of functions of Rb1 and Trp53 accelerated dedifferentiation of EC cells that were susceptible to apoptosis with expression of activated MycT58A, suggesting that the rare dedifferentiating cells escaping cell death went on to develop adenocarcinomas. Lineage tracing demonstrated that EC cells in the small intestine were short-lived compared with neuroendocrine or neuronal cells in other organs. In contrast, EC cell-derived ISCs were long-lasting and actively cycling and thus susceptible to transformation. These results suggest that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation, affect the fate and rate of tumorigenesis induced by genetic alterations and provide important insights into EC cell-derived tumorigenesis.NEW & NOTEWORTHY Small intestinal neuroendocrine tumors are of putative enterochromaffin (EC) cell origin and are the most common malignancy in the small intestine, followed by adenocarcinoma. However, the tumorigenesis of these tumor types remains poorly understood. The present lineage tracing studies showed that tissue- and cell-specific properties of EC cells such as rapid cell turnover and homeostatic dedifferentiation affect the fate and rate of tumorigenesis induced by genetic alterations toward a rare occurrence of adenocarcinoma.
Assuntos
Adenocarcinoma , Neoplasias Intestinais , Tumores Neuroendócrinos , Camundongos , Animais , Células Enterocromafins/metabolismo , Intestino Delgado/patologia , Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Intestinais/metabolismo , Tumores Neuroendócrinos/metabolismo , Adenocarcinoma/genéticaRESUMO
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a widely available curative option for patients with sickle cell disease (SCD). Our original non-myeloablative haplo-HSCT trial employing post-transplant (PT) cyclophosphamide had a low incidence of GVHD but had high rejection rates. Here, we aimed to evaluate immune reconstitution following haplo-HSCT and identify cytokines and cells associated with graft rejection/engraftment. 50 cytokines and 10 immune cell subsets were screened using multiplex-ELISA and flow cytometry, respectively, at baseline and PT-Days 30, 60, 100, and 180. We observed the most significant differences in cytokine levels between the engrafted and rejected groups at PT-Day 60, corresponding with clinical findings of secondary graft rejection. Of the 44 cytokines evaluated, plasma concentrations of 19 cytokines were different between the two groups at PT-Day 60. Factor analysis suggested two independent factors. The first factor (IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, and TGFb1 contributed significantly) was strongly associated with engraftment with OR = 2.7 (95%CI of 1.4 to 5.4), whereas the second factor (GROa and IL-18 contributed significantly) was not significantly associated with engraftment. Sufficient donor myeloid chimerism (DMC) is critical for the success of HSCT; here, we evaluated immune cells among high (H) DMC (DMC≥20%) and low (L) DMC (DMC<20%) groups along with engrafted and rejected groups. We found that early myeloid-derived suppressor cell (eMDSC) frequencies were elevated in engrafted patients and patients with HDMC at PT-Day 30 (P< 0.04 & P< 0.003, respectively). 9 of 20 patients were evaluated for the source of eMDSCs. The HDMC group had high mixed chimeric eMDSCs as compared to the LDMC group (P< 0.00001). We found a positive correlation between the frequencies of eMDSCs and Tregs at PT-Day 100 (r=0.72, P <0.0007); eMDSCs at BSL and Tregs at PT-Day 100 (r=0.63, P <0.004). Of 10 immune regulatory cells and 50 cytokines, we observed mixed chimeric eMDSCs and IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, TGFb1 as potential hits which could serve as prognostic markers in predicting allograft outcome towards engraftment following haploidentical HSCT employing post-transplant cyclophosphamide. The current findings need to be replicated and further explored in a larger cohort.
Assuntos
Anemia Falciforme/terapia , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune/imunologia , Quimeras de Transplante , Adulto , Anemia Falciforme/imunologia , Quimerismo , Ciclofosfamida/uso terapêutico , Citocinas/imunologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Células Supressoras Mieloides , Prognóstico , Condicionamento Pré-Transplante , Transplante Haploidêntico , Resultado do TratamentoRESUMO
Genetic mutations associated with acute myeloid leukemia (AML) also occur in age-related clonal hematopoiesis, often in the same individual. This makes confident assignment of detected variants to malignancy challenging. The issue is particularly crucial for AML post-treatment measurable residual disease monitoring, where results can be discordant between genetic sequencing and flow cytometry. We show here, that it is possible to distinguish AML from clonal hematopoiesis and to resolve the immunophenotypic identity of clonal architecture. To achieve this, we first design patient-specific DNA probes based on patient's whole-genome sequencing, and then use them for patient-personalized single-cell DNA sequencing with simultaneous single-cell antibody-oligonucleotide sequencing. Examples illustrate AML arising from DNMT3A and TET2 mutated clones as well as independently. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts.
Assuntos
Leucemia Mieloide Aguda , Proteogenômica , Hematopoiese Clonal , Células Clonais/patologia , Humanos , Leucemia Mieloide Aguda/diagnóstico , Neoplasia ResidualAssuntos
COVID-19/genética , Gravidade do Paciente , Receptores Androgênicos/genética , Idoso , Variação Genética , Humanos , Unidades de Terapia Intensiva , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Peptídeos/genética , Estudos Prospectivos , SARS-CoV-2 , Análise de Sequência de DNARESUMO
Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa transmitted by infected sand flies. Vaccination through leishmanization with live Leishmania major has been used successfully but is no longer practiced because it resulted in occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain (LmCen-/-). Notably, LmCen-/- is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen-/- have no visible lesions following challenge with L. major-infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen-/- immunization results in protection and an immune response comparable to leishmanization. LmCen-/- is safe since it is unable to cause disease in immunocompromised mice, induces robust host protection against vector sand fly challenge and because it is marker free, can be advanced to human vaccine trials.
Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Leishmania major/genética , Leishmania major/patogenicidade , Vacinas Atenuadas/uso terapêutico , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Dexametasona/farmacologia , Feminino , Citometria de Fluxo , Edição de Genes , Engenharia Genética , Humanos , Terapia de Imunossupressão , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Psychodidae/parasitologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Synovial chondromatosis (SC) is an infrequent, benign condition of unknown etiology affecting the synovium within articular joints. Often considered a metaplastic process, multiple cartilaginous nodules develop in the confines of the synovial membrane. In time, these cartilage nodules develop into fragments, sometimes detaching from the synovium and, thus, become loose in an adjacent synovial cavity. The temporomandibular joint (TMJ) is an unusual site of involvement, with the extracapsular compromise of the cranial base exceedingly rare. A 68-year-old woman presented with a tender mass to the left TMJ that later proved to be SC. Computed tomography illustrated a rare extension of the lesion into the middle cranial fossa. The multidisciplinary effort to remove the mass in its entirety included both oral and maxillofacial surgical and neurosurgical teams. We have reviewed the presentation, diagnosis, surgical treatment, and outcomes of the present case, with diagnostic images and photomicrographs of the lesion included. We also briefly reviewed the reported studies.
Assuntos
Condromatose Sinovial , Transtornos da Articulação Temporomandibular , Idoso , Condromatose Sinovial/diagnóstico por imagem , Condromatose Sinovial/cirurgia , Fossa Craniana Média , Feminino , Humanos , Base do Crânio/diagnóstico por imagem , Base do Crânio/cirurgia , Articulação Temporomandibular/diagnóstico por imagem , Articulação Temporomandibular/cirurgia , Transtornos da Articulação Temporomandibular/diagnóstico por imagem , Transtornos da Articulação Temporomandibular/cirurgiaRESUMO
PURPOSE: Tongue cancer is often associated with pain and perineural invasion. The purpose of the present study was to determine the association between tongue pain and otalgia and the microscopic identification of perineural invasion (PNI) in patients with squamous cell carcinoma of the tongue (SCCOT). PATIENTS AND METHODS: A retrospective cohort study was performed of patients with a diagnosis of SCCOT from January 2013 through June 2019. Patients without a history of head and neck cancer, who had SCCOT diagnosed and treated surgically by a single surgeon, were included in the present study. The primary predictor variables were tongue pain and otalgia (presence vs absence of both). Other variables included patient demographic data and TNM stage. The primary outcome variable was the histologic presence of PNI. A χ2 analysis was performed to test for any significant associations between pain, T stage, and overall stage in relation to PNI outcome. Multivariate logistic regression analysis was used to control for cancer staging variables when testing the association between pain and PNI. RESULTS: The sample included 128 subjects, of whom 76 were men. Their mean age was 60 years. Most patients (n = 97; 75.8%) complained of tongue pain and a few (n = 50; 39.1%) complained of otalgia. The patients with otalgia had a 3.15 times greater odds of PNI when controlling for T stage (P = .016) and 3.68 times greater odds of PNI when controlling for overall stage (P = .007). Increasing T stage and overall stage-with the exception of stage II-were also significantly associated with PNI (P ≤ .05). CONCLUSIONS: Our study has demonstrated a statistically significant association between preoperative otalgia and PNI in a consecutive group of patients presenting with newly diagnosed SCCOT.
Assuntos
Carcinoma de Células Escamosas , Dor de Orelha , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Dor , Prognóstico , Estudos RetrospectivosRESUMO
Proliferation of dendritic cell (DC)-restricted progenitor cells in bone marrow compartment is tightly regulated at steady state and responds to multiple tissue-specific triggers during disturbed homeostasis such as obesity. DCs in the lung stem from a rapidly dividing DC-restricted progenitor cells and are effective at generating adaptive immune responses in allergic airway inflammation. Precisely, how DC-restricted progenitor expansion and differentiation are influenced by airway inflammation to maintain constant supply of myeloid DCs is poorly understood. Here we show that a high fat diet (HFD) induces oxidative stress and accelerates the expansion of DC- restricted progenitor cells in bone marrow and correlates with persistent induction of p38 mitogen activated protein kinase (MAPK), which is blocked with a selective p38α/ß MAPK inhibitor. Mice fed a HFD and sensitized to inhaled allergen house dust mite (HDM) led to alterations of DC- restricted progenitor cells that were characterized by increased expansion and seeding of lung DCs in airway inflammation. Mechanistically, we establish that the expansion induced by HFD dysregulates the expression of a disintegrin and metallopeptidase domain 17 (Adam17) and is required for p38 MAPK activation in DC-restricted progenitors. These results demonstrates that obesity produces persistent changes in DC precursors and that elevation of Adam17 expression is tightly coupled to p38 MAPK and is a key driver of proliferation. Altogether, these data provide phenotypic and mechanistic insight into dendritic cell supply chain in obesity-associated airway inflammation.
Assuntos
Células Dendríticas/imunologia , Hipersensibilidade/imunologia , Obesidade/imunologia , Pneumonia/imunologia , Células-Tronco/imunologia , Proteína ADAM17/metabolismo , Animais , Antígenos de Dermatophagoides/imunologia , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Energy-based skin rejuvenation has, like other forms of aesthetic treatments, the capability of achieving desirable end results. These end results must be balanced with the degree and duration of morbidity, which affect recovery from treatment. Renuvion skin resurfacing protocols include a free hand approach and we describe our preferred approach of pulsing and fractionating the helium plasma resurfacing energy.
Assuntos
Terapia a Laser , Regeneração da Pele por Plasma , Envelhecimento da Pele , Hélio , HumanosRESUMO
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a destructive metastasizing neoplasm of the lung characterized by proliferation of LAM cells in specialized lung nodules. LAM cells are characterized by expression of the prometastatic and cancer-initiating hyaluronan receptor CD44v6, and loss of heterozygosity (LOH) of TSC1 and TSC2. The circulating neoplastic LAM cells are thought to be involved in metastasis. Because LAM cells display properties of neoplastic, metastatic, and stem cell-like cancer cells, we hypothesized that elevated aldehyde dehydrogenase (ALDH) activity, characteristic of cancer and stem cells, is a property of LAM cells. METHODS: We performed an in silico search of ALDH genes in microdissected LAM lung nodules. To identify circulating LAM cells, we osmotically removed red blood cells from whole blood to obtain peripheral blood mononuclear cells, which were then sorted by fluorescence-activated cell sorting based on their level of ALDH activity. RESULTS: Microdissected LAM lung nodules possess a distinctive ALDH gene profile. The cell subpopulation with high ALDH activity, isolated from circulating cells, possessed TSC2 LOH in 8 of 14 patients with LAM. Approximately 60% of the circulating cells with high ALDH activity expressed CD44v6. Cells with TSC2 LOH from patients with LAM and LAM/TSC exhibited different properties in different body locations, but all cell types showed high ALDH activity. CONCLUSIONS: This new procedure allows for isolation of circulating LAM cells from cultured cells, blood, and chylous effusions and shows that circulating LAM cells are heterogeneous with neoplastic, metastatic, and cancer-stem cell-like properties.
Assuntos
Aldeído Desidrogenase/metabolismo , Perda de Heterozigosidade/genética , Linfangioleiomiomatose/enzimologia , Linfangioleiomiomatose/genética , Células Neoplásicas Circulantes/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Humanos , Linfangioleiomiomatose/patologiaRESUMO
New techniques for single-cell analysis have led to insights into hematopoiesis and the immune system, but the ability of these techniques to cross-validate and reproducibly identify the biological variation in diverse human samples is currently unproven. We therefore performed a comprehensive assessment of human bone marrow cells using both single-cell RNA sequencing and multiparameter flow cytometry from 20 healthy adult human donors across a broad age range. These data characterize variation between healthy donors as well as age-associated changes in cell population frequencies. Direct comparison of techniques revealed discrepancy in the quantification of T lymphocyte and natural killer cell populations. Orthogonal validation of immunophenotyping using mass cytometry demonstrated a strong correlation with flow cytometry. Technical replicates using single-cell RNA sequencing matched robustly, while biological replicates showed variation. Given the increasing use of single-cell technologies in translational research, this resource serves as an important reference data set and highlights opportunities for further refinement.
Assuntos
Medula Óssea/imunologia , Citometria de Fluxo/métodos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Células da Medula Óssea/imunologia , Diferenciação Celular , Feminino , Hematopoese , Humanos , Imunofenotipagem , Células Matadoras Naturais , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Linfócitos T , Adulto JovemRESUMO
Topical minoxidil is the only US FDA approved OTC drug for the treatment of androgenetic alopecia (AGA). Minoxidil is a pro-drug converted into its active form, minoxidil sulfate, by the sulfotransferase enzymes in the outer root sheath of hair follicles. Previously, we demonstrated that sulfotransferase activity in hair follicles predicts response to topical minoxidil in the treatment of AGA. In the human liver, sulfotransferase activity is significantly inhibited by salicylic acid. Low-dose OTC aspirin (75-81 mg), a derivative of salicylic acid, is used by millions of people daily for the prevention of coronary heart disease and cancer. It is not known whether oral aspirin inhibits sulfotransferase activity in hair follicles, potentially affecting minoxidil response in AGA patients. In the present study, we determined the follicular sulfotransferase enzymatic activity following 14 days of oral aspirin administration. In our cohort of 24 subjects, 50% were initially predicted to be responders to minoxidil. However, following 14 days of aspirin administration, only 27% of the subjects were predicted to respond to topical minoxidil. To the best of our knowledge, this is the first study to report the effect of low-dose daily aspirin use on the efficacy of topical minoxidil.
Assuntos
Alopecia/tratamento farmacológico , Aspirina/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Folículo Piloso/efeitos dos fármacos , Minoxidil/administração & dosagem , Pró-Fármacos/administração & dosagem , Sulfotransferases/antagonistas & inibidores , Administração Cutânea , Adulto , Alopecia/diagnóstico , Alopecia/fisiopatologia , Aspirina/efeitos adversos , Interações Medicamentosas , Inibidores Enzimáticos/efeitos adversos , Folículo Piloso/enzimologia , Folículo Piloso/crescimento & desenvolvimento , Humanos , Masculino , Minoxidil/análogos & derivados , Minoxidil/metabolismo , Pró-Fármacos/metabolismo , Medição de Risco , Sulfotransferases/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Beige/brite adipose tissue displays morphological characteristics and beneficial metabolic traits of brown adipose tissue. Previously, we showed that TGF-ß signaling regulates the browning of white adipose tissue. Here, we inquired whether TGF-ß signals regulated presumptive beige progenitors in white fat and investigated the TGF-ß regulated mechanisms involved in beige adipogenesis. METHODS: We deleted TGF-ß receptor 1 (TßRI) in adipose tissue (TßRIAdKO mice) and, using flow-cytometry based assays, identified and isolated presumptive beige progenitors located in the stromal vascular cells of white fat. These cells were molecularly characterized to examine beige/brown marker expression and to investigate TGF-ß dependent mechanisms. Further, the cells were transplanted into athymic nude mice to examine their adipogenesis potential. RESULTS: Deletion of TßRI promotes beige adipogenesis while reducing the detrimental effects of high fat diet feeding. Interaction of TGF-ß signaling with the prostaglandin pathway regulated the appearance of beige adipocytes in white fat. Using flow cytometry techniques and stromal vascular fraction from white fat, we isolated presumptive beige stem/progenitor cells (iBSCs). Upon genetic or pharmacologic inhibition of TGF-ß signaling, these cells express high levels of predominantly beige markers. Transplantation of TßRI-deficient stromal vascular cells or iBSCs into athymic nude mice followed by high fat diet feeding and stimulation of ß-adrenergic signaling via CL316,243 injection or cold exposure promoted robust beige adipogenesis in vivo. CONCLUSIONS: TßRI signals target the prostaglandin network to regulate presumptive beige progenitors in white fat capable of developing into beige adipocytes with functional attributes. Controlled inhibition of TßRI signaling and concomitant PGE2 stimulation has the potential to promote beige adipogenesis and improve metabolism.
Assuntos
Adipócitos Marrons/citologia , Adipócitos Brancos/citologia , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Células-Tronco/citologia , Adipócitos Bege/citologia , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Bege/citologia , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular/fisiologia , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Lgr5-expressing intestinal stem cells (ISCs) maintain continuous and rapid generation of the intestinal epithelium. Here, we present evidence that dedifferentiation of committed enteroendocrine cells (EECs) contributes to maintenance of the epithelium under both basal conditions and in response to injury. Lineage-tracing studies identified a subset of EECs that reside at +4 position for more than 2 wk, most of which were BrdU-label-retaining cells. Under basal conditions, cells derived from these EECs grow from the bottom of the crypt to generate intestinal epithelium according to neutral drift kinetics that is consistent with dedifferentiation of mature EECs to ISCs. The lineage tracing of EECs demonstrated reserve stem cell properties in response to radiation-induced injury with the generation of reparative EEC-derived epithelial patches. Finally, the enterochromaffin (EC) cell was the predominant EEC type participating in these stem cell dynamics. These results provide novel insights into the +4 reserve ISC hypothesis, stem cell dynamics of the intestinal epithelium, and in the development of EC-derived small intestinal tumors. NEW & NOTEWORTHY The current manuscript demonstrating that a subset of mature enteroendocrine cells (EECs), predominantly enterochromaffin cells, dedifferentiates to fully functional intestinal stem cells (ISCs) is novel, timely, and important. These cells dedifferentiate to ISCs not only in response to injury but also under basal homeostatic conditions. These novel findings provide a mechanism in which a specified cell can dedifferentiate and contribute to normal tissue plasticity as well as the development of EEC-derived intestinal tumors under pathologic conditions.
Assuntos
Células-Tronco Adultas/citologia , Diferenciação Celular , Proliferação de Células , Células Enteroendócrinas/citologia , Intestino Delgado/citologia , Células-Tronco Adultas/metabolismo , Animais , Células Cultivadas , Células Enteroendócrinas/metabolismo , Intestino Delgado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/patologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
The CCAS EXPERT SUMMIT convened an array of international experts in Barbados on August 27-31, 2017 under the theme "From Care to Cure-Shifting the HIV Paradigm." The Caribbean Cytometry & Analytical Society (CCAS) partnered with the Joint United Nations Programme on HIV/AIDS (UNAIDS) to deliver a program that reviewed the advances in antiretroviral therapy and the public health benefits accruing from treatment as prevention. Particular emphasis was placed on reexamining stigma and discrimination through a critical appraisal of whether public health messaging and advocacy had kept pace with the advances in medicine. Persistent fear of HIV driving discriminatory behavior was widely reported in different regions and sectors, including the healthcare profession itself; continued fear of the disease was starkly misaligned with the successes of new medical treatments and progress toward the UNAIDS 90-90-90 targets. The summit therefore adopted the mantra "Test-Treat-Defeat" to help engage with the public in a spirit of optimism aimed at creating a more conducive environment for persons to be tested and treated and, thereby, help reduce HIV disease and stigma at the individual and community levels.