Efecto inmunosupresor y resistencia a apoptosis de la transferencia mitocondrial a linfocitos T de cordón umbilical
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2024
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Universidad Andrés Bello
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Resumen
El trasplante de células madre hematopoyéticas (HSC) ha demostrado ser efectivo en el tratamiento de diversas enfermedades hematológicas, incluidos ciertos tipos de cáncer y trastornos sanguíneos. Sin embargo, este procedimiento conlleva diferentes efectos adversos, como infecciones, injertos deficientes a largo plazo y el desarrollo de enfermedad de injerto contra huésped (EICH) aguda o crónica. En este contexto, las células madre mesenquimales derivadas del cordón umbilical (UC-MSC) emergen como una
herramienta valiosa con propiedades inmunosupresoras y regenerativas de tejidos, validadas en ensayos clínicos para el tratamiento de enfermedades inflamatorias o mediadas por el sistema inmunológico, incluida la EICH. Los linfocitos T reguladores (Treg) también se han identificado como cruciales en el control de la tolerancia y la autoinmunidad. Simultáneamente, la investigación sobre la transferencia mitocondrial (MitoT) entre diferentes tipos celulares ha revelado su capacidad para rescatar células con deficiencias mitocondriales. Un estudio previo evaluó el efecto de la MitoT de UC-MSC a linfocitos T naïve de sangre periférica, destacando la promoción de la diferenciación a Treg con capacidades supresoras en la proliferación de células mononucleares de sangre periférica (PBMC). Además, se observó un aumento significativo en la supervivencia de ratones con EICH inducida. Sin embargo, el impacto de la MitoT en los linfocitos T de la sangre de cordón aún es desconocido. Este trabajo tiene como objetivo evidenciar y evaluar el efecto de la MitoT en los linfocitos T de sangre de cordón y en los linfocitos T naïve aislados de la misma fuente, explorando su efecto inmunosupresor y resistencia a la apoptosis. Para abordar nuestra hipótesis, se aísla la población de células diferenciadas de sangre de cordón (CD34-) y se evalúa el efecto de la MitoT
en la resistencia a la apoptosis al desafiarlas con un inhibidor de proteína quinasa. Además, se aísla la población de linfocitos T naïve para evaluar el porcentaje de captación de mitocondrias, su capacidad de diferenciación en Treg y la capacidad de inhibir la proliferación de PBMC. Los resultados revelaron una MitoT dosis-dependiente en los linfocitos T naïve aislados, así como una tendencia en la resistencia a la apoptosis en los linfocitos T CD4 desafiados con un inhibidor de proteína quinasa. Por otro lado, los
linfocitos T naïve de la sangre de cordón, cultivados en un medio inductor/diferenciador para Treg, mostraron un menor porcentaje de inhibición de proliferación de PBMC en comparación con linfocitos T naïve de sangre periférica. Estos hallazgos contribuyen a nuestra comprensión de los efectos de la transferencia mitocondrial a los linfocitos de la sangre del cordón umbilical y sus diferencias funcionales en comparación con los linfocitos de la sangre periférica.
Hematopoietic stem cell (HSC) transplantation has proven effective in treating various hematological diseases, including certain types of cancer and blood disorders. However, this procedure poses different adverse effects, including infection, deficient long-term engraftment, and acute or chronic graft-versus-host disease (GVHD) development. In this context, umbilical cord-derived mesenchymal stem cells (UC-MSC) emerge as a valuable tool with immunosuppressive and tissue-regenerative properties validated in clinical trials for treating inflammatory or immune-mediated diseases, including GVHD. Regulatory T lymphocytes (Treg) have also been identified as crucial in controlling tolerance and autoimmunity. Simultaneously, research on mitochondrial transfer (MitoT) between different cell types has revealed its ability to rescue cells with mitochondrial deficiencies. A previous study evaluated the effect of MitoT from UC-MSC to naïve T lymphocytes from peripheral blood, highlighting the promotion of differentiation into Treg with suppressive capabilities in the proliferation of peripheral blood mononuclear cells (PBMC). Furthermore, a significant increase in the survival of mice with induced GVHD was observed. However, the impact of MitoT on cord blood T lymphocytes is still unknown. This work aims to evidence and evaluate the effect of MitoT on T lymphocytes from cord blood and naïve T lymphocytes isolated from the same source, exploring their immunosuppressive effect and resistance to apoptosis. To address our hypothesis, the population of differentiated cord blood cells (CD34-) is isolated, and the effect of MitoT on apoptosis resistance is evaluated by challenging them with a protein kinase inhibitor. Additionally, the population of naïve T lymphocytes is isolated to assess the percentage of mitochondria uptake, their differentiation capacity into Treg, and the ability to inhibit PBMC proliferation. The results revealed dose-dependent MitoT in isolated naïve T lymphocytes, as well as an increase in apoptosis resistance in CD4 T lymphocytes challenged with a protein kinase inhibitor. On the other hand, naïve T lymphocytes from cord blood, cultured in an inductive/differentiating medium for Treg, showed a lower percentage of PBMC proliferation inhibition compared to naïve T lymphocytes from peripheral blood. These findings contribute to our understanding of the effects of mitochondrial transfer to umbilical cord blood lymphocytes and their functional differences compared to peripheral blood lymphocytes.
Hematopoietic stem cell (HSC) transplantation has proven effective in treating various hematological diseases, including certain types of cancer and blood disorders. However, this procedure poses different adverse effects, including infection, deficient long-term engraftment, and acute or chronic graft-versus-host disease (GVHD) development. In this context, umbilical cord-derived mesenchymal stem cells (UC-MSC) emerge as a valuable tool with immunosuppressive and tissue-regenerative properties validated in clinical trials for treating inflammatory or immune-mediated diseases, including GVHD. Regulatory T lymphocytes (Treg) have also been identified as crucial in controlling tolerance and autoimmunity. Simultaneously, research on mitochondrial transfer (MitoT) between different cell types has revealed its ability to rescue cells with mitochondrial deficiencies. A previous study evaluated the effect of MitoT from UC-MSC to naïve T lymphocytes from peripheral blood, highlighting the promotion of differentiation into Treg with suppressive capabilities in the proliferation of peripheral blood mononuclear cells (PBMC). Furthermore, a significant increase in the survival of mice with induced GVHD was observed. However, the impact of MitoT on cord blood T lymphocytes is still unknown. This work aims to evidence and evaluate the effect of MitoT on T lymphocytes from cord blood and naïve T lymphocytes isolated from the same source, exploring their immunosuppressive effect and resistance to apoptosis. To address our hypothesis, the population of differentiated cord blood cells (CD34-) is isolated, and the effect of MitoT on apoptosis resistance is evaluated by challenging them with a protein kinase inhibitor. Additionally, the population of naïve T lymphocytes is isolated to assess the percentage of mitochondria uptake, their differentiation capacity into Treg, and the ability to inhibit PBMC proliferation. The results revealed dose-dependent MitoT in isolated naïve T lymphocytes, as well as an increase in apoptosis resistance in CD4 T lymphocytes challenged with a protein kinase inhibitor. On the other hand, naïve T lymphocytes from cord blood, cultured in an inductive/differentiating medium for Treg, showed a lower percentage of PBMC proliferation inhibition compared to naïve T lymphocytes from peripheral blood. These findings contribute to our understanding of the effects of mitochondrial transfer to umbilical cord blood lymphocytes and their functional differences compared to peripheral blood lymphocytes.
Notas
Memoria de Título (Ingeniero en Biotecnología)
Palabras clave
Células Madre, Inmunología, Trasplante de Células Madre Hematopoyéticas, Cordón Umbilical, Apoptosis.