A Mystery Unraveled: Non-tumorigenic pluripotent stem cells in human adult tissues

Embryonic stem cells and induced pluripotent stem cells have emerged as the gold standard of pluripotent stem cells and the class of 10 stem cell with the highest potential for contribution to regenerative and therapeutic application; however, their translational use is often impeded by teratoma formation, commonly associated with pluripotency. We discuss a population of nontumorigenic pluripotent stem cells, termed Multilineage Differentiating Stress Enduring (Muse) cells, which offer an innovative and 15 exciting avenue of exploration for the potential treatment of various human diseases. Areas covered: This review discusses the origin of Muse cells, describes in detail their various unique characteristics, and considers future avenues of their application and investigation with respect to what is currently known 20 of adult pluripotent stem cells in scientific literature. We begin by defining cell potency, then discussing both mesenchymal and various reported populations of pluripotent stem cells, and finally, delving into Muse cells and what sets them apart from their contemporaries. Expert opinion: Muse cells derived from adipose tissue (Muse-AT) are 25 efficiently, routinely and painlessly isolated from human lipoaspirate material, exhibit tripoblastic differentiation both spontaneously and under media-specific induction, and do not form teratomas. We describe qualities specific to Muse-ATcells and their potential impact on the field of regenerative medicine and cell therapy.Fil: Simerman, Ariel A.. University of California; Estados UnidosFil: Perone, Marcelo Javier. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires; ArgentinaFil: Gimeno, Maria Laura. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires; ArgentinaFil: Dumesic, Daniel A.. University of California; Estados UnidosFil: Chazenblak, Gregorio D.. University of California; Estados Unido

Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has antiinflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-c and an increase in IL-5 production, respectively. Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, fo

Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes

It is well established that there is a fine-tuned bidirectional communication between the immune and neuroendocrine tissues in maintaining homeostasis. Several types of immune cells, hormones, and neurotransmitters of different chemical nature are involved as communicators between organs. Apart of being key players of the adaptive arm of the immune system, it has been recently described that T lymphocytes are involved in the modulation of metabolism of several tissues in health and disease. Diabetes may result mainly from lack of insulin production (type 1 diabetes) or insufficient insulin and insulin resistance (type 2 diabetes), both influenced by genetic and environmental components. Herein, we discuss accumulating data regarding the role of the adaptive arm of the immune system in the pathogenesis of diabetes; including the action of several hormones and neurotransmitters influencing on central and peripheral T lymphocytes development and maturation, particularly under the metabolic burden triggered by diabetes. In addition, we comment on the role of T-effector lymphocytes in adipose and liver tissues during diabetes, which together enhances pancreatic β-cell stress aggravating the disease

Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas

Curcumin (diferuloylmethane), a polyphenolic compound derived from the spice plant Curcuma longa, displays multiple actions on solid tumours including anti-angiogenic effects. Here we have studied in rodent and human pituitary tumour cells the influence of curcumin on the production of hypoxia inducible factor 1α (HIF1A) and vascular endothelial growth factor A (VEGFA), two key components involved in tumour neovascularisation through angiogenesis. Curcumin dose-dependently inhibited basal VEGFA secretion in corticotroph AtT20 mouse and lactosomatotroph GH3 rat pituitary tumour cells as well as in all human pituitary adenoma cell cultures (nZ32) studied. Under hypoxia-mimicking conditions (CoCl2 treatment) in AtT20 and GH3 cells as well as in all human pituitary adenoma cell cultures (nZ8) studied, curcumin strongly suppressed the induction of mRNA synthesis and protein production of HIF1A, the regulated subunit of the hypoxia-induced transcription factor HIF1. Curcumin also blocked hypoxiainducedmRNAsynthesis and secretion ofVEGFAinGH3 cells and in all human pituitary adenoma cell cultures investigated (nZ18). Thus, curcumin may inhibit pituitary adenoma progression not only through previously demonstrated antiproliferative and pro-apoptotic actions but also by its suppressive effects on pituitary tumour neovascularisation.Fil: Shan, B.. Max Planck Institute of Psychiatry; AlemaniaFil: Schaaf, C.. Max Planck Institute of Psychiatry; AlemaniaFil: Schmidt, A.. Max Planck Institute of Psychiatry; AlemaniaFil: Lucia, K.. Max Planck Institute of Psychiatry; AlemaniaFil: Buchfelder, M.. Universitat Erlangen-Nuremberg; AlemaniaFil: Losa, M.. Istituto San Raffael; ItaliaFil: Kuhlen, D.. Universitat Technical Zu Munich; AlemaniaFil: Kreutzer, J.. Universitat Technical Zu Munich; AlemaniaFil: Perone, Marcelo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; ArgentinaFil: Arzt, Eduardo Simon. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; ArgentinaFil: Stalla, G.K.. Max Planck Institute of Psychiatry; AlemaniaFil: Renner, U.. Max Planck Institute of Psychiatry; Alemani

Dendritic Cells Expressing Transgenic Galectin-1 Delay Onset of Autoimmune Diabetes in Mice

Type 1 diabetes (T1D) is a disease caused by the destruction of the β cells of the pancreas by activated T cells. Dendritic cells (BC) are the APC that initiate the T cell response that triggers T1D. However, DC also participate in T cell tolerance, and genetic engineering of DC to modulate T cell immunity is an area of active research. Galectin-1 (gal-1) is an endogenous lectin with regulatory effects on activated T cells including induction of apoptosis and down-regulation of the Th1 response, characteristics that make gal-1 an ideal transgene to transduce DC to treat T1D. We engineered bone marrow-derived DC to synthesize transgenic gal-1 (gal-1-DC) and tested their potential to prevent T1D through their regulatory effects on activated T cells. NOD-derived gal-1-DC triggered rapid apoptosis of diabetogenic BDC2.5 TCR-transgenic CD4+ T cells by TCR-dependent and -independent mechanisms. Intravenously administered gal-1-DC trafficked to pancreatic lymph nodes and spleen and delayed onset of diabetes and insulitis in the NODrag1 -/- lymphocyte adoptive transfer model. The therapeutic effect of gal-1-DC was accompanied by increased percentage of apoptotic T cells and reduced number of IFN-γ-secreting CD4+ T cells in pancreatic lymph nodes. Treatment with gal-1-DC inhibited proliferation and secretion of IFN-γ of T cells in response to β cell Ag. Unlike other DC-based approaches to modulate T cell immunity, the use of the regulatory properties of gal-1-DC on activated T cells might help to delete β cell-reactive T cells at early stages of the disease when the diabetogenic T cells are already activated. Copyright © 2005 by The American Association of Immunologists, Inc

Diabetes autoinmune latente del adulto: LADA

La naturaleza autoinmune de la lesión beta en la diabetes tipo 1 fue demostrada inicialmente por los hallazgos de anticuerpos antiislote (ICA) en pacientes insulinodependientes con deficiencia poliendocrina, por Bottazo y cols. (1974). En publicaciones posteriores, Irvine y cols. (1977) demuestran en pacientes con diabetes tipo 2 (DM2), que el 10% presentaba anticuerpos ICA positivos, fracaso secundario a sulfonilureas y requerimiento de insulina más precoz versus aquellos pacientes con DM2 y anticuerpos negativos. En el año 1986, Groop y cols. detectaron otras características en pacientes con DM2 y anticuerpos positivos al diagnóstico, como función beta preservada y cuadro clínico diferente de la diabetes tipo 1 autoinmune (DM1A) y DM2 con anticuerpos negativos. El descubrimiento por numerosos investigadores de la enzima decarboxilasa del ácido glutámico como autoantígeno de la célula beta determinó que el dosaje de anticuerpos anti-GAD (GADA) por radioinmunoanálisis (RIA) podía reemplazar, con algunas ventajas, a la técnica de la determinación de los ICA por inmunofluorescencia indirecta (IFI) (Rowley y cols., 1992; Hagopian y cols., 1993). En la década de los 90, tanto Tuomi y cols. (Tuomi y cols., 1993) como Zimmet y cols. (Zimmet y cols., 1994) utilizaron la sigla LADA (diabetes autoinmune latente del adulto) para denominar a esta forma de diabetes autoinmune lentamente progresiva que podía inicialmente ser manejada con agentes hipoglucemiantes orales antes de requerir insulina.Fil: Taverna, Mariano Javier. Sociedad Argentina de Diabetes. Comité de Genética, Inmunología y Prevención de la Diabetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Frechtel, G.. Sociedad Argentina de Diabetes. Comité de Genética, Inmunología y Prevención de la Diabetes; ArgentinaFil: Poskus, Edgardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Sociedad Argentina de Diabetes. Comité de Genética, Inmunología y Prevención de la Diabetes; ArgentinaFil: Perone, Marcelo Javier. Sociedad Argentina de Diabetes. Comité de Genética, Inmunología y Prevención de la Diabetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Matejic, A.. Sociedad Argentina de Diabetes. Comité de Genética, Inmunología y Prevención de la Diabetes; ArgentinaFil: Trifone, L.. Sociedad Argentina de Diabetes. Comité de Genética, Inmunología y Prevención de la Diabetes; ArgentinaFil: Gonzalez, J.. Sociedad Argentina de Diabetes. Comité de Genética, Inmunología y Prevención de la Diabetes; ArgentinaFil: Alonso Amorin, M. A.. Sociedad Argentina de Diabetes. Comité de Genética, Inmunología y Prevención de la Diabetes; Argentin

Primera Red Sudamericana de Biomedicina: Investigación, educación y biotecnología aplicadas a la salud

Se da a conocer la creación del primer programa de integración regional de una red de Institutos de Investigación en Biomedicina pertenecientes a países miembros del MERCOSUR. Se analizan las bases que dieron sustento a su creación y sus objetivos en el mediano y largo plazo. Además, se estima el potencial de los resultados de este programa en los campos de la investigación médica aplicada, educación y biotecnología

Pluripotent nontumorigenic multilineage differentiating stress enduring cells (Muse cells): a seven-year retrospective

Abstract Multilineage differentiating stress enduring (Muse) cells, discovered in the spring of 2010 at Tohoku University in Sendai, Japan, were quickly recognized by scientists as a possible source of pluripotent cells naturally present within mesenchymal tissues. Muse cells normally exist in a quiescent state, singularly activated by severe cellular stress in vitro and in vivo. Muse cells have the capacity for self-renewal while maintaining pluripotent cell characteristics indicated by the expression of pluripotent stem cell markers. Muse cells differentiate into cells representative of all three germ cell layers both spontaneously and under media-specific induction. In contrast to embryonic stem and induced pluripotent stem cells, Muse cells exhibit low telomerase activity, a normal karyotype, and do not undergo tumorigenesis once implanted in SCID mice. Muse cells efficiently home into damaged tissues and differentiate into specific cells leading to tissue regeneration and functional recovery as described in different animal disease models (i.e., fulminant hepatitis, muscle degeneration, skin ulcers, liver cirrhosis, cerebral stroke, vitiligo, and focal segmental glomerulosclerosis). Circulating Muse cells have been detected in peripheral blood, with higher levels present in stroke patients during the acute phase. Furthermore, Muse cells have inherent immunomodulatory properties, which could contribute to tissue generation and functional repair in vivo. Genetic studies in Muse cells indicate a highly conserved cellular mechanism as seen in more primitive organisms (yeast, Saccharomyces cerevisiae, Caenorhabditis elegans, chlamydomonas, Torpedo californica, drosophila, etc.) in response to cellular stress and acute injury. This review details the molecular and cellular properties of Muse cells as well as their capacity for tissue repair and functional recovery, highlighting their potential for clinical application in regenerative medicine