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The coronavirus disease 2019 (COVID-19) epidemic remains worldwide. The usefulness of the intranasal vaccine and boost immunization against severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) has recently received much attention. We developed an intranasal SARS-CoV-2 vaccine by loading the receptor binding domain of the S protein (S-RBD) of SARS-CoV-2 as an antigen into an F-deficient Sendai virus vector. After the S-RBD-Fd antigen with trimer formation ability was intranasally administered to mice, S-RBD-specific IgM, IgG, IgA, and neutralizing antibody titers were increased in serum or bronchoalveolar lavage fluid for 12 weeks. Furthermore, in mice that received a booster dose at week 8, a marked increase in neutralizing antibodies in the serum and bronchoalveolar lavage fluid was observed at the final evaluation at week 12, which neutralized the pseudotyped lentivirus expressing the SARS-CoV-2 spike protein, indicating the usefulness of the Sendai virus-based SARS-CoV-2 intranasal vaccine.
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Vacinas contra COVID-19 , COVID-19 , Animais , Anticorpos Antivirais , COVID-19/prevenção & controle , Modelos Animais de Doenças , SARS-CoV-2 , Vírus Sendai/genética , CamundongosRESUMO
Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.
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Esclerose Lateral Amiotrófica , Astrócitos , Proteínas de Ligação a DNA , Proteínas Mitocondriais , Fatores de Transcrição , Feminino , Humanos , Masculino , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Astrócitos/patologia , Astrócitos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Mitocôndrias/patologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.
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Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Esclerose Lateral Amiotrófica/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Estudo de Associação Genômica Ampla , População do Leste Asiático , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Neurônios Motores/patologiaRESUMO
Composite colloidal nanoparticles were prepared by a carbonate controlled-addition method in the presence of phytic acid, in which an aqueous ammonium carbonate solution was added into an aqueous solution of phytic acid and CaCl2. The number-average particle size of the colloidal particles was 76 ± 18 nm formed by using the molar ratio [phytic acid]/[Ca2+] = 0.5 from the complexation time of 1 h. The composite nanoparticles were stable for more than 5 days in the suspension under the quiescent condition. After isolation of the nanoparticles by ultrafiltration, the dried samples could be redispersed in water. Effects of the complexation times of the aqueous solution of phytic acid and CaCl2 and the molar ratio ([phytic acid]/[Ca2+]) were studied. Increasing the concentration of the calcium reagents as well as increasing the complexation times increased the particle sizes. The minimum and maximum average particle sizes of 29 and 142 nm were obtained. The plot of the transmittance at 350 nm of the aqueous solution of the dispersion against pH values after addition of 0.05 M HCl for 6 h showed that, by gradually increasing turbidity with decreasing pH from 9.6 to 7.3, precipitates were recognized at below pH 7.5, and turbidity decreased with further decreasing pH beyond 7.2. Dynamic light scattering analysis showed that the particle diameters increased from 90 to 200 nm with decreasing pH from 9.6 to 7.2. When increasing the pH from 6.2, the precipitate was redispersed and the turbidity increased to a pH of 7.4. No precipitates were observed above a pH of 7.4. These results suggest that the present phytic acid stabilized nanoparticles exhibit pH-dependent reversible precipitation and redispersion without degradation under slightly acidic conditions.
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Carbonato de Cálcio , Nanopartículas , Concentração de Íons de Hidrogênio , Ácido Fítico , ÁguaRESUMO
BACKGROUND AND AIM: Because the risk of colorectal cancer has not been well examined in fecal immunochemistry test (FIT)-positive patients who previously underwent colonoscopy, this study aimed to investigate this topic. METHODS: This was a single-center, observational study of prospectively collected data in Japan. FIT-positive, average-risk patients who underwent colonoscopy were divided into groups as follows: those who never underwent colonoscopy in the past (no colonoscopy group), those with a history of colonoscopy between 6 months and 5 years (0.5- to 5-year colonoscopy group), and those with a history of colonoscopy more than 5 years ago (> 5-year colonoscopy group). We investigated the prevalence of advanced neoplasia and invasive cancer among these groups using multiple logistic regression analysis. RESULTS: Detection rates of advanced neoplasia in the no colonoscopy group, 0.5- to 5-year colonoscopy group, and > 5-year colonoscopy group were 14.8% (240/1626), 3.9% (13/330), and 6.9% (17/248), respectively. Detection rates of invasive cancer in each aforementioned group were 5.7% (92/1,626), 0.3% (1/330), and 1.2% (3/248), respectively. Odds ratios of advanced neoplasia in the 0.5- to 5-year colonoscopy group and > 5-year colonoscopy were 0.23 (95% confidence interval [CI]: 0.13-0.42) and 0.40 (95% CI: 0.24-0.68), respectively, in multivariate analysis. The odds ratios of invasive cancer in each aforementioned group were 0.05 (95% CI: 0.01-0.37) and 0.19 (95% CI: 0.06-0.61), respectively. CONCLUSION: Re-screening with the FIT should not be recommended for at least 5 years for average-risk patients after colonoscopy without high-risk neoplasms, because the risks of colorectal cancer are low in such patients.
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Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/métodos , Fezes/química , Imunoquímica , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Japão/epidemiologia , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Estudos Prospectivos , Risco , Fatores de TempoRESUMO
Neural stem/progenitor cell (NSPC) multipotency is highly regulated so that specific neural networks form during development. NSPCs cannot respond to gliogenic signals without acquiring gliogenic competence and decreasing their neurogenic competence as development proceeds. Coup-tfI and Coup-tfII are triggers of these temporal NSPC competence changes. However, the downstream effectors of Coup-tfs that mediate the neurogenic-to-gliogenic competence transition remain unknown. Here, we identified the microRNA-17/106 (miR-17/106)-p38 axis as a critical regulator of this transition. Overexpression of miR-17 inhibited the acquisition of gliogenic competence and forced stage-progressed NSPCs to regain neurogenic competence without altering the methylation status of a glial gene promoter. We also identified Mapk14 (also known as p38) as a target of miR-17/106 and found that Mapk14 inhibition restored neurogenic competence after the neurogenic phase. These results demonstrate that the miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic NSPC competence transition and that manipulation of this axis permits bidirectional control of NSPC multipotency.
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Diferenciação Celular/fisiologia , MicroRNAs/fisiologia , Células-Tronco Neurais/citologia , Neuroglia/citologia , Neurônios/citologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Sequência de Bases , Proteína Glial Fibrilar Ácida/genética , Camundongos , Camundongos Endogâmicos ICR , MicroRNAs/química , Células-Tronco Neurais/metabolismo , Regiões Promotoras Genéticas , Homologia de Sequência de AminoácidosRESUMO
Since the hardness and toughness of natural nacre are determined by hierarchical microstructures with organic matters, it is of great importance to control the microstructures of artificial free-standing CaCO3 thin films. However, the fabrication of such films has so far been quite limited, to the extent that their mechanical properties have not been reported. To address this, free-standing calcite thin films were prepared through repeated cycles of layer-by-layer deposition of vaterite precursor composite particles with organic polymers, followed by a phase transition to calcite. In this way, two distinct calcite thin film types were produced based on either 3.2 or 1.0 wt % organic material, with subsequent three-point bending tests revealing that both exhibit elastic bending prior to fracture. More importantly, by increasing the organic content from 1.0 to 3.2 wt %, the bending strength increased from 0.95 ± 0.26 MPa to 1.90 ± 0.21 MPa.
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Carbonato de Cálcio/química , Fenômenos Mecânicos , Elasticidade , Vidro/química , Dureza , Teste de MateriaisRESUMO
BACKGROUND: Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs. METHODS: We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment. RESULTS: The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search. CONCLUSIONS: Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.
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Vaterite composite particles with a size-controlled sphere were obtained by a carbonate controlled-addition method by using a carboxylate-terminated poly(amidoamine) (PAMAM)-type polyhedral oligomeric silsesquioxane (POSS)-core dendrimer. An aqueous ammonium carbonate solution was added to an aqueous solution of the dendrimer and CaCl2 at different times (3 min, 30 min, and 1 h) and stirred for 1 h at 30 °C. When the complexation time of the POSS-core dendrimer-CaCl2 solution was increased from 3 min to 1 h, the average particle sizes of the spheres increased from 0.71 ± 0.08 to 1.86 ± 0.22 µm, respectively. However, the average particle sizes decreased with decreasing temperature. Particles with minimum sizes of 70 ± 6 nm were obtained when COONa to calcium ion molar ratio was 16 and the complexation time was 3 min at 20 °C. Incubation of the vaterite composite particles in distilled water for 3 days led to complete phase transition to calcite. Negative zeta potential values, ranging from -30 to -10 mV, were detected for the vaterite particles, indicating that the POSS-core dendrimers were exposed on the CaCO3 particles. The CaCO3 particle surfaces were successfully coated with poly(diallyldimethylammonium chloride) (PDDA) in aqueous dispersions by adding a controlled concentration of the polymer. Alternate vaterite composite particles and polyelectroyte multilayer films were prepared by a layer-by-layer method. The obtained (PDDA/vaterite)10(PDDA) multilayer films were incubated in distilled water at 30 °C. Incubation for 5 days led to complete phase transition to calcite, as estimated by Fourier transform infrared (FTIR) spectroscopic and XRD analyses. The SEM observation of the sample after 5 days of incubation showed a granular network structure of irregularly shaped calcite particles. Although some patches and pores were present in the films, the SEM image clearly demonstrated that large-area and continuous CaCO3 films were formed.
Assuntos
Carbonato de Cálcio/química , Dendrímeros/química , Compostos de Organossilício/química , Tamanho da Partícula , Poliaminas/química , Cloreto de Cálcio/química , Modelos Moleculares , Conformação Molecular , Propriedades de Superfície , Água/químicaRESUMO
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is an inherited cerebral small vessel disease (CSVD) caused by biallelic mutations in the high-temperature requirement serine peptidase A1 (HTRA1) gene. Even heterozygous mutations in HTRA1 are recently revealed to cause cardinal clinical features of CSVD. Here, we report the first establishment of a human induced pluripotent stem cell (hiPSC) line from a patient with heterozygous HTRA1-related CSVD. Peripheral blood mononuclear cells (PBMCs) were reprogrammed by the transfection of episomal vectors encoding human OCT3/4 (POU5F1), SOX2, KLF4, L-MYC, LIN28, and a murine dominant-negative mutant of p53 (mp53DD). The established iPSCs had normal morphology as human pluripotent stem cells and normal karyotype (46XX). Moreover, we found that the HTRA1 missense mutation (c.905G>A, p.R302Q) was heterozygous. These iPSCs expressed pluripotency-related markers and had the potential to differentiate into all three germ layers in vitro. HTRA1 and the supposed disease-associated gene NOG were differentially expressed in the patient iPSCs at mRNA levels compared to those of control lines. The iPSC line would facilitate in vitro research for understanding the cellular pathomechanisms caused by the HTRA1 mutation including its dominant-negative effect.
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iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received ropinirole or placebo for 24 weeks in the double-blind period to evaluate safety, tolerability, and therapeutic effects. Adverse events were similar in both groups. During the double-blind period, muscle strength and daily activity were maintained, but a decline in the ALSFRS-R, which assesses the functional status of ALS patients, was not different from that in the placebo group. However, in the open-label extension period, the ropinirole group showed significant suppression of ALSFRS-R decline and an additional 27.9 weeks of disease-progression-free survival. iPSC-derived motor neurons from participants showed dopamine D2 receptor expression and a potential involvement of the SREBP2-cholesterol pathway in therapeutic effects. Lipid peroxide represents a clinical surrogate marker to assess disease progression and drug efficacy. Limitations include small sample sizes and high attrition rates in the open-label extension period, requiring further validation.
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Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Indóis/efeitos adversos , Indóis/farmacologia , Neurônios MotoresRESUMO
BACKGROUND AND OBJECTIVE: Interstitial lung diseases (ILD) are characterized by progressive interstitial pulmonary fibrosis and a decline in lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that may play a role in the pathogenesis of pulmonary fibrosis. Circulating fibrocyte numbers have been correlated with the prognosis of patients with idiopathic pulmonary fibrosis. The aim of the present study was to evaluate the relationship between circulating fibrocytes, and parameters of disease activity and progression in several groups of patients with ILD. METHODS: The study population comprised 41 patients with ILD and seven healthy control subjects. Circulating CD45(+) collagen-I(+) fibrocytes were evaluated by flow cytometry. RESULTS: The number of circulating fibrocytes was significantly increased in all patients with ILD and particularly in patients with idiopathic interstitial pneumonitis and interstitial pneumonitis associated with collagen vascular disease as compared with healthy control subjects. The numbers of circulating fibrocytes were significantly correlated with pulmonary function test parameters and with serum levels of sialylated carbohydrate antigen, a marker of disease activity. Temporal changes in circulating fibrocyte numbers were evaluated in two patients, and the results suggested that these changes correlated with the activity of ILD. CONCLUSIONS: The results from this study provide further evidence for the role of circulating fibrocytes in fibrotic lung diseases.
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Doenças Pulmonares Intersticiais/sangue , Células-Tronco Mesenquimais/metabolismo , Biomarcadores/sangue , Quimiocina CCL2/sangue , Quimiocina CXCL12/sangue , Progressão da Doença , Feminino , Fibroblastos/patologia , Citometria de Fluxo , Humanos , Antígenos Comuns de Leucócito/metabolismo , Pessoa de Meia-Idade , Fibrose Pulmonar/patologiaRESUMO
Amyotrophic Lateral Sclerosis is the most common motor neuron degenerative disease in adults, and TARDBP gene mutations have been reported to be involved in the pathogenesis. We present here how we generated the human induced pluripotent stem cell (hiPSC) line KEIOi001-A/SM4-4-5 from the peripheral blood of a 63-year-old male patient presenting the c.1035C > G heterozygous SNP mutation in the TARDBP gene locus. The established hiPSC line does not express the exogenous reprogramming factors oriP nor EBNA1 and shows no karyotypic abnormalities, while it expresses pluripotent stem cell markers, presents the SNP mutation and is capable of three-germ layers differentiation in vitro.
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Amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC) is a unique endemic neurodegenerative disease, with high-incidence foci in Kii Peninsula, Japan. To gather new insights into the pathological mechanisms underlying Kii ALS/PDC, we performed transcriptome analyses of patient brains. We prepared frozen brains from three individuals without neurodegenerative diseases, three patients with Alzheimer's disease, and 21 patients with Kii ALS/PDC, and then acquired microarray data from cerebral gray and white matter tissues. Microarray results revealed that expression levels of genes associated with heat shock proteins, DNA binding/damage, and senescence were significantly altered in patients with ALS/PDC compared with healthy individuals. The RNA expression pattern observed for ALS-type brains was similar to that of PDC-type brains. Additionally, pathway and network analyses indicated that the molecular mechanism underlying ALS/PDC may be associated with oxidative phosphorylation of mitochondria, ribosomes, and the synaptic vesicle cycle; in particular, upstream regulators of these mechanisms may be found in synapses and during synaptic trafficking. Furthermore, phenotypic differences between ALS-type and PDC-type were observed, based on HLA haplotypes. In conclusion, determining the relationship between stress-responsive proteins, synaptic dysfunction, and the pathogenesis of ALS/PDC in the Kii peninsula may provide new understanding of this mysterious disease.
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Intra-bone marrow injection is a novel strategy for hematopoietic stem cell transplantation. Here, we investigated whether ex vivo culture of cord blood hematopoietic stem/progenitor cells influences their reconstitution in bone marrow after intra-bone marrow transplantation. Freshly isolated AC133(+) cells or cells derived from AC133(+) cells cultured with cytokines (stem cell factor, flt-3 ligand, and thrombopoietin) for 5 days were injected into the bone marrow of the left tibia in irradiated NOD/SCID mice. In the bone marrow of the injected left tibia, the engraftment levels of human CD45(+) cells at 6 weeks after transplantation did not differ considerably between transplantation of noncultured and cytokine-cultured cells. However, the migration and distribution of transplanted cells to the bone marrow of other, noninjected bones were extremely reduced for cytokine-treated cells compared with noncultured cells. Similar findings were observed for engraftment of CD34(+) cells. Administration of granulocyte colony-stimulating factor to mice after transplantation induced the migration of cytokine-cultured cells to the bone marrow of previously aspirated bone but not to other intact bones. These data suggest that ex vivo manipulation of hematopoietic progenitor/stem cells significantly affects their migration properties to other bone marrow compartments after intra-bone marrow transplantation. Our data raise a caution for future clinical applications of the intra-bone marrow transplantation method using ex vivo-manipulated hematopoietic stem cells.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Antígeno AC133 , Animais , Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea , Técnicas de Cultura de Células , Movimento Celular , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Glicoproteínas/metabolismo , Sobrevivência de Enxerto , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Peptídeos/metabolismo , Transplante HeterólogoRESUMO
Vascular apoptosis-inducing proteins (VAPs) from hemorrhagic snake venom are apoptosis-inducing toxins that target vascular endothelial cells. We now show that VAP1 and VAP2 from Crotalus atrox have hemorrhagic activity in mouse skin following intradermal injection. Following intravenous injection, VAP2 induced hemorrhage in the lung, intestine and kidney. Although the hemorrhagic activity was relatively weak, these apoptosis toxins may play a role in the complex mechanism of snake venom-induced hemorrhage.