Biomedical research in Spain: the patient's point of view

Hi ha un desfasament clar entre el lloc que l'Estat espanyol ocupa a Europa des del punt de vista econòmic i el lloc que ocupa en recerca, en general, i en biomedicina, en particular. La biomedicina serà, sense cap mena de dubte, la ciència principal que protagonitzarà els canvis i avenços del segle xxi. Per això és essencial que el resultat del coneixement arribi a la pràctica clínica i es converteixi en teràpies efectives. Per a aconseguir que aquest desfasament desaparegui, el govern espanyol ha elaborat una sèrie d'iniciatives que promouen el desenvolupament i la recerca biomèdica, i que inclouen accions conjuntes entre les institucions, les universitats, les empreses i la resta de la societat. Aquestes iniciatives, agrupades sota el pla Ingenio 2010, promouen les polítiques del Ministeri de Sanitat i Consum. Juntament amb l'Institut de Salut Carles III i els Centres d'Investigació Biomèdica en Xarxa (CIBER), han permès un ràpid creixement de l'R+D a Espanya. El Consell de Ministres també ha aprovat una sèrie d'accions estratègiques amb l'objectiu que els beneficis de la recerca biomèdica arribin als pacients al més aviat possible. Aquestes accions transversals se centren en els camps del càncer, la medicina regenerativa, la nanobiotecnologia, les molècules innovadores i la Biblioteca Virtual del Sistema Nacional de Salut.There is a clear gap between Spain’s economic ranking and its position among other European countries, both in general research and in biomedicine. Biomedicine in particular is and will be, without a doubt, the premier science in the 21st century, initiating the most changes and leading to the most significant discoveries. It is therefore essential that the knowledge gained reaches clinical practice and is converted into efficient therapies. In order to reduce this gap, the Spanish government has set forth a series of initiatives that support biomedical research and development, and which encompass institutes, universities, and private companies. These initiatives, grouped under the Ingenio 2010 plan, promote the policies of the Ministry of Health and Consumer production. Together with the Carlos III Health Institute and the Network of Biomedical Research Centers (CIBER), it will allow the rapid growth of R&D in Spain. The Minister’s Council has also approved a series of strategic actions whose goal is to ensure that the benefits of biomedical research reach patients as quickly as possible. These actions are focused on cancer therapy, regenerative medicine, nanobiotechnology, molecular innovation, and the Virtual Library of the National Health System

Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy

Mesenchymal stem cells (MSCs) are among the most frequently used cell type for regenerative medicine. A large number of studies have shown the beneficial effects of MSC-based therapies to treat different pathologies, including neurological disorders, cardiac ischemia, diabetes, and bone and cartilage diseases. However, the therapeutic potential of MSCs in cancer is still controversial. While some studies indicate that MSCs may contribute to cancer pathogenesis, emerging data reported the suppressive effects of MSCs on cancer cells. Because of this reality, a sustained effort to understand when MSCs promote or suppress tumor development is needed before planning a MSC-based therapy for cancer. Herein, we provide an overview on the therapeutic application of MSCs for regenerative medicine and the processes that orchestrates tissue repair, with a special emphasis placed on cancer, including central nervous system tumors. Furthermore, we will discuss the current evidence regarding the double-edged sword of MSCs in oncological treatment and the latest advances in MSC-based anti-cancer agent delivery systems.Junta de Andalucía PI-0272-2017Ministerio de Ciencia, Innovación y Universdad CD16/00118, CP19/00046, PI16/00259, BFU2017-83588-P, CP14/00105, PI18/01590, PI17/02104, PIC18/0010, IC19/0052Juvenile Diabetes Research Foundation (USA) 2-SRA-2019-837-S-BFundación Española para la Ciencia y la Tecnología 2018-00023

Terapia celular en la Diabetes mellitus

La diabetes mellitus tipo 1 (DM1) es una enfermedad crónica que se caracteriza por una deficiencia en la masa de células β, que trae consigo un fallo en la homeostasis de la glucosa. Ambas circunstancias dan lugar a una variedad de complicaciones severas y a un acortamiento en la expectativa de vida. La normalización de la homeostasis de la glucosa puede conseguirse mediante trasplante del páncreas o de los islotes, pero la escasez de donantes ha propiciado gran interés por el estudio de fuentes alternativas de células β, lo cual ha estimulado la investigación de las células madre apropiadas. Por tanto, la diabetes representa una candidata atractiva para la terapia celular. Tanto las células madre em- brionarias como las adultas han sido utilizadas para generar sustitutos celulares, que podrían potencialmente restaurar el funcionamiento de las células β. Diversos estudios han descrito la generación de células secre- toras de insulina procedentes de células madre embrionarias y adultas, que normalizaron los valores de glucosa sanguínea cuando se trasplan- taron a modelos de animales diabéticos. Debido a la complejidad de las células β, las células productoras de insulina generadas a partir de las células madre no poseen todos los atributos de las células β. Esto indica la necesidad de desarrollar métodos para la diferenciación y selección de células β con funcionalidad completa. Mientras se superan estos pro- blemas, los pacientes diabéticos pueden beneficiarse de estrategias tera- péuticas basadas en terapias autólogas con células madre, dirigidas a las complicaciones diabéticas tardías. En este artículo se discuten los progresos recientes en la generación de células productoras de insulina a partir de células madre adultas y embrionarias, unidos a los desafíos para el futuro uso clínico de la terapia con células madre

A role for the host in the roadmap to diabetes stem cell therapy

Stem cells represent an unlimited source for cell therapy (1), and considerable efforts have been made to overcome barriers to introducing this revolutionary therapy into clinical practice. Briefly, the following actions must be taken: 1) design in vitro differentiation strategies to generate either mature postmitotic b-cells or b-cell progenitors that may be safely implanted into the host (e.g., without uncontrolled proliferation), 2) devise selection methods to produce a pure b-cell population, 3) validate standard characterization protocols to determine the real differentiation stage of the cells ready to be transplanted, 4) obtain encapsulation devices to implant the cells, 5) develop preclinical controls in representative animal models, and 6) de fine cell-host interactions (for a recent review see ref. 2

Single mechanosensitive and ca(2+)-sensitive channel currents recorded from mouse and human embryonic stem cells

Cell-attached and inside-out patch clamp recording was used to compare the functional expression of membrane ion channels in mouse and human embryonic stem cells (ESCs). Both ESCs express mechanosensitive Ca(2+) permeant cation channels (MscCa) and large conductance (200 pS) Ca(2+)-sensitive K(+) (BK(Ca2+)) channels but with markedly different patch densities. MscCa is expressed at higher density in mESCs compared with hESCs (70 % vs. 3 % of patches), whereas the BK(Ca2+) channel is more highly expressed in hESCs compared with mESCs (~50 % vs. 1 % of patches). ESCs of both species express a smaller conductance (25 pS) nonselective cation channel that is activated upon inside-out patch formation but is neither mechanosensitive nor strictly Ca(2+)-dependent. The finding that mouse and human ESCs express different channels that sense membrane tension and intracellular [Ca(2+)] may contribute to their different patterns of growth and differentiation in response to mechanical and chemical cues.OH was supported by a travel/stay Grant from Ministerio de Educación y Ciencia (SAB2006-0211) and in the United States by grants from the National Cancer Institute and the Department of Defense. BS and AH are supported by the Fundación Progreso y Salud, Consejería de Salud, Junta de Andalucía (PI-0022/ 2008); Consejería de Innovación Ciencia y Empresa, Junta de Andalucía (CTS-6505; INP-2011-1615-900000); FEDER cofunded grants from Instituto de Salud Carlos III (Red TerCel-RD06/0010/0025; PI10/00964), and the Ministry of Health and Consumer Affairs (Advanced Therapies Program TRA-120). CIBERDEM is an initiative of the Instituto de Salud Carlos III.Peer Reviewe

EGF-induced adipose tissue mesothelial cells undergo functional vascular smooth muscle differentiation

Recent studies suggested that the post-natal mesothelium retain differentiative potential of the embryonic mesothelium, which generates fibroblasts and vascular smooth muscle cells (VSMCs), in developing coelomic organs via epithelial-to-mesenchymal transition (EMT). Whether adult mesothelial cells (MCs) are able to give rise to functional VSMCs in vitro and which are the factors and mechanisms directing this process remain largely unknown. Here, we isolated adipose tissue MCs (ATMCs) from adult mice, and demonstrated that ATMCs cultured in a serum-containing media supplemented with epidermal growth factor (EGF) efficiently increased both their proliferation and EMT above levels found in only serum-containing media cultures. EGF-induced ATMCs gained phosphorylation of the EGF receptor and activated simultaneously ILK/Erk1/2, PI3K/Akt and Smad2/3-dependent pathways. Sequential subculture onto collagen-I surface efficiently improved their vasculogenic EMT towards cells featuring VSMCs (α-SMA, calponin, caldesmon, SM22α, desmin, SM-MHC, smoothelin-B and PDGFR-β) that could actively contract in response to receptor and non-receptor-mediated vasoactive agonists. Overall, our results indentify EGF signalling as a robust vasculogenic inductive pathway for ATMCs, leading to their transdifferentiation into functional VSMC-like cells.Junta de Andalucía Grant PI-0022/2008Junta de Andalucía, Consejería de Innovación Ciencia y Empresa P07-CVI-279

Mesothelial cells: A cellular surrogate for tissue engineering of corneal endothelium

[Purpose]: To evaluate whether mouse adipose tissue mesothelial cells (ATMCs) share morphologic and biochemical characteristics with mouse corneal endothelial cells (CECs) and to evaluate their capacity to adhere to the decellularized basal membrane of human anterior lens capsules (HALCs) as a potential tissue-engineered surrogate for corneal endothelium replacement. [Methods]: Adipose tissue mesothelial cells were isolated from the visceral adipose tissue of adult mice, and their expression of several corneal endothelium markers was determined with quantitative RT-PCR, immunofluorescence, and Western blotting. Adipose tissue mesothelial cells were cultured in a mesothelial retaining phenotype medium (MRPM) and further seeded and cultured on top of the decellularized basal membrane of HALCs. ATMC-HALC composites were evaluated by optical microscopy, immunofluorescence, and transmission electron microscopy. [Results]: Mesothelial retaining phenotype medium-cultured ATMCs express the corneal endothelium markers COL4A2, COL8A2, SLC4A4, CAR2, sodium- and potassium-dependent adenosine triphosphatase (Na+/K+-ATPase), b-catenin, zona occludens-1, and N-cadherin in a pattern similar to that in mouse CECs. Furthermore, ATMCs displayed strong adhesion capacity onto the basal membrane of HALCs and formed a confluent monolayer within 72 hours of culture in MRPM. Ultrastructural morphologic and marker characteristics displayed by ATMC monolayer on HALCs clearly indicated that ATMCs retained their original phenotype of squamous epithelial-like cells. [Conclusions]: Corneal epithelial cells and ATMCs share morphologic (structural) and marker (functional) similarities. The ATMCs adhered and formed structures mimicking focal adhesion complexes with the HALC basal membrane. Monolayer structure and achieved density of ATMCs support the proposal to use adult human mesothelial cells (MCs) as a possible surrogate for damaged corneal endothelium.Supported by Fondos FEDER, Fundación Progreso y Salud, Consejería de Salud, Junta de Andalucía (Grant PI-0022/2008), INNPACTO Program (INP-2011-1615-900000), and SUDOE Program-BIOREG (Intereg SOE3/P1/E750); Consejer´ıa de Innovación Ciencia y Empresa, Junta de Andalucía (Grant CTS-6505); Ministry of Science and Innovation (Red TerCel-FEDER Grant RD12/0019/ 0028); Instituto de Salud Carlos III Grant PI10/00964); the Ministry of Health and Consumer Affairs Advanced Therapies Program Grant TRA-120 (BS); and Corporación Tecnológica de Andalucía CTA (NBT). CIBERDEM is an initiative of the Instituto de Salud Carlos III.Peer Reviewe

Gene-Diet Interactions in Type 2 Diabetes: The Chicken and Egg Debate

Consistent evidence from both experimental and human studies indicates that Type 2 diabetes mellitus (T2DM) is a complex disease resulting from the interaction of genetic, epigenetic, environmental, and lifestyle factors. Nutrients and dietary patterns are important environmental factors to consider in the prevention, development and treatment of this disease. Nutritional genomics focuses on the interaction between bioactive food components and the genome and includes studies of nutrigenetics, nutrigenomics and epigenetic modifications caused by nutrients. There is evidence supporting the existence of nutrient-gene and T2DM interactions coming from animal studies and family-based intervention studies. Moreover, many case-control, cohort, cross-sectional cohort studies and clinical trials have identified relationships between individual genetic load, diet and T2DM. Some of these studies were on a large scale. In addition, studies with animal models and human observational studies, in different countries over periods of time, support a causative relationship between adverse nutritional conditions during in utero development, persistent epigenetic changes and T2DM. This review provides comprehensive information on the current state of nutrient-gene interactions and their role in T2DM pathogenesis, the relationship between individual genetic load and diet, and the importance of epigenetic factors in influencing gene expression and defining the individual risk of T2DM

Impact of transient down-regulation of DREAM in human embryonic stem cell pluripotency: The role of DREAM in the maintenance of hESCs

Little is knownabout the functions of downstreamregulatory element antagonist modulator (DREAM) inembryonic stem cells (ESCs). However, DREAM interacts with cAMP response element-binding protein (CREB) in a Ca2+-dependent manner, preventing CREB binding protein (CBP) recruitment. Furthermore, CREB and CBP are involved in maintaining ESC self-renewal and pluripotency. However, a previous knockout study revealed the protective function of DREAMdepletion in brain aging degeneration and that aging is accompanied by a progressive decline in stem cells (SCs) function. Interestingly, we found that DREAM is expressed in different cell types, including human ESCs (hESCs), human adipose-derived stromal cells (hASCs), human bone marrow-derived stromal cells (hBMSCs), and human newborn foreskin fibroblasts (hFFs), and that transitory inhibition of DREAMin hESCs reduces their pluripotency, increasing differentiation.We stipulate that these changes are partly mediated by increased CREB transcriptional activity. Overall, our data indicates that DREAMacts in the regulation of hESC pluripotency and could be a target to promote or prevent differentiation in embryonic cells.Junta de Andalucía, Consejería de Innovación Ciencia y Empresa, FEDER CTS-6505; INP-2011- 1615-900000; P10-CVI-6095Instituto de Salud Carlos III, FEDER RD12/0019/0028; PI10/00964; PI14/0101

miR-7 Modulates hESC Differentiation into Insulin-Producing Beta-like Cells and Contributes to Cell Maturation

Human pluripotent stem cells retain the extraordinary capacity to differentiate into pancreatic beta cells. For this particular lineage, more effort is still required to stress the importance of developing an efficient, reproducible, easy, and cost-effective differentiation protocol to obtain more mature, homogeneous, and functional insulin-secreting cells. In addition, microRNAs (miRNAs) have emerged as a class of small non-coding RNAs that regulate many cellular processes, including pancreatic differentiation. Some miRNAs are known to be preferentially expressed in islets. Of note, miR-375 and miR-7 are two of the most abundant pancreatic miRNAs, and they are necessary for proper pancreatic islet development. Here we provide new insight into specific miRNAs involved in pancreatic differentiation. We found that miR-7 is differentially expressed during the differentiation of human embryonic stem cells (hESCs) into a beta cell-like phenotype and that its modulation plays an important role in generating mature pancreatic beta cells. This strategy may be exploited to optimize the potential for in vitro differentiation of hESCs into insulin-producing beta-like cells for use in preclinical studies and future clinical applications as well as the prospective uses of miRNAs to improve this process.Spanish Ministry of Economy and Competitiveness BFU2016-74932-C2 BFU2013-45564-C2FEDER Funds PI-0272-2017Andalusian Regional Ministry of Health PI-0272-2017European Cooperation in Science and Technology BM1305Spanish Ministry of Economy, Industry and Competitiveness CD16/00118Spanish Institute of Health Carlos III PI16/00259 PI17/02104 RD16/0011/0034 CD16/0011