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1.
Cell Biochem Funct ; 42(3): e4010, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38613217

RESUMEN

Mesenchymal stromal cells (MSCs) together with malignant cells present in the tumor microenvironment (TME), participate in the suppression of the antitumor immune response through the production of immunosuppressive factors, such as transforming growth factor beta 1 (TGF-ß1). In previous studies, we reported that adenosine (Ado), generated by the adenosinergic activity of cervical cancer (CeCa) cells, induces the production of TGF-ß1 by interacting with A2AR/A2BR. In the present study, we provide evidence that Ado induces the production of TGF-ß1 in MSCs derived from CeCa tumors (CeCa-MSCs) by interacting with both receptors and that TGF-ß1 acts in an autocrine manner to induce the expression of programmed death ligand 1 (PD-L1) in CeCa-MSCs, resulting in an increase in their immunosuppressive capacity on activated CD8+ T lymphocytes. The addition of the antagonists ZM241385 and MRS1754, specific for A2AR and A2BR, respectively, or SB-505124, a selective TGF-ß1 receptor inhibitor, in CeCa-MSC cultures significantly inhibited the expression of PD-L1. Compared with CeCa-MSCs, MSCs derived from normal cervical tissue (NCx-MSCs), used as a control and induced with Ado to express PD-L1, showed a lower response to TGF-ß1 to increase PD-L1 expression. Those results strongly suggest the presence of a feedback mechanism among the adenosinergic pathway, the production of TGF-ß1, and the induction of PD-L1 in CeCa-MSCs to suppress the antitumor response of CD8+ T lymphocytes. The findings of this study suggest that this pathway may have clinical importance as a therapeutic target.


Asunto(s)
Células Madre Mesenquimatosas , Neoplasias del Cuello Uterino , Femenino , Humanos , Antígeno B7-H1 , Adenosina/farmacología , Factor de Crecimiento Transformador beta1 , Microambiente Tumoral
2.
Int J Mol Sci ; 25(4)2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38396665

RESUMEN

Mesenchymal stem/stromal cells (MSCs) are multipotent cells located in different areas of the human body. The oral cavity is considered a potential source of MSCs because they have been identified in several dental tissues (D-MSCs). Clinical trials in which cells from these sources were used have shown that they are effective and safe as treatments for tissue regeneration. Importantly, immunoregulatory capacity has been observed in all of these populations; however, this function may vary among the different types of MSCs. Since this property is of clinical interest for cell therapy protocols, it is relevant to analyze the differences in immunoregulatory capacity, as well as the mechanisms used by each type of MSC. Interestingly, D-MSCs are the most suitable source for regenerating mineralized tissues in the oral region. Furthermore, the clinical potential of D-MSCs is supported due to their adequate capacity for proliferation, migration, and differentiation. There is also evidence for their potential application in protocols against autoimmune diseases and other inflammatory conditions due to their immunosuppressive capacity. Therefore, in this review, the immunoregulatory mechanisms identified at the preclinical level in combination with the different types of MSCs found in dental tissues are described, in addition to a description of the clinical trials in which MSCs from these sources have been applied.


Asunto(s)
Células Madre Mesenquimatosas , Humanos , Células Madre Mesenquimatosas/metabolismo , Inmunomodulación , Células Madre Multipotentes , Diferenciación Celular , Tratamiento Basado en Trasplante de Células y Tejidos , Proliferación Celular , Células Cultivadas
3.
Int J Mol Sci ; 25(17)2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39273524

RESUMEN

Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to bone marrow-derived mesenchymal stem cells (BM-MSCs) for potential clinical applications because of their accessibility and anti-inflammatory capacity. We previously demonstrated that DT-MSCs from dental pulp (DP-MSCs), periodontal ligaments (PDL-MSCs), and gingival tissue (G-MSCs) show immunosuppressive effects similar to those of BM, but to date, the DT-MSC-mediated immunoregulation of T lymphocytes through the purinergic pathway remains unknown. In the present study, we compared DP-MSCs, PDL-MSCs, and G-MSCs in terms of CD26, CD39, and CD73 expression; their ability to generate adenosine (ADO) from ATP and AMP; and whether the concentrations of ADO that they generate induce an immunomodulatory effect on T lymphocytes. BM-MSCs were included as the gold standard. Our results show that DT-MSCs present similar characteristics among the different sources analyzed in terms of the properties evaluated; however, interestingly, they express more CD39 than BM-MSCs; therefore, they generate more ADO from ATP. In contrast to those produced by BM-MSCs, the concentrations of ADO produced by DT-MSCs from ATP inhibited the proliferation of CD3+ T cells and promoted the generation of CD4+CD25+FoxP3+CD39+CD73+ Tregs and Th17+CD39+ lymphocytes. Our data suggest that DT-MSCs utilize the adenosinergic pathway as an immunomodulatory mechanism and that this mechanism is more efficient than that of BM-MSCs.


Asunto(s)
5'-Nucleotidasa , Adenosina , Apirasa , Pulpa Dental , Células Madre Mesenquimatosas , Ligamento Periodontal , Linfocitos T , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/inmunología , Humanos , Adenosina/metabolismo , Pulpa Dental/citología , Pulpa Dental/inmunología , Pulpa Dental/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , 5'-Nucleotidasa/metabolismo , Apirasa/metabolismo , Ligamento Periodontal/citología , Ligamento Periodontal/metabolismo , Adenosina Trifosfato/metabolismo , Células Cultivadas , Encía/citología , Encía/metabolismo , Encía/inmunología , Antígenos CD/metabolismo , Inmunomodulación , Diferenciación Celular , Proliferación Celular , Dipeptidil Peptidasa 4/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Proteínas Ligadas a GPI
4.
Int J Mol Sci ; 24(22)2023 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-38003447

RESUMEN

Acute ST-elevation myocardial infarction (STEMI) leads to myocardial injury or necrosis, and M1 macrophages play an important role in the inflammatory response. Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are capable of modulating macrophage plasticity, principally due to their immunoregulatory capacity. In the present study, we analyzed the capacity of MSCs to modulate macrophages derived from monocytes from patients with STEMI. We analyzed the circulating levels of cytokines associated with M1 and M2 macrophages in patients with STEMI, and the levels of cytokines associated with M1 macrophages were significantly higher in patients with STEMI than in controls. BM-MSCs facilitate the generation of M1 and M2 macrophages. M1 macrophages cocultured with MSCs did not have decreased M1 marker expression, but these macrophages had an increased expression of markers of the M2 macrophage phenotype (CD14, CD163 and CD206) and IL-10 and IL-1Ra signaling-induced regulatory T cells (Tregs). M2 macrophages from patients with STEMI had an increased expression of M2 phenotypic markers in coculture with BM-MSCs, as well as an increased secretion of anti-inflammatory cytokines and an increased generation of Tregs. The findings in this study indicate that BM-MSCs have the ability to modulate the M1 macrophage response, which could improve cardiac tissue damage in patients with STEMI.


Asunto(s)
Células Madre Mesenquimatosas , Infarto del Miocardio con Elevación del ST , Humanos , Infarto del Miocardio con Elevación del ST/terapia , Infarto del Miocardio con Elevación del ST/metabolismo , Macrófagos/metabolismo , Citocinas/metabolismo , Fenotipo , Células Madre Mesenquimatosas/metabolismo
5.
Cytokine ; 158: 155977, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35933851

RESUMEN

Adenosine (ADO) generation in the tumor microenvironment (TME) plays important roles in the promotion of tumor growth, invasion, and metastasis and in suppression of the antitumor immune response. Recently, adenosine deaminase (ADA) activity in the TME has been proposed to be a compensatory mechanism against toxic accumulation of ADO in cancerous tissues. In the present study, the expression and functional activity of ADA in cervical cancer (CeCa) tumor cells were analyzed: C33A (HPV-), CaSki (HPV + ), and HeLa (HPV + ) cells. CeCa tumor cells, as well as activated T lymphocytes (ATLs), which were used as a positive control, showed different ADA contents in the membrane and intracellularly and a strong ability to convert ADO into inosine (INO). Treatment of tumor cells with EHNA, a specific ADA inhibitor, decreased the viability of CeCa tumor cells in a dose-dependent manner. In C33A (EHNA half maximal inhibitory concentration (IC50) = 374 µM), CaSki (EHNA IC50 = 273.6 µM), and HeLa (EHNA IC50 = 252.2 µM) cells, EHNA strongly reversed the resistance of tumor cells to the cytotoxic effect of high concentrations of ADO; 38.82 ± 3.1%, 47.18 ± 4.7%, and 71.63 ± 6.9% of the cells were apoptotic, and 40 ± 4.8%, 52 ± 5.3% and 70 ± 6.8% of the cells had mitochondrial membrane damage, respectively. In ATLs (EHNA IC50 = 391.8 µM) treated with EHNA, 32.4 ± 4.4% were apoptotic, and 32 ± 4.3% had mitochondrial membrane damage. These results suggest that the presence and activity of ADA in CeCa tumor cells can provide protection against the cytotoxic effect of high ADO contents in the TME. Therefore, the inhibition of ADA could be a strategy for the treatment of CeCa.


Asunto(s)
Antineoplásicos , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Adenina/farmacología , Adenosina/metabolismo , Adenosina/farmacología , Adenosina Desaminasa/metabolismo , Femenino , Humanos , Microambiente Tumoral , Neoplasias del Cuello Uterino/tratamiento farmacológico
6.
Cell Biochem Funct ; 40(7): 760-772, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36070413

RESUMEN

Recently, a link between the biological activity of CD73 and tumorigenicity in solid tumors has been proposed. We previously reported that the generation of adenosine (Ado) by the activity of CD73 in cervical cancer (CC) cells induces transforming growth factor-beta 1 (TGF-ß1) production to maintain CD73 expression. In the present study, we analyzed the participation of TGF-ß1 in CD73 expression and the development of protumoral characteristics in CaSki CC cells cultured as tumorspheres (CaSki-T) and in monolayers (CaSki-M). Compared with those in CaSki-M cells, CD73 expression and Ado generation ability were significantly increased in CaSki-T cells. CaSki-T cells exhibited enrichment in the CSC-like phenotype due to increases in the expression levels of stem cell markers (CD49f, CK17, and P63; OCT4 and SOX2), greater sphere formation efficiency (SFE), and an increase in the percentage of side population (SP) cells. Interestingly, compared with CaSki-M cells, CaSki-T cells produced a greater amount of TGF-ß1 and presented a marked protumor phenotype characterized by a significant decrease in the expression of major histocompatibility complex class-I (MHC-I) molecules, an increase in the expression of multidrug resistance protein-I (MRP-I) and vimentin, and an increase in the protein expression levels of Snail-1 and Twist, which was strongly reversed with TGF-ß1 inhibition. These results suggest that the presence of TGF-ß1-CD73-Ado feedback loop can promote protumoral characteristics in the CC tumor microenvironment.


Asunto(s)
Neoplasias del Cuello Uterino , 5'-Nucleotidasa/metabolismo , Adenosina/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Integrina alfa6 , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Crecimiento Transformadores , Microambiente Tumoral , Neoplasias del Cuello Uterino/patología , Vimentina
7.
Cancer Control ; 28: 10732748211038735, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34565215

RESUMEN

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.


Asunto(s)
Investigación Biomédica/organización & administración , Oncología Médica/organización & administración , Neoplasias/fisiopatología , Neoplasias/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Epigénesis Genética , Genómica , Accesibilidad a los Servicios de Salud , Humanos , Invasividad Neoplásica/fisiopatología , Neoplasias/epidemiología , Neoplasias/genética , Células Madre Neoplásicas/fisiología
8.
Cytokine ; 130: 155082, 2020 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-32259773

RESUMEN

Cervical cancer (CeCa) produces large amounts of IL-10, which downregulates the major histocompatibility complex class I molecules (HLA-I) in cancer cells and inhibits the immune response mediated by cytotoxic T lymphocytes (CTLs). In this study, we analyzed the ability of CeCa cells to produce IL-10 through the CD73-adenosine pathway and its effect on the downregulation of HLA-I molecules to evade CTL-mediated immune recognition. CeCa cells cultured in the presence of ≥10 µM AMP or adenosine produced 4.5-6 times as much IL-10 as unstimulated cells. The silencing of CD73 or the blocking of A2BR with the specific antagonist MRS1754 reversed this effect. In addition, IL-10 decreased the expression of HLA-I molecules, resulting in the protection of CeCa cells against the cytotoxic activity of CTLs. The addition of MRS1754 or anti-IL-10 reversed the decrease in HLA-I molecules and favored the cytotoxic activity of CTLs. These results strongly suggest the presence of a feedback loop encompassing the adenosinergic pathway, the production of IL-10, and the downregulation of HLA-I molecules in CeCa cells that favors immune evasion and thus tumor progression. This pathway may have clinical importance as a therapeutic target.

9.
Mediators Inflamm ; 2020: 1678780, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33488292

RESUMEN

Persistent infection with high-risk human papillomavirus (HR-HPV) is the main factor in the development of cervical cancer (CC). The presence of immunosuppressive factors plays an important role in the development of this type of cancer. To determine whether CD39 and CD73, which participate in the production of immunosuppressive adenosine (Ado), are involved in the progression of CC, we compared the concentrations and hydrolytic activity of these ectonucleotidases in platelet-free plasma (PFP) samples between patients with low-grade squamous intraepithelial lesions (LSILs) (n = 18), high-grade squamous intraepithelial lesions (HSILs) (n = 12), and CC (n = 19) and normal donors (NDs) (n = 15). The concentrations of CD39 and CD73 in PFP increased with disease progression (r = 0.5929, p < 0.001). The PFP of patients with HSILs or CC showed the highest concentrations of CD39 (2.3 and 2.2 times that of the NDs, respectively) and CD73 (1.7 and 2.68 times that of the NDs, respectively), which were associated with a high capacity to generate Ado from the hydrolysis of adenosine diphosphate (ADP) and adenosine monophosphate (AMP). The addition of POM-1 and APCP, specific inhibitors of CD39 and CD73, respectively, inhibited the ADPase and AMPase activity of PFP by more than 90%. A high level of the 90 kD isoform of CD73 was detected in the PFP of patients with HSILs or CC. Digestion with endoglycosidase H and N-glycanase generated CD73 with weights of approximately 90 kD, 85 kD, 80 kD, and 70 kD. In addition, the levels of transforming grow factor-ß (TGF-ß) in the PFPs of patients with LSIL, HSIL and CC positively correlated with those of CD39 (r = 0.4432, p < 0.001) and CD73 (r = 0.5786, p < 0.001). These results suggest that persistent infection by HR-HPV and the concomitant production of TGF-ß promote the expression of CD39 and CD73 to favor CC progression through Ado generation.


Asunto(s)
5'-Nucleotidasa/metabolismo , Antígenos CD/metabolismo , Apirasa/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Adenosina Difosfato/metabolismo , Adenosina Monofosfato/metabolismo , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos
10.
Rev Med Chil ; 148(8): 1155-1170, 2020 Aug.
Artículo en Español | MEDLINE | ID: mdl-33399782

RESUMEN

Biological medications are effective for the treatment of cancer and inflammatory diseases. The aim of this review is to summarize the available evidence in systematic reviews or meta-analyses about the risk of infection in patients with cancer, arthritis, psoriasis and inflammatory bowel disease who use biological medications. We included systematic reviews or meta-analyses of controlled clinical trials and case/control studies that analyze infections during and after treatment with FDA-approved biological medications for the treatment of cancer, arthritis, inflammatory bowel disease and psoriasis, both in adults and children. The following databases were consulted: PubMed, Epistemonikos, Crochrane reviews, JIB, and Prospero. A quality guideline (AMSTAR) was applied to the selected studies. We included 26 studies. The risk of infections in patients with solid organ cancer is consistent in the literature. In psoriasis there is a risk of non-serious infections. In arthritis and other inflammatory diseases there is a risk of serious infections. In inflammatory bowel disease there is a risk for opportunistic infections. In conclusion, in patients with cancer and inflammatory diseases use biological medications entails a risk of infection. The evidence is different depending on the underlying disease of each patient.


Asunto(s)
Terapia Biológica , Infecciones , Enfermedades Inflamatorias del Intestino , Neoplasias , Psoriasis , Adulto , Terapia Biológica/efectos adversos , Estudios de Casos y Controles , Niño , Humanos , Infecciones/inducido químicamente , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Metaanálisis como Asunto , Neoplasias/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Riesgo , Revisiones Sistemáticas como Asunto
11.
Neurochem Res ; 42(2): 415-427, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27804011

RESUMEN

Neural progenitors (NP), found in fetal and adult brain, differentiate into neurons potentially able to be used in cell replacement therapies. This approach however, raises technical and ethical problems which limit their potential therapeutic use. Alternately, NPs can be obtained by transdifferentiation of non-neural somatic cells evading these difficulties. Human bone marrow mesenchymal stromal cells (MSCs) are suggested to transdifferentiate into NP-like cells, which however, have a low proliferation capacity. The present study demonstrates the requisite of cell adhesion for proliferation and survival of NP-like cells and re-evaluates some neuronal features after differentiation by standard procedures. Mature neuronal markers, though, were not detected by these procedures. A chemical differentiation approach was used in this study to convert MSCs-derived NP-like cells into neurons by using a cocktail of six molecules, CHIR99021, I-BET151, RepSox, DbcAMP, forskolin and Y-27632, defined after screening combinations of 22 small molecules. Direct transdifferentiation of MSCs into neuronal cells was obtained with the small molecule cocktail, without requiring the NP-like intermediate stage.


Asunto(s)
Proliferación Celular/fisiología , Transdiferenciación Celular/fisiología , Células Madre Mesenquimatosas/fisiología , Células-Madre Neurales/fisiología , Neuronas/fisiología , Adolescente , Adulto , Amidas/administración & dosificación , Proliferación Celular/efectos de los fármacos , Transdiferenciación Celular/efectos de los fármacos , Células Cultivadas , Colforsina/administración & dosificación , Combinación de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Neuronas/efectos de los fármacos , Piridinas/administración & dosificación , Adulto Joven
13.
J Transl Med ; 14(1): 302, 2016 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-27782859

RESUMEN

BACKGROUND: In recent years, immunomodulatory mechanisms of mesenchymal stem/stromal cells (MSCs) from bone marrow and other "classic" sources have been described. However, the phenotypic and functional properties of tumor MSCs are poorly understood. The aim of this study was to analyze the immunosuppressive capacity of cervical cancer-derived MSCs (CeCa-MSCs) on effector T lymphocytes through the purinergic pathway. METHODS: We determined the expression and functional activity of the membrane-associated ectonucleotidases CD39 and CD73 on CeCa-MSCs and normal cervical tissue-derived MSCs (NCx-MSCs). We also analyzed their immunosuppressive capacity to decrease proliferation, activation and effector cytotoxic T (CD8+) lymphocyte function through the generation of adenosine (Ado). RESULTS: We detected that CeCa-MSCs express higher levels of CD39 and CD73 ectonucleotidases in cell membranes compared to NCx-MSCs, and that this feature was associated with the ability to strongly suppress the proliferation, activation and effector functions of cytotoxic T-cells through the generation of large amounts of Ado from the hydrolysis of ATP, ADP and AMP nucleotides. CONCLUSIONS: This study suggests that CeCa-MSCs play an important role in the suppression of the anti-tumor immune response in CeCa through the purinergic pathway.


Asunto(s)
Adenosina/farmacología , Células Madre Mesenquimatosas/patología , Linfocitos T Citotóxicos/inmunología , Neoplasias del Cuello Uterino/patología , Antígenos CD/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Femenino , Humanos , Hidrólisis , Inmunofenotipificación , Activación de Linfocitos/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos
15.
J Clin Endocrinol Metab ; 109(11): 2943-2955, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-38589986

RESUMEN

CONTEXT: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSCs) and immune cells, among others. MSC have been isolated from different tumors and they favor tumor cell growth; however, their role in pituitary tumors (PTs) remains unknown. OBJECTIVE: Herein we report the presence of MSCs in 2 adrenocorticotropin (ACTH)-secreting PTs causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF), and 2 nontumoral pituitary glands (MS). METHODS: We have analyzed the transcriptomic profiles by RNA sequencing and compared MSCs in terms of their immunosuppressive effects against lymphoid T-cell and macrophage populations by means of cocultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSCs derived from nontumoral pituitaries and MSCs derived from PTs. Two distinct subpopulations of MSC emerged: one displaying immunosuppressive properties and the other with increased proproliferative capabilities, regardless of their origin. MSCs derived from ACTH- and nonfunctioning PTs, but not those derived from nontumoral glands, significantly inhibited the proliferation of activated T cells, favored the generation of regulatory T cells, and promoted M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony-stimulating factor (M-CSF) and interleukin-10. Importantly, MSC derived from ACTH-PTs showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least 2 MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSCs may have important implications in PT growth.


Asunto(s)
Células Madre Mesenquimatosas , Neoplasias Hipofisarias , Microambiente Tumoral , Humanos , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Microambiente Tumoral/inmunología , Neoplasias Hipofisarias/inmunología , Neoplasias Hipofisarias/patología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Adenoma/patología , Adenoma/inmunología , Adenoma/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/inmunología , Hipófisis/inmunología , Hipófisis/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo
16.
World J Gastrointest Oncol ; 16(5): 1705-1724, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38764833

RESUMEN

Colorectal cancer (CRC) remains one of the most commonly diagnosed and deadliest types of cancer worldwide. CRC displays a desmoplastic reaction (DR) that has been inversely associated with poor prognosis; less DR is associated with a better prognosis. This reaction generates excessive connective tissue, in which cancer-associated fibroblasts (CAFs) are critical cells that form a part of the tumor microenvironment. CAFs are directly involved in tumorigenesis through different mechanisms. However, their role in immunosuppression in CRC is not well understood, and the precise role of signal transducers and activators of transcription (STATs) in mediating CAF activity in CRC remains unclear. Among the myriad chemical and biological factors that affect CAFs, different cytokines mediate their function by activating STAT signaling pathways. Thus, the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors. Here, we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

17.
Bioengineering (Basel) ; 10(5)2023 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-37237641

RESUMEN

Bone defects lead to the structural loss of normal architecture, and those in the field of bone tissue engineering are searching for new alternatives to aid bone regeneration. Dental pulp-mesenchymal stem cells (DP-MSC) could provide a promising alternative to repair bone defects, principally due to their multipotency and capacity to fabricate three-dimensional (3D) spheroids. The present study aimed to characterize the 3D DP-MSC microsphere and the osteogenic differentiation capacity potential cultured by a magnetic levitation system. To achieve this, the 3D DP-MSC microsphere was grown for 7, 14, and 21 days in an osteoinductive medium and compared to 3D human fetal osteoblast (hFOB) microspheres by examining the morphology, proliferation, osteogenesis, and colonization onto PLA fiber spun membrane. Our results showed good cell viability for both 3D microspheres with an average diameter of 350 µm. The osteogenesis examination of the 3D DP-MSC microsphere revealed the lineage commitment, such as the hFOB microsphere, as evidenced by ALP activity, the calcium content, and the expression of osteoblastic markers. Finally, the evaluation of the surface colonization exhibited similar patterns of cell-spreading over the fibrillar membrane. Our study demonstrated the feasibility of forming a 3D DP-MSC microsphere structure and the cell-behavior response as a strategy for the applications of bone tissue guiding.

18.
Cells ; 12(7)2023 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-37048119

RESUMEN

Macrophages with the M2 phenotype promote tumor development through the immunosuppression of antitumor immunity. We previously demonstrated the presence of mesenchymal stem/stromal cells (MSCs) in cervical cancer (CeCa-MSCs), suggesting an immune protective capacity in tumors, but to date, their effect in modulating macrophage polarization remains unknown. In this study, we compared the capacities of MSCs from normal cervix (NCx) and CeCa to promote M2 macrophage polarization in a coculture system. Our results demonstrated that CeCa-MSCs, in contrast to NCx-MSCs, significantly decreased M1 macrophage cell surface marker expression (HLA-DR, CD80, CD86) and increased M2 macrophage expression (CD14, CD163, CD206, Arg1) in cytokine-induced CD14+ monocytes toward M1- or M2-polarized macrophages. Interestingly, compared with NCx-MSCs, in M2 macrophages generated from CeCa-MSC cocultures, we observed an increase in the percentage of phagocytic cells, in the intracellular production of IL-10 and IDO, the capacity to decrease T cell proliferation and for the generation of CD4+CD25+FoxP3+ Tregs. Importantly, this capacity to promote M2 macrophage polarization was correlated with the intracellular expression of macrophage colony-stimulating factor (M-CSF) and upregulation of IL-10 in CeCa-MSCs. Furthermore, the presence of M2 macrophages was correlated with the increased production of IL-10 and IL-1RA anti-inflammatory molecules. Our in vitro results indicate that CeCa-MSCs, in contrast to NCx-MSCs, display an increased M2-macrophage polarization potential and suggest a role of CeCa-MSCs in antitumor immunity.


Asunto(s)
Interleucina-10 , Neoplasias del Cuello Uterino , Humanos , Femenino , Interleucina-10/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Macrófagos/metabolismo , Citocinas/metabolismo , Células del Estroma/metabolismo
19.
World J Stem Cells ; 15(7): 701-712, 2023 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-37545756

RESUMEN

BACKGROUND: Mesenchymal stromal cells (MSCs) are multipotent cell populations obtained from fetal and adult tissues. They share some characteristics with limb bud mesodermal cells such as differentiation potential into osteogenic, chondrogenic, and tenogenic lineages and an embryonic mesodermal origin. Although MSCs differentiate into skeletal-related lineages in vitro, they have not been shown to self-organize into complex skeletal structures or connective tissues, as in the limb. In this work, we demonstrate that the expression of molecular markers to commit MSCs to skeletal lineages is not sufficient to generate skeletal elements in vivo. AIM: To evaluate the potential of MSCs to differentiate into skeletal lineages and generate complex skeletal structures using the recombinant limb (RL) system. METHODS: We used the experimental system of RLs from dissociated-reaggregated human placenta (PL) and umbilical cord blood (UCB) MSCs. After being harvested and reaggregated in a pellet, cultured cells were introduced into an ectodermal cover obtained from an early chicken limb bud. Next, this filled ectoderm was grafted into the back of a donor chick embryo. Under these conditions, the cells received and responded to the ectoderm's embryonic signals in a spatiotemporal manner to differentiate and pattern into skeletal elements. Their response to differentiation and morphogenetic signals was evaluated by quantitative polymerase chain reaction, histology, immunofluorescence, scanning electron microscopy, and in situ hybridization. RESULTS: We found that human PL-MSCs and UCB-MSCs constituting the RLs expressed chondrogenic, osteogenic, and tenogenic molecular markers while differentially committing into limb lineages but could not generate complex structures in vivo. MSCs-RL from PL or UCB were committed early to chondrogenic lineage. Nevertheless, the UCB-RL osteogenic commitment was favored, although preferentially to a tenogenic cell fate. These findings suggest that the commitment of MSCs to differentiate into skeletal lineages differs according to the source and is independent of their capacity to generate skeletal elements or connective tissue in vivo. Our results suggest that the failure to form skeletal structures may be due to the intrinsic characteristics of MSCs. Thus, it is necessary to thoroughly evaluate the biological aspects of MSCs and how they respond to morphogenetic signals in an in vivo context. CONCLUSION: PL-MSCs and UCB-MSCs express molecular markers of differentiation into skeletal lineages, but they are not sufficient to generate complex skeletal structures in vivo.

20.
J Leukoc Biol ; 114(6): 672-683, 2023 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-37820030

RESUMEN

Neutrophils infiltrate several types of cancer; however, whether their presence is associated with disease progression remains controversial. Here, we show that colon tumors overexpress neutrophil chemoattractants compared to healthy tissues, leading to their recruitment to the invasive margin and the central part of colon tumors. Of note, tumor-associated neutrophils expressing tumor necrosis factor α, which usually represents an antitumoral phenotype, were predominantly located in the invasive margin. Tumor-associated neutrophils from the invasive margin displayed an antitumoral phenotype with higher ICAM-1 and CD95 expression than neutrophils from healthy adjacent tissues. A higher neutrophil/lymphocyte ratio was found at later stages compared to the early phases of colon cancer. A neutrophil/lymphocyte ratio ≤3.5 predicted tumor samples had significantly more neutrophils at the invasive margin and the central part. Moreover, tumor-associated neutrophils at the invasive margin of early-stage tumors showed higher ICAM-1 and CD95 expression. Coculture of colon cancer cell lines with primary neutrophils induced ICAM-1 and CD95 expression, confirming our in situ findings. Thus, our data demonstrate that tumor-associated neutrophils with an antitumoral phenotype characterized by high ICAM-1 and CD95 expression infiltrate the invasive margin of early-stage colon tumors, suggesting that these cells can combat the disease at its early courses. The presence of tumor-associated neutrophils with antitumoral phenotype could help predict outcomes of patients with colon cancer.


Asunto(s)
Neoplasias del Colon , Neutrófilos , Humanos , Neutrófilos/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Neoplasias del Colon/patología , Fenotipo
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