The role of extracellular vesicles in cutaneous remodeling and hair follicle dynamics

Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are cell-derived membranous structures that were originally catalogued as a way of releasing cellular waste products. Since the discovery of their function in intercellular communication as carriers of proteins, lipids, and DNA and RNA molecules, numerous therapeutic approaches have focused on the use of EVs, in part because of their minimized risk compared to cell-based therapies. The skin is the organ with the largest surface in the body. Besides the importance of its body barrier function, much attention has been paid to the skin in regenerative medicine because of its cosmetic aspect, which is closely related to disorders affecting pigmentation and the presence or absence of hair follicles. The use of exosomes in therapeutic approaches for cutaneous wound healing has been reported and is briefly reviewed here. However, less attention has been paid to emerging interest in the potential capacity of EVs as modulators of hair follicle dynamics. Hair follicles are skin appendices that mainly comprise an epidermal and a mesenchymal component, with the former including a major reservoir of epithelial stem cells but also melanocytes and other cell types. Hair follicles continuously cycle, undergoing consecutive phases of resting, growing, and regression. Many biomolecules carried by EVs have been involved in the control of the hair follicle cycle and stem cell function. Thus, investigating the role of either naturally produced or therapeutically delivered EVs as signaling vehicles potentially involved in skin homeostasis and hair cycling may be an important step in the attempt to design future strategies towards the efficient treatment of several skin disordersThis research was funded by the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (CP 14/00219), Fondo Europeo de Desarrollo Regional (FEDER), H2020-EU.1.1.—European Research Council (ERC-2016-StG 715322-EndoMitTalk), and Instituto de Salud Carlos III (FIS16/188). E.C. was supported by the Atracción de Talento Investigador grant 2017-T2/BMD-5766 (Comunidad de Madrid and Universidad Autónoma de Madrid). G.S.-H. was funded by an FPI grant (Universidad Autónoma de Madrid). M.M. was supported by the Miguel Servet program (Instituto de Investigación del Hospital 12 de Octubre

T cells with dysfunctional mitochondria induce multimorbidity and premature senescence

The effect of immunometabolism on age-associated diseases remains uncertain. In this work, we show that T cells with dysfunctional mitochondria owing to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles the chronic inflammation that is characteristic of aging (“inflammaging”). This cytokine storm itself acts as a systemic inducer of senescence. Blocking tumor necrosis factor-a signaling or preventing senescence with nicotinamide adenine dinucleotide precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and life span, which highlights the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.This study was supported by the Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/02188 and PI19/00855; and PI16/02110 to B.I.), the European Regional Development Fund (ERDF), and the European Commission through H2020-EU.1.1 and European Research Council grant ERC-2016-StG 715322-EndoMitTalk. This work was partially supported by Comunidad de Madrid (S2017/BMD-3867 RENIM-CM). M.M. is supported by the Miguel Servet Program (CPII 19/00014). G.S.-H. is supported by FPI-UAM, J.O. (FJCI-2017-33855) and E.G.-R. (IJC2018-036850) by Juan de la Cierva, and E.C. by Atracción de Talento Investigador 2017-T2/BMD-5766 (Comunidad de Madrid and UAM). B.I. was supported by ERC research grant ERC-2018-CoG 819775-MATRIX

Caracterización de los linfocitos T asociados a la edad y su contribución al envejecimiento

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 09-02-2024Esta tesis tiene embargado el acceso al texto completo hasta el 09-08-2025El deterioro del sistema inmune que se produce con el envejecimiento se conoce como inmunosenescencia y reduce la capacidad de desarrollar respuestas inmunes específicas frente a amenazas externas, como virus o bacterias, y frente a amenazas internas, como el cáncer. En esta tesis hemos investigado los cambios moleculares que ocurren en los linfocitos T durante el envejecimiento. Dado que se ha descrito en muchos tipos celulares que ocurre un declive de la función mitocondrial durante el envejecimiento, en primer lugar, hemos investigado y confirmado que este deterioro mitocondrial asociado a la edad ocurre también en los linfocitos T CD4+. A continuación, hemos estudiado las consecuencias que tiene este declive mitocondrial en el envejecimiento de las células T. Para ello, hemos utilizado un modelo genético con una disfunción mitocondrial únicamente en los linfocitos T y hemos observado que esta deficiencia mitocondrial precipita la aparición de las marcas de envejecimiento del sistema inmune adaptativo. Sin embargo, el envejecimiento no afecta por igual a todos los linfocitos T, por lo que hemos desarrollado una nueva herramienta que permite distinguir mediante citometría de flujo espectral las distintas subpoblaciones de linfocitos T CD4+ asociados al envejecimiento y evaluar simultáneamente en todas ellas si existen indicios de disfunción mitocondrial. Con esta herramienta, hemos identificado dos subpoblaciones de linfocitos T CD4+ asociados a la edad que presentan este declive mitocondrial de forma más acusada. Por un lado, hemos identificado una subpoblación de linfocitos T CD4+ reguladores que expresan el marcador KLRG1, se acumulan en tejidos periféricos con la edad y presentan mayor disfunción mitocondrial y otras marcas de senescencia celular que las demás subpoblaciones. Estos linfocitos T reguladores KLRG1+ también adquieren un fenotipo frágil, caracterizado por la co-expresión de moléculas pro y antinflamatorias. Por otro lado, hemos identificado una subpoblación de células T CD4+ asociadas al envejecimiento caracterizadas por un fenotipo citotóxico con una alta expresión de la quimioquina CCL5 y que también presentan disfunción mitocondrial. Estas células T CD4+ citotóxicas migran preferencialmente a la médula ósea durante el envejecimiento y allí inducen de forma específica la mielopoyesis, favoreciendo una producción excesiva de neutrófilos que puede contribuir al deterioro de los tejidos durante el envejecimiento. En conjunto, nuestros datos apoyan que los linfocitos T también sufren un deterioro mitocondrial durante el envejecimiento, y esta disfunción mitocondrial tiene amplias consecuencias en los linfocitos T, en la función del sistema inmune y en el envejecimiento de todo el organismoEsta investigación ha estado financiada por los proyectos FIS (PI19/855 y PI16/188, Instituto de Salud Carlos III), ERC-StG (715322 EndoMitTalk, European Research Council), Synergy Grant (Y2020/BIO-6350 NutriSION, Comunidad de Madrid) y ERC-CoG (101044248 LetTBe, European Research Council

Interorganelle Communication between Mitochondria and the Endolysosomal System

The function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct physical contacts between mitochondria and the endolysosomal compartment have been reported as a rapid means of interorganelle communication, mediating lipid or other metabolite exchange. Moreover, mitochondrial derived vesicles can traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation or secretion to the extracellular milieu as exosomes, representing an additional mitochondrial quality control mechanism that connects mitochondria and lysosomes independently of autophagosome formation. Here, we present what is currently known about the functional and physical communication between mitochondria and lysosomes or lysosome-related organelles, and their role in sustaining cellular homeostasis.Fondo de Investigación Sanitaria del Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the European Research Council (ERC-2016-StG 715322-EndoMitTalk) and the Instituto de Salud Carlos III (FIS16/188)Peer Reviewe

Mitochondrial dysfunction defines T cell exhaustion

When T cells are exposed to continuous antigen stimulation, they become exhausted. Here, we preview findings from Scharping et al., who have illuminated the molecular mechanism by which the persistent antigen stimulation and severe hypoxic conditions in the intratumoral environment drive T cell exhaustion, losing their cytotoxic function and anticancer effects.When T cells are exposed to continuous antigen stimulation, they become exhausted. Here, we preview findings from Scharping et al. (2021), who have illuminated the molecular mechanism by which the persistent antigen stimulation and severe hypoxic conditions in the intratumoral environment drive T cell exhaustion, losing their cytotoxic function and anticancer effects.Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/188 and PI19/855) and the European Research Council grant ERC-2016-StG 715322-EndoMitTalk. M.M. is supported by the Miguel Servet Program (CP 19/014, Fundación de Investigación del Hospital 12 de Octubre). G.S.-H. is supported by FPI-UAM (Universidad Autónoma de Madrid

Interorganelle Communication between Mitochondria and the Endolysosomal System

The function of mitochondria and lysosomes has classically been studied separately. However, evidence has now emerged of intense crosstalk between these two organelles, such that the activity or stress status of one organelle may affect the other. Direct physical contacts between mitochondria and the endolysosomal compartment have been reported as a rapid means of interorganelle communication, mediating lipid or other metabolite exchange. Moreover, mitochondrial derived vesicles can traffic obsolete mitochondrial proteins into the endolysosomal system for their degradation or secretion to the extracellular milieu as exosomes, representing an additional mitochondrial quality control mechanism that connects mitochondria and lysosomes independently of autophagosome formation. Here, we present what is currently known about the functional and physical communication between mitochondria and lysosomes or lysosome-related organelles, and their role in sustaining cellular homeostasis

Extremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging

There is a dramatic remodeling of the T cell compartment during aging. The most notorious changes are the reduction of the naive T cell pool and the accumulation of memory-like T cells. Memory-like T cells in older people acquire a phenotype of terminally differentiated cells, lose the expression of costimulatory molecules, and acquire properties of senescent cells. In this review, we focus on the different subsets of age-associated T cells that accumulate during aging. These subsets include extremely cytotoxic T cells with natural killer properties, exhausted T cells with altered cytokine production, and regulatory T cells that gain proinflammatory features. Importantly, all of these subsets lose their lymph node homing capacity and migrate preferentially to nonlymphoid tissues, where they contribute to tissue deterioration and inflammaging.This study was supported by the Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI19/855), the European Regional Development Fund (ERDF) and the European Commission through H2020-EU.1.1, European Research Council grant ERC-2016-StG 715322-EndoMitTalk, and the Y2020/BIO-6350 NutriSION-CM synergy grant from Comunidad de Madrid. G.S.-H. is supported by an FPI-UAM grant (Universidad Autónoma de Madrid). M.M.G.H. and J.I.E.-L. are supported by FPU grants (FPU19/02576 and FPU20/04066, respectively), both from Ministerio de Ciencia, Innovación y Universidades (Spain

Glycolysis – a key player in the inflammatory response

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.European Research Council (ERC-2016-StG 715322-EndoMitTalk), and Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), Fondo Europeo de Desarrollo Regional (FEDER). GS-H was funded by a FPIUAM grant (Universidad Autonoma de Madrid). MMGH was funded by ERC. EG-R was funded by a Juan de la Cierva grant (IJC2018-036850-I; Universidad Autónoma de Madrid). JO was funded by a Juan de la Cierva grant (FJCI-2017-33855; Universidad Autónoma de Madrid)

Glycolysis – a key player in the inflammatory response

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.European Research Council (ERC-2016-StG 715322-EndoMitTalk), and Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), Fondo Europeo de Desarrollo Regional (FEDER). GS-H was funded by a FPIUAM grant (Universidad Autonoma de Madrid). MMGH was funded by ERC. EG-R was funded by a Juan de la Cierva grant (IJC2018-036850-I; Universidad Autónoma de Madrid). JO was funded by a Juan de la Cierva grant (FJCI-2017-33855; Universidad Autónoma de Madrid)