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1.
Biomaterials ; 312: 122719, 2025 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39088912

RESUMO

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.


Assuntos
Sobrevivência Celular , Leucemia Mieloide Aguda , Células-Tronco Mesenquimais , Fenótipo , Microambiente Tumoral , Humanos , Leucemia Mieloide Aguda/patologia , Microambiente Tumoral/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura/métodos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Medula Óssea/patologia , Medula Óssea/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Células da Medula Óssea/citologia , Masculino , Diferenciação Celular/efeitos dos fármacos , Feminino
2.
Int J Med Sci ; 21(11): 2233-2243, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39239546

RESUMO

Purpose: Cognitive dysfunction caused by chronic cerebral hypoperfusion (CCH) is the leading cause of vascular dementia. Therefore, it is necessary to explore the mechanism that causes cerebral injury and find an effective therapy. Methods: Bone marrow mononuclear cells (BMMNCs) were extracted to detect the activity by CCK-8 kit and verify the transfection efficiency using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). A CCH rat model was established. Superparamagnetic iron oxide nanoparticles (BMPs)-PEI-Slit2/BMMNCs were injected into the tail vein and intervened with an external magnetic field. Hematoxylin and eosin staining was used to observe the pathological changes in brain tissue. The Slit/Robo pathway-related proteins Slit2 and Robo4 were detected by RT-qPCR and Western blotting. Results: The neurological score of the CCH group significantly increased compared with that of the sham group (P<0.05). The levels of brain injury markers S-100ß and NSE were significantly higher in the CCH group than in the sham group (P<0.05). Neuronal apoptosis in the frontal cortex and hippocampus of CCH rats significantly increased compared with that of the sham group (P<0.05). The expression levels of Slit2 and Robo4 mRNAs and proteins in brain tissue of CCH rats significantly increased (P<0.05). The neurological function scores of CCH rats treated with BMP-PEI-Slit2/BMMNC significantly increased after Robo4 siRNA administration (P<0.05). Conclusion: BMP combination with the CCH-related gene Slit2 can effectively improve the efficiency of BMMNC transplantation in treatment.


Assuntos
Isquemia Encefálica , Disfunção Cognitiva , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas do Tecido Nervoso , Animais , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ratos , Disfunção Cognitiva/terapia , Disfunção Cognitiva/etiologia , Isquemia Encefálica/terapia , Isquemia Encefálica/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Humanos , Masculino , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/química , Nanopartículas Magnéticas de Óxido de Ferro/administração & dosagem , Células da Medula Óssea , Apoptose/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Ratos Sprague-Dawley , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Terapia Genética/métodos , Proteínas Roundabout
3.
Stem Cell Res Ther ; 15(1): 301, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39278909

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS. METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 106 cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129. RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects. CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients. TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.


Assuntos
Esclerose Lateral Amiotrófica , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Proteômica , Transplante Autólogo , Humanos , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/terapia , Esclerose Lateral Amiotrófica/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteômica/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/líquido cefalorraquidiano , Idoso , Apolipoproteína A-I/líquido cefalorraquidiano , Apolipoproteína A-I/metabolismo , Adulto , Células da Medula Óssea/metabolismo , Mapas de Interação de Proteínas
4.
Stem Cell Res Ther ; 15(1): 304, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39278922

RESUMO

BACKGROUND: Although bone marrow-derived cells with high aldehyde dehydrogenase activity (ALDHbr) have shown therapeutic potential against various diseases in animal studies, clinical trials have failed to show concurrent findings. We aimed to clarify the optimal conditions for the efficacy of ALDHbr cells by using a murine bleomycin-induced pulmonary fibrosis model. METHODS: We intravenously transferred male or female donor C57BL/6 mice-derived ALDHbr cells into recipient C57BL/6 mice under various conditions, and used mCherry-expressing mice as a donor to trace the transferred ALDHbr cells. RESULTS: Pulmonary fibrosis improved significantly when (1) female-derived, not male-derived, and (2) lineage (Lin)-negative, not lineage-positive, ALDHbr cells were transferred during the (3) fibrotic, not inflammatory, phase. Consistent with the RNA-sequencing results, female-derived Lin-/ALDHbr cells were more resistant to oxidative stress than male-derived cells in vitro, and transferred female-derived Lin-/ALDHbr cells were more viable than male-derived cells in the fibrotic lung. The mechanism underlying the antifibrotic effects of Lin-/ALDHbr cells was strongly associated with reduction of oxidative stress. CONCLUSIONS: Our results indicated that Lin-/ALDHbr cell therapy could ameliorate pulmonary fibrosis by reducing oxidative stress and suggested that their efficacy was mediated by sex-related differences. Thus, sex-awareness strategies may be important for clinical application of bone marrow ALDHbr cells as a therapeutic tool.


Assuntos
Aldeído Desidrogenase , Células da Medula Óssea , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Animais , Camundongos , Feminino , Masculino , Fibrose Pulmonar/patologia , Fibrose Pulmonar/terapia , Fibrose Pulmonar/induzido quimicamente , Células da Medula Óssea/citologia , Aldeído Desidrogenase/metabolismo , Aldeído Desidrogenase/genética , Bleomicina , Modelos Animais de Doenças , Estresse Oxidativo
5.
J Orthop Surg Res ; 19(1): 572, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39285416

RESUMO

BACKGROUND: Osteoporosis results from decreased bone mass and disturbed bone structure. Human bone marrow mesenchymal stem cells (hBMSCs) demonstrate robust osteogenic differentiation, a critical process for bone formation. This research was designed to examine the functions of LINC01133 in osteogenic differentiation. METHODS: Differentially expressed lncRNAs affecting osteogenic differentiation in hBMSCs were identified from the GEO database. A total of 74 osteoporosis patients and 70 controls were enrolled. hBMSCs were stimulated to undergo osteogenic differentiation using an osteogenic differentiation medium (OM). RT-qPCR was performed to evaluate LINC01133 levels and osteogenesis-related genes such as osteocalcin, osteopontin, and RUNX2. An alkaline phosphates (ALP) activity assay was conducted to assess osteogenic differentiation. Cell apoptosis was detected using flow cytometry. Dual luciferase reporter assay and RIP assay were employed to investigate the association between miR-214-3p and LINC01133 or CTNNB1. Loss or gain of function assays were conducted to elucidate the impact of LINC01133 and miR-214-3p on osteogenic differentiation of hBMSCs. RESULTS: LINC01133 and CTNNB1 expression decreased in osteoporotic patients but increased in OM-cultured hBMSCs, whereas miR-214-3p showed an opposite trend. Depletion of LINC01133 suppressed the expression of genes associated with bone formation and ALP activity triggered by OM in hBMSCs, leading to increased cell apoptosis. Nevertheless, this suppression was partially counteracted by the reduced miR-214-3p levels. Mechanistically, LINC01133 and CTNNB1 were identified as direct targets of miR-214-3p. CONCLUSIONS: Our study highlights the role of LINC01133 in positively regulating CTNNB1 expression by inhibiting miR-214-3p, thereby promoting osteogenic differentiation of BMSCs. These findings may provide valuable insights into bone regeneration in osteoporosis.


Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais , MicroRNAs , Osteogênese , Osteoporose , RNA Longo não Codificante , Regulação para Cima , beta Catenina , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Osteogênese/fisiologia , Diferenciação Celular/genética , RNA Longo não Codificante/genética , beta Catenina/genética , beta Catenina/metabolismo , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Células Cultivadas , Feminino , Pessoa de Meia-Idade , Masculino , Apoptose/genética , Células da Medula Óssea/metabolismo
6.
Front Immunol ; 15: 1374838, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39281683

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells, which are key components of the immune system and involved in early immune responses. DCs are specialized in capturing, processing, and presenting antigens to facilitate immune interactions. Chickens infected with avian influenza virus (AIV) demonstrate a wide range of clinical symptoms, based on pathogenicity of the virus. Low pathogenic avian influenza (LPAI) viruses typically induce mild clinical signs, whereas high pathogenic avian influenza (HPAI) induce more severe disease, which can lead to death. For this study, chicken bone marrow-derived DC (ckBM-DC)s were produced and infected with high and low pathogenic avian influenza viruses of H5N2 or H7N3 subtypes to characterize innate immune responses, study effect on cell morphologies, and evaluate virus replication. A strong proinflammatory response was observed at 8 hours post infection, via upregulation of chicken interleukin-1ß and stimulation of the interferon response pathway. Microscopically, the DCs underwent morphological changes from classic elongated dendrites to a more general rounded shape that eventually led to cell death with the presence of scattered cellular debris. Differences in onset of morphologic changes were observed between H5 and H7 subtypes. Increases in viral titers demonstrated that both HPAI and LPAI are capable of infecting and replicating in DCs. The increase in activation of infected DCs may be indicative of a dysregulated immune response typically seen with HPAI infections.


Assuntos
Galinhas , Citocinas , Células Dendríticas , Influenza Aviária , Animais , Células Dendríticas/imunologia , Células Dendríticas/virologia , Galinhas/virologia , Influenza Aviária/imunologia , Influenza Aviária/virologia , Influenza Aviária/patologia , Citocinas/metabolismo , Citocinas/imunologia , Vírus da Influenza A/imunologia , Replicação Viral , Células da Medula Óssea/imunologia , Células da Medula Óssea/virologia
7.
FASEB J ; 38(17): e23892, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39230563

RESUMO

Mesenchymal stromal stem cells (MSCs) or skeletal stem cells (SSCs) play a major role in tissue repair due to their robust ability to differentiate into osteoblasts, chondrocytes, and adipocytes. Complex cell signaling cascades tightly regulate this differentiation. In osteogenic differentiation, Runt-related transcription factor 2 (RUNX2) and ALP activity are essential. Furthermore, during the latter stages of osteogenic differentiation, mineral formation mediated by the osteoblast occurs with the secretion of a collagenous extracellular matrix and calcium deposition. Activation of nuclear factor erythroid 2-related factor 2 (NRF2), an important transcription factor against oxidative stress, inhibits osteogenic differentiation and mineralization via modulation of RUNX2 function; however, the exact role of NRF2 in osteoblastogenesis remains unclear. Here, we demonstrate that NRF2 activation in human bone marrow-derived stromal cells (HBMSCs) suppressed osteogenic differentiation. NRF2 activation increased the expression of STRO-1 and KITLG (stem cell markers), indicating NRF2 protects HBMSCs stemness against osteogenic differentiation. In contrast, NRF2 activation enhanced mineralization, which is typically linked to osteogenic differentiation. We determined that these divergent results were due in part to the modulation of cellular calcium flux genes by NRF2 activation. The current findings demonstrate a dual role for NRF2 as a HBMSC maintenance factor as well as a central factor in mineralization, with implications therein for elucidation of bone formation and cellular Ca2+ kinetics, dystrophic calcification and, potentially, application in the modulation of bone formation.


Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais , Fator 2 Relacionado a NF-E2 , Osteoblastos , Osteogênese , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Osteogênese/fisiologia , Diferenciação Celular/fisiologia , Osteoblastos/metabolismo , Osteoblastos/citologia , Calcificação Fisiológica/fisiologia , Células Cultivadas , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética
8.
PLoS One ; 19(9): e0309455, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39231178

RESUMO

Hemorrhage, a condition that accompanies most physical trauma cases, remains an important field of study, a field that has been extensively studied in the immunological context for myeloid and lymphoid cells, but not as much for erythroid cells. In this study, we studied the immunological response of murine erythroid cells to acute blood loss using flow cytometry, NanoString immune transcriptome profiling, and BioPlex cytokine secretome profiling. We observed that acute blood loss forces the differentiation of murine erythroid cells in both bone marrow and spleen and that there was an up-regulation of several immune response genes, in particular pathogen-associated molecular pattern sensing gene Clec5a in post-acute blood loss murine bone marrow erythroid cells. We believe that the up-regulation of the Clec5a gene in bone marrow erythroid cells could help bone marrow erythroid cells detect and eliminate pathogens with the help of reactive oxygen species and antimicrobial proteins calprotectin and cathelicidin, the genes of which (S100a8, S100a9, and Camp) dominate the expression in bone marrow erythroid cells of mice.


Assuntos
Diferenciação Celular , Quimiocina CCL3 , Células Eritroides , Antígenos Comuns de Leucócito , Animais , Camundongos , Células Eritroides/metabolismo , Células Eritroides/citologia , Quimiocina CCL3/metabolismo , Quimiocina CCL3/genética , Antígenos Comuns de Leucócito/metabolismo , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Camundongos Endogâmicos C57BL , Calgranulina A/metabolismo , Calgranulina A/genética , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia , Calgranulina B/metabolismo , Calgranulina B/genética , Masculino
9.
Int J Mol Sci ; 25(17)2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39273235

RESUMO

Ionizing radiation exposure can cause damage to diverse tissues and organs, with the hematopoietic system being the most sensitive. However, limited information is available regarding the radiosensitivity of various hematopoietic cell populations in the bone marrow due to the high heterogeneity of the hematopoietic system. In this study, we observed that granulocyte-macrophage progenitors, hematopoietic stem/progenitor cells, and B cells within the bone marrow showed the highest sensitivity, exhibiting a rapid decrease in cell numbers following irradiation. Nonetheless, neutrophils, natural killer (NK) cells, T cells, and dendritic cells demonstrated a certain degree of radioresistance, with neutrophils exhibiting the most pronounced resistance. By employing single-cell transcriptome sequencing, we investigated the early responsive genes in various cell types following irradiation, revealing that distinct gene expression profiles emerged between radiosensitive and radioresistant cells. In B cells, radiation exposure led to a specific upregulation of genes associated with mitochondrial respiratory chain complexes, suggesting a connection between these complexes and cell radiosensitivity. In neutrophils, radiation exposure resulted in fewer gene alterations, indicating their potential for distinct mechanisms in radiation resistance. Collectively, this study provides insights into the molecular mechanism for the heterogeneity of radiosensitivity among the various bone marrow hematopoietic cell populations.


Assuntos
Radiação Ionizante , Análise de Célula Única , Transcriptoma , Animais , Camundongos , Análise de Célula Única/métodos , Transcriptoma/efeitos da radiação , Células da Medula Óssea/efeitos da radiação , Células da Medula Óssea/metabolismo , Camundongos Endogâmicos C57BL , Tolerância a Radiação/genética , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/efeitos da radiação , Células-Tronco Hematopoéticas/metabolismo , Neutrófilos/efeitos da radiação , Neutrófilos/metabolismo
10.
Chin J Dent Res ; 27(3): 215-224, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39221982

RESUMO

OBJECTIVE: To investigate whether bone marrow mesenchymal stem cells (BMMSCs) modulate periodontal bone repair through the hydroxylase domain-containing protein 2 (PHD2)/hypoxia- inducible factor-1 (HIF-1) signalling pathway in response to inflammatory conditions. METHODS: Osteogenic differentiation of PHD2 shRNA-modified BMMSCs and the possible mechanism were explored in an inflammatory microenvironment stimulated by porphyromonas gingivalis lipopolysaccharide (Pg-LPS) in vitro. The effect of PHD2 gene-modified BMMSCs on periodontal bone loss was evaluated with experimental periodontitis. RESULTS: Pg-LPS stimulation greatly impaired the osteogenic differentiation of BMMSCs, whereas the silence of PHD2 significantly enhanced the osteogenesis of BMMSCs. More importantly, increased level of vascular endothelial growth factor (VEGF) was detected under Pg-LPS stimulation, which was verified to be associated with the augmented osteogenesis. In experimental periodontitis, PHD2-modified BMMSCs transplantation elevated osteogenic parameters and the expression of VEGF in periodontal tissue. CONCLUSION: This study highlighted that PHD2 gene silencing could be a feasible approach to combat inflammatory bone loss by rescuing the dysfunction of seed cells.


Assuntos
Prolina Dioxigenases do Fator Induzível por Hipóxia , Células-Tronco Mesenquimais , Osteogênese , RNA Interferente Pequeno , Animais , RNA Interferente Pequeno/genética , Osteogênese/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Porphyromonas gingivalis , Periodontite/terapia , Periodontite/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Diferenciação Celular , Lipopolissacarídeos , Perda do Osso Alveolar , Camundongos , Masculino , Células da Medula Óssea , Regeneração Óssea/genética
11.
Chin J Dent Res ; 27(3): 225-234, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39221983

RESUMO

OBJECTIVE: To reveal the role and mechanism of cannabinoid receptor 1 (CB1) and mitochondria in promoting osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in the inflammatory microenvironment. METHODS: Bidirectional mitochondrial transfer was performed in bone mesenchymal stem cells (BMSCs) and PDLSCs. Laser confocal microscopy and quantitative flow cytometry were used to observe the mitochondrial transfer and quantitative mitochondrial transfer efficiency. Realtime reverse transcription polymerase chain reaction (RT-PCR) was employed to detect gene expression. Alkaline phosphatase (ALP) activity, alizarin red staining (ARS) and quantitative calcium ion analysis were used to evaluate the degree of osteogenic differentiation of PDLSCs. RESULTS: Bidirectional mitochondrial transfer was observed between BMSCs and PDLSCs. The indirect co-culture system could simulate intercellular mitochondrial transfer. Compared with the conditioned medium (CM) for BMSCs, that for HA-CB1 BMSCs could significantly enhance the mineralisation ability of PDLSCs. The mineralisation ability of PDLSCs could not be enhanced after removing the mitochondria in CM for HA-CB1 BMSCs. The expression level of HO-1, PGC-1α, NRF-1, ND1 and HK2 was significantly increased in HA-CB1 BMSCs. CONCLUSION: CM for HA-CB1 BMSCs could significantly enhance the damaged osteogenic differentiation ability of PDLSCs in the inflammatory microenvironment, and the mitochondria of CM played an important role. CB1 was related to the activation of the HO-1/PGC-1α/NRF-1 mitochondrial biogenesis pathway, and significantly increased the mitochondrial content in BMSCs.


Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais , Mitocôndrias , Osteogênese , Ligamento Periodontal , Receptor CB1 de Canabinoide , Adolescente , Humanos , Células da Medula Óssea , Células Cultivadas , Técnicas de Cocultura , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Mitocôndrias/metabolismo , Osteogênese/fisiologia , Ligamento Periodontal/citologia , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/genética
12.
BMC Res Notes ; 17(1): 253, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39252057

RESUMO

OBJECTIVES: Current data suggests that Bacille Calmette-Guerin (BCG) vaccination contributes to nonspecific enhancement of resistance to various infections. Thus, BCG vaccination induces both specific immunity against mycobacteria and non-specific "trained immunity" against various pathogens. To understand the fundamental mechanisms of "trained" immunity, studies of transcriptome changes occurring during BCG vaccination in innate immunity cells, as well as in their precursors, are necessary. Furthermore, this data possesses important significance for practical applications associated with the development of recombinant BCG strains aimed to enhance innate immunity against diverse infectious agents. DATA DESCRIPTION: We performed RNA sequencing of innate immune cells derived from murine bone marrow and spleen three days after subcutaneous BCG vaccination. Using fluorescence-activated cell sorting we obtained three cell populations for each mouse from both control and BCG vaccinated groups: bone marrow monocytes and neutrophils and splenic NK-cells. Then double-indexed cDNA libraries for Illumina sequencing from the collected samples were prepared, the resulting cDNA library mix was subjected to NovaSeq 6000 sequencing. This paper describes the collection of 24 RNA sequencing samples comprising 4 sets of immune cell populations obtained from subcutaneously BCG-vaccinated and control mice.


Assuntos
Vacina BCG , Imunidade Inata , Baço , Transcriptoma , Animais , Vacina BCG/imunologia , Vacina BCG/administração & dosagem , Camundongos , Transcriptoma/genética , Baço/imunologia , Vacinação/métodos , Células Matadoras Naturais/imunologia , Camundongos Endogâmicos C57BL , Injeções Subcutâneas , Monócitos/imunologia , Feminino , Neutrófilos/imunologia , Análise de Sequência de RNA/métodos , Células da Medula Óssea/imunologia
13.
J Ovarian Res ; 17(1): 184, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39267091

RESUMO

Ovarian insufficiency is one of the common reproductive disorders affecting women with limited therapeutic aids. Mesenchymal stem cells have been investigated in such disorders before yet, the exact mechanism of MSCs in ovarian regeneration regarding their epigenetic regulation remains elusive. The current study is to investigate the role of the bone marrow-derived mesenchymal stem cells (BM-MSCs) lncRNA (Neat-1 and Hotair1) and miRNA (mir-21-5p, mir-144-5p, and mir-664-5p) in mitigating ovarian granulosa cell apoptosis as well as searching BM-MSCs in altering the expression of ovarian and hypothalamic IGF-1 - kisspeptin system in connection to HPG axis in a cyclophosphamide-induced ovarian failure rat model. Sixty mature female Sprague Dawley rats were divided into 3 equal groups; control group, premature ovarian insufficiency (POI) group, and POI + BM-MSCs. POI female rat model was established with cyclophosphamide. The result revealed that BM-MSCs and their conditioned media displayed a significant expression level of Neat-1, Hotair-1, mir-21-5p, mir-144-5p, and mir-664-5p. Moreover, BM-MSCs transplantation in POI rats improves; the ovarian and hypothalamic IGF-1 - kisspeptin, HPG axis, ovarian granulosa cell apoptosis, steroidogenesis, angiogenesis, energy balance, and oxidative stress. BM-MSCs expressed higher levels of antiapoptotic lncRNAs and microRNAs that mitigate ovarian insufficiency.


Assuntos
Apoptose , Ciclofosfamida , Fator de Crescimento Insulin-Like I , Células-Tronco Mesenquimais , MicroRNAs , Insuficiência Ovariana Primária , RNA Longo não Codificante , Ratos Sprague-Dawley , Animais , Feminino , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Mesenquimais/metabolismo , Ciclofosfamida/efeitos adversos , Ratos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Insuficiência Ovariana Primária/metabolismo , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/induzido quimicamente , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/genética , Ovário/metabolismo , Células da Medula Óssea/metabolismo , Angiogênese
14.
Int J Mol Sci ; 25(17)2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39273096

RESUMO

In recent years, with the advent of a super-aged society, lifelong dental care has gained increasing emphasis, and implant therapy for patients with an edentulous jaw has become a significant option. However, for implant therapy to be suitable for elderly patients with reduced regenerative and immunological capabilities, higher osteoconductive and antimicrobial properties are required on the implant surfaces. Silicon nitride, a non-oxide ceramic known for its excellent mechanical properties and biocompatibility, has demonstrated high potential for inducing hard tissue differentiation and exhibiting antibacterial properties. In this study, silicon nitride was deposited on pure titanium metal surfaces and evaluated for its biocompatibility and antibacterial properties. The findings indicate that silicon nitride improves the hydrophilicity of the material surface, enhancing the initial adhesion of rat bone marrow cells and promoting hard tissue differentiation. Additionally, the antibacterial properties were assessed using Staphylococcus aureus, revealing that the silicon nitride-coated surfaces exhibited significant antibacterial activity. Importantly, no cytotoxicity was observed, suggesting that silicon nitride-coated titanium could serve as a novel implant material.


Assuntos
Antibacterianos , Materiais Revestidos Biocompatíveis , Compostos de Silício , Staphylococcus aureus , Propriedades de Superfície , Titânio , Titânio/química , Titânio/farmacologia , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Ratos , Staphylococcus aureus/efeitos dos fármacos , Compostos de Silício/química , Compostos de Silício/farmacologia , Teste de Materiais , Adesão Celular/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos
15.
Zhonghua Xue Ye Xue Za Zhi ; 45(7): 651-659, 2024 Jul 14.
Artigo em Chinês | MEDLINE | ID: mdl-39231769

RESUMO

Objective: To analyze the clinical characteristics and prognosis of patients with myelodysplastic syndrome (MDS) with a bone marrow nucleated erythroid cell proportion of greater than or equal to 50% (MDS-E) . Methods: The clinical characteristics and prognostic factors of patients with MDS-E were retrospectively analyzed by collecting the case data of 1 436 newly treated patients with MDS diagnosed in the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences from May 2014 to June 2023. Results: A total of 1 436 newly diagnosed patients with complete data were included in the study, of which 337 (23.5%) patients with MDS-E had a younger age of onset and lower neutrophil and platelet counts compared with those in patients with an erythroid cell proportion of less than 50% (MDS-NE) (all P<0.05). The proportion of MDS cases with ring sideroblasts (MDS-RS) was higher in the MDS-E group than in the MDS-NE group, and multi-hit TP53 mutations were more enriched in the MDS-E group than in the MDS-NE group (all P<0.05). Among patients with MDS-RS, the frequency of complex karyotypes and the TP53 mutation rate were significantly lower in the MDS-E group than in the MDS-NE group (0 vs 11.9%, P=0.048 and 2.4% vs 15.1%, P=0.053, respectively). Among patients with TP53 mutations, the frequencies of complex karyotypes and multi-hit TP53 mutations were significantly higher in the MDS-E group than in the MDS-NE group (87.5% vs 64.6%, P=0.003 and 84.0% vs 54.2%, P<0.001, respectively). Survival analysis of patients with MDS-RS found that the overall survival (OS) in the MDS-E group was better than that in the MDS-NE group [not reached vs 63 (95% CI 53.3-72.7) months, P=0.029]. Among patients with TP53 mutations and excess blasts, the OS in the MDS-E group was worse than that in the MDS-NE group [6 (95% CI 2.2-9.8) months vs 12 (95% CI 8.9-15.1) months, P=0.022]. Multivariate analysis showed that age of ≥65 years (HR=2.47, 95% CI 1.43-4.26, P=0.001), mean corpuscular volume (MCV) of ≤100 fl (HR=2.62, 95% CI 1.54-4.47, P<0.001), and TP53 mutation (HR=2.31, 95% CI 1.29-4.12, P=0.005) were poor prognostic factors independent of the Revised International Prognostic Scoring System (IPSS-R) prognosis stratification in patients with MDS-E. Conclusion: Among patients with MDS-RS, MDS-E was strongly associated with a lower proportion of complex karyotypes and TP53 mutations, and the OS in the MDS-E group was longer than that in the MDS-NE group. Among patients with TP53 mutations, MDS-E was strongly associated with complex karyotypes and multi-hit TP53 mutations, and among TP53-mutated patients with excess blasts, the OS in the MDS-E group was shorter than that in the MDS-NE group. Age of ≥65 years, MCV of ≤100 fl, and TP53 mutation were independent adverse prognostic factors affecting OS in patients with MDS-E.


Assuntos
Mutação , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/diagnóstico , Prognóstico , Estudos Retrospectivos , Medula Óssea/patologia , Células da Medula Óssea , Masculino , Feminino , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Pessoa de Meia-Idade
16.
Toxicology ; 508: 153932, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39179171

RESUMO

Hydroquinone (HQ), a metabolite of benzene, is frequently utilized as a surrogate for benzene in in vitro studies and is associated with the development of acute myeloid leukemia (AML). In the hemotoxicity caused by benzene and HQ, cell apoptosis plays a key role. However, the molecular mechanisms underlying HQ are unknown. Studies have indicated that Suv39h1 is involved in regulating cell division and proliferation by regulating histone H3K9me3. Meanwhile, the Wnt/ß-catenin signaling pathway also plays a significant role in cell proliferation and apoptosis. Therefore, this study was aimed at exploring the regulatory role of Suv39h1 and the Wnt/ß-catenin signaling pathway in the effects of HQ on bone marrow mesenchymal stem cells (BMSCs), as well as its influence on cell proliferation and apoptosis. The results demonstrated that HQ elevated the levels of Suv39h1 and H3K9me3 and activated the Wnt/ß-catenin signaling pathway by upregulating ß-catenin, Wnt2b, C-myc, and Cyclin D1 and downregulating Wnt5a, resulting in an increase in cell growth and a decrease in apoptosis. Suv39h1 knockdown inhibited the Wnt/ß-catenin signaling pathway. Meanwhile, inhibition of the Wnt/ß-catenin signaling pathway resulted in the down-regulation of Suv39h1 and H3K9me3 in BMSCs. They both promoted cell proliferation and inhibited apoptosis in the effects of HQ on BMSCs by downregulating the expression of Cyt-C, Bax, Caspase 3, and Caspase 9 and upregulating the expression of Bcl-xl. Therefore, we concluded that Suv39h1 and the Wnt/ß-catenin signaling pathway may mutually regulate each other in the effects of HQ on BMSCs in order to ameliorate the altered function of BMSCs.


Assuntos
Apoptose , Proliferação de Células , Hidroquinonas , Células-Tronco Mesenquimais , Via de Sinalização Wnt , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Apoptose/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Animais , Hidroquinonas/toxicidade , Células Cultivadas , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , beta Catenina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Masculino
17.
Mol Med Rep ; 30(4)2024 10.
Artigo em Inglês | MEDLINE | ID: mdl-39129299

RESUMO

Tanshinone IIA (Tan IIA) may have therapeutic effects on avascular necrosis of the femoral head (ANFH) by targeting bone marrow mesenchymal stem cells (BMSCs). The effect and underlying mechanism of Tan IIA on adipogenesis and osteogenesis ability of BMSCs remain to be elucidated. In the present study BMSCs were treated with osteogenic or adipogenic differentiation medium with or without Tan IIA under hypoxic environment. Osteogenic differentiation potential was evaluated by alkaline phosphatase (ALP) measurement, alizarin red staining and reverse transcription­quantitative (RT­q) PCR of osteogenic marker genes. Adipogenic differentiation potential was evaluated with oil red staining and RT­qPCR of adipogenic marker genes. Detailed mechanism was explored by RNA­seq and small molecular treatment during osteogenesis and adipogenesis of BMSCs. ALP level, mineralized nodules and expression level of osteogenic marker genes significantly increased following Tan IIA treatment during osteogenic differentiation of BMSCs. Lipid droplet and expression levels of adipogenic marker genes significantly decreased following Tan IIA treatment during adipogenic differentiation of BMSCs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of RNA­seq data indicated increased Akt and TGFß signaling following Tan IIA treatment. Further western blot assay confirmed that Tan IIA significantly activated Akt/cAMP response element­binding protein signaling and TGFß/Smad3 signaling. Application of Akti1/2 (an Akt inhibitor) significantly decreased the promotion effect of osteogenesis induced by Tan IIA, while the addition of SB431542 significantly reduced inhibition effect of adipogenesis caused by Tan IIA. Tan IIA could promote osteogenic differentiation potential of BMSCs by activating AKT signaling and suppress adipogenic differentiation potential of BMSCs by activating TGFß signaling.


Assuntos
Abietanos , Adipogenia , Diferenciação Celular , Células-Tronco Mesenquimais , Osteogênese , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Osteogênese/efeitos dos fármacos , Abietanos/farmacologia , Adipogenia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Cultivadas , Proteína Smad3/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/citologia
18.
J Bone Miner Res ; 39(9): 1356-1370, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39126376

RESUMO

The skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.


The bone is a self-renewing tissue that continues to reshape throughout life. Bone marrow mesenchymal stem cells (BMSCs) are essential for bone homeostasis as they are capable of osteogenic differentiation. Recent evidence suggests that BMSCs drive the osteogenic differentiation through metabolic reprogramming, but the mechanism remains unclear. In this paper, we explored the metabolic alteration following osteogenic induction of BMSCs and found that one-carbon metabolism was obviously promoted in this process. The underlining mechanisms of the osteogenic potential driven by one-carbon metabolism seem to be its contribution on N6-methyladenosine (m6A) methylation and consequent glycolysis level by providing methyl donor. We demonstrated that one-carbon metabolism-mediated m6A methylation was a potential promoter in BMSC osteogenesis, and metabolic-epigenetic coupling might provide novel therapeutic targets for bone regeneration.


Assuntos
Adenosina , Carbono , Osteogênese , Ratos Sprague-Dawley , S-Adenosilmetionina , Animais , S-Adenosilmetionina/metabolismo , S-Adenosilmetionina/farmacologia , Osteogênese/efeitos dos fármacos , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/metabolismo , Metilação/efeitos dos fármacos , Carbono/metabolismo , Carbono/farmacologia , Ratos , Células da Medula Óssea/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Metotrexato/farmacologia , Glicólise/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos
19.
Int J Mol Sci ; 25(16)2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39201546

RESUMO

Philadelphia-Negative Myeloproliferative neoplasms (MPNs) are a diverse group of blood cancers leading to excessive production of mature blood cells. These chronic diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), can significantly impact patient quality of life and are still incurable in the vast majority of the cases. This review examines the mechanobiology within a bone marrow niche, emphasizing the role of mechanical cues and the primary cilium in the pathophysiology of MPNs. It discusses the influence of extracellular matrix components, cell-cell and cell-matrix interactions, and mechanosensitive structures on hematopoietic stem cell (HSC) behavior and disease progression. Additionally, the potential implications of the primary cilium as a chemo- and mechanosensory organelle in bone marrow cells are explored, highlighting its involvement in signaling pathways crucial for hematopoietic regulation. This review proposes future research directions to better understand the dysregulated bone marrow niche in MPNs and to identify novel therapeutic targets.


Assuntos
Cílios , Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/fisiopatologia , Cílios/metabolismo , Cílios/patologia , Animais , Medula Óssea/patologia , Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Mecanotransdução Celular , Matriz Extracelular/metabolismo , Transdução de Sinais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia
20.
Front Immunol ; 15: 1439510, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39188716

RESUMO

Background and aim: Bone marrow stem cells (BM-SCs) and their progeny play a central role in tissue repair and regeneration. In patients with chronic liver failure, bone marrow (BM) reserve is severally compromised and they showed marked defects in the resolution of injury and infection, leading to liver failure and the onset of decompensation. Whether BM failure is the cause or consequence of liver failure during cirrhosis is not known. In this study, we aimed to determine the underlying relationship between BM failure and regeneration failure in cirrhosis. Methodology: C57Bl/6(J) mice were used to develop chronic liver injury through intra-peritoneal administration of carbon tetrachloride (CCl4) for 15 weeks (0.1-0.5 ml/kg). Animals were sacrificed to study the transition of cirrhosis and BM defects. To restore the BM-SC reserve; healthy BM cells were infused via intra-BM infusion and assessed for changes in liver injury, regeneration, and BM-SC reserve. Results: Using a CCl4-induced animal - model of cirrhosis, we showed the loss of BM-SCs reserve occurred before regeneration failure and the onset of non-acute decompensation. Intra-BM infusion of healthy BM cells induced the repopulation of native hematopoietic stem cells (HSCs) in cirrhotic BM. Restoring BM-HSCs reserve augments liver macrophage-mediated clearance of infection and inflammation dampens neutrophil-mediated inflammation, accelerates fibrosis regression, enhances hepatocyte proliferation, and delays the onset of non-acute decompensation. Conclusion: These findings suggest that loss of BM-HSCs reserve underlies the compromised innate immune function of the liver, drives regeneration failure, and the onset of non-acute decompensation. We further provide the proof-of-concept that rejuvenating BM-HSC reserve can serve as a potential therapeutic approach for preventing regeneration failure and transition to decompensated cirrhosis.


Assuntos
Tetracloreto de Carbono , Modelos Animais de Doenças , Células-Tronco Hematopoéticas , Cirrose Hepática , Regeneração Hepática , Camundongos Endogâmicos C57BL , Animais , Camundongos , Cirrose Hepática/terapia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Fígado/patologia , Transplante de Medula Óssea , Células da Medula Óssea
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