Tres estudios demuestran la eficacia de la terapia celular en la 'piel de mariposa'

Fuente: http://www.abc.es/salud/noticias/20141127/abci-piel-mariposa-terapia-celular-201411271056.html

Las células iPS logran corregir los defectos en la piel de los pacientes con epidermolisis bullosa.

A partir de una biopsia de la piel del paciente se extraen las células que se reprograman y se convierten en células iPS. Después de un proceso de recombinación que corrige los defectos genéticos que causan la enfermedad, las células se cultivan in vitro para posteriormente trasplantarse al mismo paciente

Los resultados de tres estudios diferentes ofrecen una evidencia convincente sobre la eficacia del tratamiento con una terapia basada en células madre pluripotentes inducidas (iPS) para corregir defectos genéticos en la piel y tratar la epidermolisis bullosa, un grupo de enfermedades de la piel hereditario poco frecuente también llamada ‘piel de mariposa’.

La epidermolisis bullosa es una patología dolorosa que exacerba la fragilidad de la piel y hace que ésta se despegue con facilidad, además de que también puede causar infecciones potencialmente mortales. Los pacientes con epidermolisis bullosa nacen con ampollas extensas y parches de piel y tienen la piel extremadamente frágil por el resto de sus vidas. No hay cura para la enfermedad, que se produce por una falta de colágeno funcional, y los tratamientos actuales se centran en el control de la cicatrización de heridas y la prevención de la ampolla.

En el primero de los tres estudios publicados en «Science Traslational of Medicine», el equipo de Vittorio Sebastiano de la Stanford University (EE.UU.) obtuvieron células de la piel enfermas de tres pacientes adultos con epidermolisis bullosa y las convirtieron en células iPS utilizando un vector lentiviral. Los expertos saben que las células madre pluripotentes inducidas son una opción de tratamiento particularmente atractivo para esta enfermedad, ya que pueden generar continuamente nuevas células de la piel.

Los expertos de Stanford utilizaron herramientas de edición de genes en las células iPS para corregir una mutación responsable de la producción defectuosa de proteínas de colágeno. De esta forma, las células iPS corregidas se emplearon para generar hojas de tejido de la piel humana que producen colágeno funcional. A continuación, los autores injertaron estas ‘láminas’ epiteliales humanas en ratones y observaron que la vida de los injertos se prolongó durante unas tres semanas, más tiempo de la que había logrado hasta ahora.

Además, debido a que las células iPS utilizadas en este estudio habían sido creadas a partir de células del propio paciente, se reduce el riesgo de rechazo del injerto. Estos resultados apoyan la idea de que este método, conocido como reprogramación terapéutica, puede ser un tratamiento clínicamente viable para los pacientes con epidermolisis bullosa.

Un segundo estudio del equipo del Instituto de Biotecnología Molecular de la Academia Austríaca de Ciencias (Viena) de Daniel Wenzel confirmó estos hallazgos en el laboratorio, lo que demuestra que es posible emplear las células iPS genéticamente modificadas de ratones con epidermolisis bullosa para curar la piel con ampollas.

Y el tercer estudio realizado por Noriko Umegaki-Arao, de la Columbia University (EE.UU.), explora la posibilidad de que las células de la piel obtenidas de pacientes con epidermolisis bullosa con mosaicismo revertiente -donde algunas de sus células de la piel se han vuelto espontáneamente normales- pueden tener un potencial terapéutico para la creación de injertos de piel.

iPS cells used to correct genetic mutations that cause muscular dystrophy

Fuente: http://medicalxpress.com/news/2014-11-ips-cells-genetic-mutations-muscular.html

This image shows immunofluorescence staining of skeletal cells differentiated from DMD-iPS cells. Untreated DMD skeletal cells do not express dystrophin (green) due to the deletion of exon 44. However, after any of the three correction strategies are applied to iPS cells, differentiation into skeletal cells results in normal dystrophin expression. Scale bar, 50 μm. 

Researchers at the Center for iPS Cell Research and Application (CiRA), Kyoto University, show that induced pluripotent stem (iPS) cells can be used to correct genetic mutations that cause Duchenne muscular dystrophy (DMD). The research, published in Stem Cell Reports, demonstrates how engineered nucleases, such as TALEN and CRISPR, can be used to edit the genome of iPS cells generated from the skin cells of a DMD patient. The cells were then differentiated into skeletal muscles, in which the mutation responsible for DMD had disappeared.

DMD is a severe muscular degenerative disease caused by a loss-of-function mutation in the dystrophin gene. It inflicts 1 in 3500 boys and normally leads to death by early adulthood. Currently, very little is available in terms of treatment for patients outside palliative care. One option gaining interest is genomic editing by TALEN and CRISPR, which have quickly become invaluable tools in molecular biology. These enzymes allow scientists to cleave genes at specific locations and then modify the remnants to produce a genomic sequence to their liking. However, programmable nucleases are not pristine and often mistakenly edit similar sequences that vary a few base pairs from the target sequence, making them unreliable for clinical use because of the potential for undesired mutations.

For this reason, induced pluripotent stem cells (iPS cells) are ideal models, because they provide researchers an abundance of patient cells on which to test the programmable nucleases and find optimal conditions that minimize off-target modifications. CiRA scientists took advantage of this feature by generating iPS cells from a DMD patient. They used several different TALEN and CRISPR to modify the genome of the iPS cells, which were then differentiated into skeletal muscle cells. In all cases, dystrophin protein expression was convalesced, and in some cases, the dystrophin gene was fully corrected.

One key to the success was the development of a computational protocol that minimized the risk of off-target editing. The team built a database that all possible permutations of sequences up to 16 base pairs long. Among these, they extracted those that only appear once in the human genome, i.e. unique sequences. DMD can be caused by several different mutations; in the case of the patient used in this study, it was the result of the deletion of exon 44. The researchers therefore built a histogram of unique sequences that appeared in a genomic region that contained this exon. They found a stack of unique sequences in exon 45. According to Akitsu Hotta, who headed the project and holds joint positions at CiRA and the Institute for Integrated Cell-Materials Sciences at Kyoto University, "Nearly half the human genome consists of repeated sequences. So even if we found one unique sequence, a change of one or two base pairs may result in these other repeated sequences, which risks the TALEN or CRISPR editing an incorrect region. To avoid this problem, we sought a region that hit high in the histogram".

With this target, the team considered three strategies to modify the frame-shift mutation of the dystrophin gene: exon skipping by connecting exons 43 and 46 to restore the reading frame, frame shifting by incorporating insertion or deletion (indel) mutations, and exon knock-in by inserting exon 44 before exon 45. All three strategies effectively increased dystrophin synthesis in differentiated skeletal cells, but only the exon knock-in approach recovered the gene to its natural state. Importantly, editing showed very high specificity, suggesting that their computational approach can be used to minimize off-target editing by the programming nucleases.

Moreover, the paper provides a proof-of-principle for using iPS cell technology to treat DMD in combination with TALEN or CRISPR. The group now aims to expand this protocol to other diseases. First author Lisa Li explains, "We show that TALEN and CRISPR can be used to correct the mutation of the DMD gene. I want to apply the nucleases to correct mutations for other genetic-based diseases like point mutations".

More information: Precise correction of the DYSTROPHIN gene in Duchenne Muscular Dystrophy patient-derived iPS cells by TALEN and CRISPR-Cas9, Stem Cell Reports, 2014.

Funding to investigate an alternative to chemotherapy

Fuente: http://medicalxpress.com/news/2014-11-funding-alternative-chemotherapy.html

Professor Simon Rule, Professor in Haematology at Plymouth University Peninsula Schools of Medicine and Dentistry and Consultant Haematologist at Plymouth Hospitals NHS Trust, has been awarded a significant grant by Cancer Research UK to carry out a research study into the treatment of older patients with mantle cell lymphoma.

The award, which is in the region of £600,000 and will be split over 90 months, will enable Professor Rule to lead a national research study to look at and compare the efficacy and side effects of using a BTK (Bruton's Tyrosine Kinase) inhibiting drug in a trial against standard chemotherapy.

The first patients will join the clinical trials in summer 2015.

Current therapies, such as chemotherapy, intensive chemo-immunotherapy (chemotherapy combined with immunotherapy) or stem cell transplant are effective but due to the aggressive nature of these cancers, patients always relapse and eventually run out of options.

These new drugs work by inhibiting Bruton's tyrosine kinase (BTK), a protein which plays a role in the signals that cause growth in cancerous cells. Blocking this causes the cancerous cells to die but normal cells are unaffected.

Newly diagnosed patients who take part in this Phase 2 trial will either be treated with standard chemotherapy, alongside a commonly used drug that is given in combination with chemotherapy, Rituximab, or they will be given the BTK drug Ibrutinib and Rituximab.

Professor Rule, who led the first worldwide study of its kind into a new class of BTK inhibiting drugs at Derriford Hospital in Plymouth, describes how this will be a randomised trial to see the differences for patients who have chemotherapy first against those who have the drugs.

Professor Rule explains: "We've been talking about chemo-free treatment for years and now thanks to the grant from Cancer Research UK it might now be a reality. Studies like these have the very real prospect of changing the management of these difficult forms of cancer.

"These drugs are transformational and the astonishing thing about them is that they have virtually no side effects, which is unprecedented in my experience. In some patients the effects are immediate. Patients with lots of symptoms, particularly those with lymphoma, will feel better the next day after taking the medication.

"This is the only study of its kind in which patients who are newly diagnosed with mantle cell lymphoma will be offered a first line treatment for this disease that does not include a form of chemotherapy. At the moment we do not know which treatment will be better and the only way to find out is by designing research studies to collect information about what happens to patients and their mantle cell lymphoma."

A total of 400 patients will be studied from many hospitals in the UK. 200 of these will receive Ibrutinib with Rituximab and the other 200 will receive chemotherapy with Rituximab. Depending on the patient's response to their treatment they might only stay in the study for a few weeks, whereas others may remain in the study for a number of years.

Professor Simon Rule runs the only mantle cell lymphoma clinic in Europe, with one other clinic in America. As a leading clinician in mantle cell lymphoma, patients have come from around the world to seek out Professor Rule's expertise.

Professor Rule added: "The UK is at the forefront of this drug development and all of the studies into these new drugs are being run from Plymouth. This will completely change the way we manage these diseases. We have access to the next generation of the drug to be part of the next trial phases. This is not a cure for cancer but it will mean we are significantly improving our patients' life expectancy and quality of life; similar to managing a chronic condition. I have yet to come across another class of drugs in my career that has been so successful for leukaemia or lymphoma."

Jonathan Pearce, Lymphoma Association chief executive, said: "The Lymphoma Association wants everyone affected by lymphoma to have the best possible treatment and care. This is an exciting study with the potential to make a huge difference to lymphoma patients and we welcome it."

With an average survival rate of four to five years, the new developments in BTK inhibiting drugs could dramatically improve the life expectancy and quality of life for patients with terminal forms of leukaemia and lymphoma who have run out of other treatment options.

The trial will begin in January 2015.

Two studies identify a detectable, pre-cancerous state in the blood

Fuente: http://medicalxpress.com/news/2014-11-pre-cancerous-state-blood.html

Scanning electron micrograph of blood cells. From left to right: human erythrocyte, thrombocyte (platelet), leukocyte. 

Researchers from the Broad Institute of MIT and Harvard, Harvard Medical School, and Harvard-affiliated hospitals have uncovered an easily detectable, "pre-malignant" state in the blood that significantly increases the likelihood that an individual will go on to develop blood cancers such as leukemia, lymphoma, or myelodysplastic syndrome. The discovery, which was made independently by two research teams affiliated with the Broad and partner institutions, opens new avenues for research aimed at early detection and prevention of blood cancer. Findings from both teams appear in the New England Journal of Medicine.

Most genetic research on cancer to date has focused on studying the genomes of advanced cancers, to identify the genes that are mutated in various cancer types. These two new studies instead looked at somatic mutations - mutations that cells acquire over time as they replicate and regenerate within the body - in DNA samples collected from the blood of individuals not known to have cancer or blood disorders.

Taking two very different approaches, the teams found that a surprising percentage of those sampled had acquired a subset - some but not all - of the somatic mutations that are present in blood cancers. These individuals were more than ten times more likely to go on to develop blood cancer in subsequent years than those in whom such mutations were not detected.

The "pre-malignant" state identified by the studies becomes more common with age; it is rare in those under the age of 40, but appears with increasing frequency with each decade of life that passes, ultimately appearing in more than 10% of those over the age of 70. Carriers of the mutations are at an overall 5% risk of developing some form of blood cancer within five years. This "pre-malignant" stage can be detected simply by sequencing DNA from blood.

"People often think about disease in black and white - that there's 'healthy' and there's 'disease' - but in reality most disease develops gradually over months or years. These findings give us a window on these early stages in the development of blood cancer," said Steven McCarroll, senior author of one of the papers. McCarroll is an assistant professor of genetics at Harvard Medical School and director of genetics at the Broad's Stanley Center for Psychiatric Research. Benjamin Ebert, an associate member of the Broad and associate professor at Harvard Medical School and Brigham and Women's Hospital, is the senior author of the other paper.

The mutations identified by both studies are thought to originate in blood stem cells, and confer a growth-promoting advantage to the mutated cell and all of its "clones" - cells that derive from that original stem cell during the normal course of cell division. These cells then reproduce at an accelerated rate until they account for a large fraction of the cells in a person's blood. The researchers believe these early mutations lie in wait for follow-on, "cooperating" mutations that, when they occur in the same cells as the earlier mutations, drive the cells toward cancer. The majority of mutations occurred in just three genes; DNMT3A, TET2, and ASXL1.

"Cancer is the end-stage of the process," said Siddhartha Jaiswal, a Broad associated scientist and clinical fellow from Massachusetts General Hospital who was first author of Ebert's paper. "By the time a cancer has become clinically detectable it has accumulated several mutations that have evolved over many years. What we are primarily detecting here is an early, pre-malignant stage in which the cells have acquired just one initiating mutation."

The teams converged on these findings through very different approaches. Ebert's team had hypothesized that, since blood cancers increase with age, it might be possible to detect early somatic mutations that could be initiating the disease process, and that these mutations also might increase with age. They looked specifically at 160 genes known to be recurrently mutated in blood malignancies, using genetic data derived from approximately 17,000 blood samples originally obtained for studies on the genetics of type 2 diabetes.

They found that somatic mutations in these genes did indeed increase the likelihood of developing cancer, and they saw a clear association between age and the frequency of these mutations. They also found that men were slightly more likely to have mutations than women, and Hispanics were slightly less likely to have mutations than other groups.

Ebert's team also found an association between the presence of this "pre-malignant" state, and risk of overall mortality independent of cancer. Individuals with these mutations had a higher risk of type 2 diabetes, coronary heart disease, and ischemic stroke as well. However, additional research will be needed to determine the nature of these associations.

In the related paper, McCarroll's team discovered the phenomenon while studying a different disease. They, too, were looking at somatic mutations, but they were initially interested in determining whether such mutations contributed to risk for schizophrenia. The team studied roughly 12,000 DNA samples drawn from the blood of patients with schizophrenia and bipolar disorder, as well as healthy controls, searching across the whole genome at all of the protein-coding genes for patterns in somatic mutations.

They found that the somatic mutations were concentrated in a handful of genes; the scientists quickly realized that they were cancer genes. The team then used electronic medical records to follow the patients' subsequent medical histories, finding that the subjects with these acquired mutations had a 13-times elevated risk of blood cancer.

McCarroll's team conducted follow-up analyses on tumor samples from two patients who had progressed from this pre-malignant state to cancer. These genomic analyses revealed that the cancer had indeed developed from the same cells that had harbored the "initiating" mutations years earlier.

"The fact that both teams converged on strikingly similar findings, using very different approaches and looking at DNA from very different sets of patients, has given us great confidence in the results," said Giulio Genovese, a computational biologist at the Broad and first author of McCarroll's paper. "It has been gratifying to have this corroboration of each other's findings."

Jaiswal will be presenting the findings on December 9 at the American Society of Hematology Annual Meeting in San Francisco.

All of the researchers involved emphasized that there is no clinical benefit today for testing for this pre-malignant state; there are no treatments currently available that would address this condition in otherwise healthy people. However, they say the results open the door to entirely new directions for blood cancer research, toward early detection and even prevention.

"The results demonstrate a way to identify high-risk cohorts - people who are at much higher than average risk of progressing to cancer - which could be a population for clinical trials of future prevention strategies," McCarroll said. "The abundance of these mutated cells could also serve as a biomarker - like LDL cholesterol is for cardiovascular disease - to test the effects of potential prevention therapies in clinical trials."

Ebert agrees: "A new focus of investigation will now be to develop interventions that might decrease the likelihood that individuals with these mutations will go on to develop overt malignancies, or therapeutic strategies to decrease mortality from other conditions that may be instigated by these mutations," he said.

The researchers also say that the findings show just how important it is to collect and share large datasets of genetic information: both studies relied on DNA samples collected for studies completely unrelated to cancer.

"These two papers are a great example of how unexpected and important discoveries can be made when creative scientists work together and with access to genomic and clinical data," said Broad deputy director David Altshuler, one of Ebert's co-authors. "For example, Steve's team found stronger genetic relationships to cancer than they have yet found for the schizophrenia endpoint that motivated their original study. The pace of discovery can only accelerate if researchers have the ability to apply innovative methods to large datasets."

More information: Jaiswal, S et al. Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine. Online First: November 26, 2014. DOI: 10.1056/NEJMoa1408617

Genovese, G et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. New England Journal of Medicine. Online First: November 26, 2014.DOI: 10.1056/NEJMoa1409405

Un consorcio internacional intentará curar el VIH con células madre del cordón umbilical

Fuente: http://www.abc.es/salud/noticias/20141126/abci-curar-celulas-cordon-201411261757.html

Sería la segunda curación tras el caso del paciente de Berlín, en el que las células procedían de la médula ósea.

El único caso reportado en el mundo de curación del VIH ha sido el del «paciente de Berlín», un estadounidense llamado Timothy Brown, que lleva más de un lustro limpio del virus. Diagnosticado en 1995, Brown comenzó una terapia con antirretrovirales que cronificó el VIH y le permitió llevar una vida normal hasta que, en 2006, se le diagnosticó una leucemia mieloide aguda, y obligó a los médicos a actuar rápido. Tras un tratamiento de quimioterapia sin resultados, un oncólogo alemán le hizo en 2007 un trasplante de células madre de un donante portador de un gen hereditario poco común. A día de hoy, el paciente sigue libre del virus.

Su caso despertó un enorme interés científico, pero hasta ahora no se ha podido reproducir ya que es un procedimiento de alto riesgo y solo se indica en pacientes con VIH y una enfermedad hematológica potencialmente mortal, como era el caso de Brown. Según los especialistas, la mutación genética rara del donante parece ser el principal factor que determinó la curación, pero hay otros procesos clínicos que también pudieron haber contribuido.

Ahora, el Instituto de Investigación del SIDA IrsiCaixa y la University Medical Center Utrecht han iniciado un proyecto para tratar de mejorar la intervenciones para curar a estos pacientes y comprender mejor la implicación de las células madre en el control y en la erradicación de la infección.

El equipo científico que impulsa el proyecto está codirigido por el investigador del IrsiCaixa Javier Martínez-Picado y lo integran hematólogos, infectólogos, virólogos e inmunólogos con experiencia en el campo del VIH, entre ellos Gero Hütter, el oncólogo que lideró la curación del paciente de Berlín.

«Si queremos erradicar esta infección, tenemos que entender las razones específicas de la curación del VIH en el paciente de Berlín. También queremos usar la sangre del cordón umbilical como fuente de células madre, para aumentar las posibilidades de compatibilidad entre los donantes y los pacientes», explica Martínez-Picado.

Según el investigador, usar células madre de sangre del cordón umbilical tiene una clara ventaja, ya que son mucho más compatibles que las extraídas de la médula ósea.

Con esta nueva estrategia, las posibilidades de encontrar un donante que sea compatible y que, además, tenga la mutación genética que confiere resistencia natural al VIH se multiplica por 100.

En paralelo, el consorcio, denominado Epistem y financiado por el amfAR Research Consortium on HIV Eradication (ARCHE), creará un inventario que permita identificar cuáles de las 10.000 unidades de sangre de cordón disponibles en los bancos de sangre del norte de Europa contienen la mutación genética rara que confieren resistencia al VIH. Esto permitirá que estas unidades estén inmediatamente disponibles para el trasplante.

Los investigadores ya han comenzado a poner en práctica esta estrategia en personas VIH positivas que necesitan un trasplante de células madre y ahora están buscando pacientes para participar en el estudio, por lo que han hecho un llamamiento a médicos, investigadores y ciudadanos para hallar candidatos a formar parte del proyecto, que se pueden inscribir en epistem@irsicaixa.es. El consorcio, en el que colaborarán expertos del Instituto Catalán de Oncología (ICO) y del Hospital Gregorio Marañón de Madrid, lleva a cabo un exhaustivo estudio y seguimiento de estos pacientes para recopilar información completa sobre la quimioterapia, el procedimiento del trasplante, la selección de donantes, la variabilidad y el tratamiento del VIH. También está recogiendo muestras para ser almacenadas antes y después del trasplante.

Tras ese logro, son muchos los equipos que han intentado repetirlo. Ahora, un consorcio internacional liderado por el Instituto de Investigación del SIDA IrsiCaixa, en Barcelona (impulsado por La Caixa y el departamento de Salud), y el University Medical Center Utrecht, quiere repetir éxito y conseguir la segunda curación utilizando células madre del cordón umbilical.

Según avanzó el IrsiCaixa, el proyecto se presentará a la comunidad científica internacional en el Congreso Nacional de Gesida, que se celebra en el Palacio de Congresos y Ferias de Málaga.

Efficacy of new drug against stem cells that provoke cancer and its metastasis

Fuente: http://medicalxpress.com/news/2014-11-efficacy-drug-stem-cells-provoke.html

Histological section cutting of a primary tumour before and after treatment with Bozepinib.

An Andalusian team of researchers led by the University of Granada has demonstrated the efficacy of a new drug against cancerogenic stem cells, which cause the onset and development of cancer, of relapse after chemotherapy and metastasis. This drug, called Bozepinib, has proved to be effective in tests with mice. The results have been published in the prestigious journal Oncotarget.

Cancerogenic stem cells appear in small quantities in tumours, and one of their important features is that they contribute to the formation of metastasis in different places within the original tumour. Cancerogenic stem cells remain dormant under normal conditions (i.e. they do not divide). Conventional chemotherapy and radiotherapy act upon those cancer cells which are clearly differentiated—i.e. which are undergoing processes of division—but they cannot destroy these dormant cancerogenic stem cells. Actually, after a positive initial response to treatment, many cancer patients suffer a relapse because these cancerogenic stem cells have not been destroyed.

During the last few years, research in fight against cancer has focused on the search for new drugs that can selectively attack these cancerogenic stem cells. If they can be eliminated, the tumour will then be eliminated in its entirety, which will lead to the complete curation of patients.

Scientists in the "Advanced therapies: differentiation, regeneration and cancer" research group led by UGR professor Juan Antonio Marchal have collaborated with Joaquín Campos, from the School of Pharmacy, U. of Granada, and María Ángeles García, from Virgen de las Nieves University Hospital in Granada, as well as with the universities of Jaen and Miami (US) to develop the new drug Bozepinib.

This new drug shows a selective type of activity against cancerogenic stem cells in breast, colon, and skin cancers. "The powerful anti-tumour activity of Bozepinib is due to the inhibition of the HER2 signalling pathway, and to the fact that this drug inhibits the invasiveness and the formation of new vessels in the tumour (angiogenesis)", says prof. Juan Antonio Marchal. Researchers have also revealed the specific mechanism by means of which Bozepinib acts against cancerogenic stem cells.

This new drug proved to be nontoxic for healthy mice when it was intraperitoneally or orally administered, and it also inhibited tumoural growth and the formation of lung metastasis in those mice in which the tumour was induced.

Researchers are currently conducting safety tests and they expect that this new drug, as well as its derivatives, can be run through clinical tests with actual patients in the near future.

More information: "HER2-signaling pathway, JNK and ERKs kinases, and cancer stem-like cells are targets of Bozepinib." Alberto Ramírez, Houria Boulaiz, Cynthia Morata-Tarifa, Macarena Perán, Gema Jiménez, Manuel Picon-Ruiz, Ahmad Agil, Olga Cruz-López, Ana Conejo-García, Joaquín M. Campos, Ana Sánchez, María A. García, Juan A. Marchal. Oncotarget, Vol. 5, No. 11

Identificadas unas raras células madre que dan lugar a la fibrosis

Fuente: http://noticias.lainformacion.com/salud/enfermedades-cardiacas/identificadas-unas-raras-celulas-madre-que-dan-lugar-a-la-fibrosis_jXd2TAQlD29gND7fsoS1E3/

Científicos del Instituto de Células Madre de Harvard en el Hospital Brigham y de la Mujer, en Estados Unidos, han encontrado en unas raras células madre el origen celular de la cicatrización del tejido causada por el daño a los órganos asociado con la diabetes, la enfermedad pulmonar, la presión arterial alta, la enfermedad renal y otras condiciones. Esta acumulación de tejido cicatricial se conoce como fibrosis.

La fibrosis tiene una serie de consecuencias, como la inflamación y una disminución de la sangre y el oxígeno que llega a los órganos, por lo que, a largo plazo, la cicatrización del tejido crónica puede conducir a insuficiencia orgánica y muerte eventual. Se estima que la fibrosis contribuye al 45 por ciento de todas las muertes en el mundo desarrollado.

Los investigadores, dirigidos por Benjamin Humphreys, detectaron una población rara de células madre localizadas fuera de los vasos sanguíneos en ratones que se convierten en miofibroblastos que secretan proteínas que causan el tejido cicatrizal. Matar estas células madre evita las complicaciones mortales de la fibrosis, como revelan los autores en un artículo en la edición digital de 'Cell Stem Cell'.

"En circunstancias normales, los miofibroblastos estimulan la cicatrización de la herida, pero cuando hay una lesión permanente de un órgano, por ejemplo, el hígado de un paciente con hepatitis C, el corazón de un individuo con presión arterial alta o el riñón de una persona con diabetes, estas proteínas obstruyen el funcionamiento normal", explica Rafael Humphreys, profesor asociado de la Escuela de Medicina de Harvard en el Hospital Brigham y de Mujeres y director del Programa de Riñón del Instituto de Células Madre de Harvard.

Los investigadores están ahora en conversaciones con una empresa farmacéutica para identificar fármacos que pudieran apuntar a estas células madre que causan fibrosis en los casos de enfermedad orgánica crónica y desactivarlas.

"Queríamos saber si la erradicación de esta pequeña población de células madre podría mejorar la función de órganos, y los dos riñones y el corazón resultaron completamente protegidos de desarrollar complicaciones relacionadas con la fibrosis, como insuficiencia renal e insuficiencia cardiaca --detalla Humphreys, quien también dirige el Programa de OncoNefrología en el Instituto del Cáncer Dana-Farber--. Esto proporciona una prueba importante de que los fármacos que se dirigen a las células madre podrían servir como terapia".

El origen celular de la fibrosis renal tiene perplejos a los investigadores desde hace mucho tiempo porque no se sabía qué tipo de células madre forman miofibroblastos y dónde se encuentran dichas células madre. Una hipótesis mantenida durante mucho tiempo era que las células madre que generan miofibroblastos se encuentran en la médula ósea, pero la investigación de Humphreys refuta esa posibilidad.

Mediante el etiquetado de una proteína específica llamada Gli1 expresada por las células madre de formación de miofibroblastos, los científicos demostraron que las células se encuentran en la periferia de los vasos sanguíneos y que también residen dentro de los órganos.

Humphreys advierte de que la población de células hallada en su laboratorio es responsable de aproximadamente el 60 por ciento de todos los miofibroblastos de órganos, lo que significa que parecen ser la fuente más dominante, pero que pueden existir otras células que también contribuyen a la población de miofibroblastos.

Cell therapy trial offers new hope to liver disease patients

Fuente: http://medicalxpress.com/news/2014-11-cell-therapy-trial-liver-disease.html

Liver disease patients could be helped by a new cell therapy to treat the condition.

Researchers from the University of Edinburgh have received funding to start testing the therapy in patients within the next year.

It will be the world's first clinical trial of a new type of cell therapy to treat liver cirrhosis, a common disease where scar tissue forms in the organ as a result of long-term damage.

The Edinburgh team has received funding from the Medical Research Council and Innovate UK to investigate the disease, which claims 4000 lives in the UK each year.

The only successful treatment for end-stage liver cirrhosis at present is an organ transplant. The new therapy is based on a type of white blood cell called a macrophage, which is key to normal repair processes in the liver.

Macrophages reduce scar tissue and stimulate the liver's own stem cells to expand and form into healthy new liver cells.

Scientists will take cells from the blood of patients with liver cirrhosis and turn them into macrophages in the lab using chemical signals.

These new cells will then be re-injected into the patient in the hope they will reduce scarring and help to rebuild the damaged organ from within.

The Scottish National Blood Transfusion Service and the Cell Therapy Catapult are collaborating on the project.

Causes of liver cirrhosis include infections such as hepatitis C, obesity, alcohol abuse and some genetic and immune conditions.

Liver transplants are limited by a lack of available donors and the risk that a recipient's immune system will reject the transplanted organ. Many people die each year just waiting for an organ to become available.

Professor Stuart Forbes, of the MRC Centre for Regenerative Medicine at the University of Edinburgh, said: "Liver cirrhosis is on the increase in the UK and is one of the top five killers. If successful, we hope that this approach could offer a new way to tackle the condition."

Scientists identify bone cells that could help children who need corrective facial surgery

Fuente: http://medicalxpress.com/news/2014-11-scientists-bone-cells-children-facial.html

Our bones are smart. Bones know that by adolescence it's time to stop growing longer and stronger, and from that point on bones keep their shape by healing injuries.

This question of why bones grow longer and stronger in children, but stay static in adults—yet retain the ability to heal themselves, has long perplexed scientists in the bone regeneration field. But researchers from the University of Michigan, Kyoto University and Harvard University believe they may have unearthed a big piece of this puzzle.

The team discovered that a certain subset of cartilage-making cells, known as chondrocytes, replicate themselves, make other bone cells and drive bone growth—findings that could lead to new treatments for children with facial deformities who normally have to wait until adulthood for corrective surgery.

The study by Dr. Noriaki Ono, U-M assistant professor of dentistry, and colleagues appears online in Nature Cell Biology.

It's long been thought that these chondrocytes die when children reached adolescence and their bones stopped growing, Ono said. However, the fact that bone still heals itself even without chondrocytes caused intense debate among researchers.

Ono's group found that some chondrocytes don't die, but rather transform themselves into other types of bone-growing and bone-healing cells.

"Up until now, the cells that drive this bone growth have not been understood very well. As an orthodontist myself, I have special interest in this aspect, especially for finding a cure for severe bone deformities of the face in children," he said. "If we can find a way to make bones that continue to grow along with the child, maybe we would be able to put these pieces of growing bones back into children and make their faces look much better than they do."

Ono said one of the challenges in the bone and cartilage field is that stem cells haven't really been identified. The only widely accepted idea is that certain stem cells help bones grow and heal, but that's only discussed in the context of adults with bone disorders such as osteoporosis.

Many factors cause craniofacial deformities, and all are devastating to children, he said. In children with Goldenhar syndrome, underdeveloped facial tissues can harm the developing jawbone. Another bone deformity called deformational plagiocephaly causes a child's head to grow asymmetrically.

More information: "A Subset of Chondrogenic Cells Provides Early Mesenchymal Progenitors in Growing Bones" Nature Cell Biology, DOI: 10.1038/ncb3067

Pain in a dish: Researchers turn skin cells into pain sensing neurons

Fuente: http://medicalxpress.com/news/2014-11-pain-dish-skin-cells-neurons.html

Human noxious stimulus detecting sensory neurons produced by converting skin cells with a set of five genes to this new fate -- enabling study of 'pain' in a dish. 

After more than six years of intensive effort, and repeated failures that made the quest at times seem futile, Harvard Stem Cell Institute (HSCI) researchers at Boston Children's Hospital (BCH) and Harvard's Department of Stem Cell and Regenerative Biology (HSCRB) have successfully converted mouse and human skin cells into pain sensing neurons that respond to a number of stimuli that cause acute and inflammatory pain.

This "disease in a dish" model of pain reception may advance the understanding of different types of pain, identify why individuals differ in their pain responses or risk of developing chronic pain, and make possible the development of improved drugs to treat pain. A report on the work was given advance on-line release by the journal Nature Neuroscience.

Clifford Woolf, M.D./Ph.D, co-director of HSCI's Nervous Systems Diseases Program lead the research effort. Post doctoral fellows Brian Wainger and Liz Buttermore are first authors on the Nature Neuroscience paper. Woolf's collaborators on the project included Lee Rubin and Kevin Eggan, both professors in HSCRB.

The neuronal pain receptors created by Woolf and his team are reported to respond to both the kind of intense stimuli triggered by a physical injury and that causing "ouch" pain, and the more subtle stimuli triggered by inflammation, which results in pain tenderness, and even by some forms of cancer chemotherapy. The fact that the neurons respond to both the gross and fine forms of stimulation that produce distinct pains in humans provides confirmation that the neurons are functioning as naturally developed neurons would, Woolf said.

When the project began, Woolf's team was attempting to create pain sensing neurons from embryonic stem cells, but the task proved far more challenging than first envisioned. "We spent three years trying to recapitulate the developmental steps involved, and it turned out to be a total bust," said Woolf, who in addition to his HSCI roles is a Harvard Medical School professor of neurology and neurobiology, and director of the F.M. Kirby Neurobiology Center at BCH. But effort to develop pain sensing neurons was occurring at just the right moment in the evolution of stem cell biology, coinciding with the development of iPS technology, the ability to transform adult human cells into stem cells, and then into other forms of adult cells.

The project was the original effort of a still ongoing collaboration between HSCI researchers and pharmaceutical giant GSK, and, said Woolf, "for the first three years we had nothing to show for all our efforts but they, like us, were in it for the long haul."

Brock Reeve, HSCI's Executive Director, said the pain neuron project "exemplifies the type of long-term collaboration between academia and industry that is critical for advancing basic science and providing new ways to discover drugs."

Describing the early days of the project as "hitting our head against a brick wall," Woolf said that "we had a dogged kind of persistence," and once the team began attempting to create the neurons directly from mouse and human skin cells, everything began to fall into place.

"We took mature pain neurons from mice, and found transcription factors that hadn't been described in them before," the scientist said. Then using a total of five factors - including the three previously undescribed factors - the team was able to transform skin cells directly into the pain sensing neurons.

Asked what kept him pushing through repeated failures to make pain neurons using different approach initially starting with human embryonic stem cells, project leader Clifford Woolf, M.D./Ph.D., said "It's really complicated, because there are many projects I do pull the plug on, when I can't see anyway out of it. Here, even though we experienced failure constantly, I always felt there was something else we could do that would advance the work. Whether it was worth this long haul, time will tell. I'm optimistic," Woolf said. "I think the ability to make human pain neurons for the pain field is going to be very important. Furthermore, our failure with embryonic stem cells lead us to work with adult tissue samples making the technology much more clinically relevant since these are easy to collect from patients suffering from different kinds of pain", he added.

Woolf noted that the pain sensing neurons his team developed "beautifully model" neuropathies and hypersensitivity to pain experienced by some of the patients who donated skin cells to the project. "Many pain conditions are due to genetic mutations, and we can now model these" Woolf said.

More information: Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts, Nature Neuroscience, DOI: 10.1038/nn.3886

Identifican una molécula de señalización crucial para detener la reprogramación celular

Fuente: http://noticias.lainformacion.com/salud/genetica/investigadores-identifican-una-molecula-de-senalizacion-crucial-para-detener-la-reprogramacion-celular_E9nMHaz5tJtwp8jotnJCg6/

Mientras investigaban una enfermedad genética rara, científicos de la Escuela de Medicina de la Universidad de California, San Diego, Estados Unidos, han descubierto que una molécula de señalización omnipresente es crucial para la reprogramación celular, un hallazgo con implicaciones importantes para la medicina regenerativa basada en células madre, terapias de reparación de heridas y potenciales tratamientos contra el cáncer.

Karl Willert, profesor asistente en el Departamento de Medicina Celular y Molecular, y sus colegas estaban tratando de utilizar las células madre pluripotentes inducidas (iPSC) para crear un modelo de la hipoplasia dérmica focal (FDH, por sus siglas en inglés), un raro trastorno hereditario causado por mutaciones en un gen llamado PORCN. Los coautores del estudio V. Reid Sutton e Ignatia Van den Veyver, en el Colegio Baylor de Medicina, en Texas, Estados Unidos, habían publicado en 2007 la observación de que las mutaciones PORCN subyacen en la FDH en los seres humanos.

La FDH se caracteriza por anormalidades de la piel, como manchas de la piel muy fina o diferentes tonos, grupos de venas visibles y crecimientos de verrugas y muchos individuos con FDH también sufren de anomalías en manos y pies y rasgos faciales diferentes. La condición también se conoce como síndrome de Goltz después de que Robert Goltz la describiera por primera vez en la década de 1960. Goltz pasó la última parte de su carrera como profesor en la Universidad de California en San Diego en la Escuela de Medicina y se retiró en 2004, falleciendo a principios de este año.

Para su sorpresa, Willert y sus colegas descubrieron que los intentos por reprogramar fibroblastos con FDH o células de la piel con la mutación PORCN en iPSCs fallaron con los métodos estándar, pero tuvieron éxito cuando agregaron proteínas WNT, una familia de moléculas de señalización altamente conservadas que regulan las interacciones entre células durante la embriogénesis, como detallan en un artículo en la edición digital de 'Cell Reports'.

"La señalización de WNT es omnipresente --afirma Willert--. Cada célula expresa uno o más genes WNT y cada célula es capaz de recibir señales de WNT. Las células individuales en un plato pueden crecer y se dividen sin WNT, pero en un organismo, WNT es crítica para la comunicación de célula a célula para que las células se distingan de sus vecinas y, por lo tanto, generen distintos tejidos, órganos y partes del cuerpo".

La señalización de WNT también es crítica en la regeneración de miembros (en algunos organismos) y la reparación tisular. "Hemos demostrado que se requiere de señalización de WNT para la reprogramación celular --señala Willert. Algunos de los procesos que se producen durante la reprogramación celular se asemejan a los que suceden durante los procesos de regeneración y reparación de heridas".

Por ejemplo, la regeneración de miembros en organismos como el ajolote y el pez cebra requieren células en el sitio de la lesión para cambiar su función y luego reconstruir el tejido dañado, con WNT jugando un papel esencial en estos procesos regenerativos. Willert advierte que "sería una exageración decir que la activación de la señalización de WNT permitirá regenerar extremidades", pero cree que la activación de WNT es valiosa para ayudar a la reparación de tejidos.

De hecho, ya están en marcha una variedad de esfuerzos para explorar cómo aprovechar la señalización WNT para promover la curación de heridas, como en las reparaciones de fracturas óseas e, incluso, el crecimiento del cabello. No obstante, Willert señala que "hay una línea muy fina entre la reparación de los tejidos y promover el crecimiento del cáncer.

Por ello, ya hay trabajos en marcha para crear terapias que bloqueen la señalización WNT como un mecanismo para detener el crecimiento del cáncer. A principios de este año, por ejemplo, Willert y sus colegas publicaron hallazgos que describen el uso de un anticuerpo para perturbar la señalización WNT en las células madre embrionarias. En las células cancerosas con mutaciones en la vía de señalización WNT, este anticuerpo puede inhibir su crecimiento y desarrollo.