A team of international researchers has turned to stem cells in a quest to find an a more effective treatment for patients with drug-resistant tuberculosis (TB). The new method being investigated involves using the patients own bone marrow mesenchymal stromal cells (MSCs) to boost immune response and heal damaged tissue.

Multi-drug resistant TB effects around 450,000 in Eastern Europe, Asia, and South Africa according to the World Health Organization, and conventional treatments have a low rate of success.

Currently in its preliminary stages, the study is designed to investigate the possibility that MSCs can help organs to regulate themselves and repair damaged or traumatized tissues. Specifically in this case, the stem cells migrate to the lung with TB bacteria inflammation and improve the immune response to help the body get rid of the bacteria.

Between September 2009 and June 2011, the study looked at 30 patients from a specialist center in Minsk, Belarus, whose age varied from 21 to 65 years old, and who were resistant to TB drugs. They chose Belarus because of the high rate of resistant tuberculosis (76 percent) among treated patients in that region. They also observed 30 patients who met the inclusion criteria and who opted not to have MSC therapy.

Besides giving patients the anti-TB antibiotics, the researchers collected cells from their own bone marrow, cultured them and introduced them back into the patient within four weeks of the start of the anti-TB drug treatment. Eighteen months later, the rate of cure for patients who received MSC therapy was more than three times higher compared with those who didnt get treated with the cells.

MSC therapy produced a few side effects, which the researchers considered mild. Fourteen patients had high cholesterol, 11 patients suffered from nausea while 10 others had lymphopenia (low level of lymphocytes in the blood) or diarrhoea.

The researchers noted MSC cells harvested from TB patients did not present any aberrant features in comparison with those extracted from healthy donors. Neither did the anti-TB drugs seem to have a negative impact on the harvest. Concerns over the risk of suppressing an immune response, leading to the worsening of tuberculosis, did not materialize. However, they highlight that future studies would need to assess whether certain anti-M tuberculosis drug combinations or concomitant M. tuberculosis infection (a type of TB infection) could have an impact.

The results of this novel and exciting study show that the current challenges and difficulties of treating multi-drug resistant TB are not insurmountable, and they bring a unique opportunity with a fresh solution to treat hundreds of thousands of people who die unnecessarily of drug-resistant TB," says co-author Professor Alimuddin Zumla. "Further evaluation in phase 2 trials is now urgently required to ascertain efficacy and further safety in different geographical regions such as South Africa where multi-drug resistant and extensively-drug resistant TB are rife.

Details of the study are published in The Lancet Respiratory Medicine.

Source: UCL

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Stem cells could offer alternative treatment for patients with resistant tuberculosis

2 hours ago Endodermal cells, they form organs such as lung, liver and pancreas. Credit: IDR, Helmholtz Zentrum Mnchen

The Wnt/-catenin signaling pathway and microRNA 335 are instrumental in helping form differentiated progenitor cells from stem cells. These are organized in germ layers and are thus the origin of different tissue types, including the pancreas and its insulin-producing beta cells. With these findings, Helmholtz Zentrum Mnchen scientists have discovered key molecular functions of stem cell differentiation which could be used for beta cell replacement therapy in diabetes. The results of the two studies were published in the renowned journal Development.

The findings of the scientists of the Institute of Diabetes and Regeneration Research (IDR) at Helmholtz Zentrum Mnchen (HMGU) provide new insights into the molecular regulation of stem cell differentiation. These results reveal important target structures for regenerative therapy approaches to chronic diseases such as diabetes.

During embryonic development, organ-specific cell types are formed from pluripotent stem cells, which can differentiate into all cell types of the human body. The pluripotent cells of the embryo organize themselves at an early stage in germ layers: the endoderm, mesoderm and ectoderm. From these three cell populations different functional tissue cells arise, such as skin cells, muscle cells, and specific organ cells.

Various signaling pathways are important for this germ layer organization, including the Wnt/-catenin signaling pathway. The cells of the pancreas, such as the beta cells, originate from the endoderm, the germ layer from which the gastrointestinal tract, the liver and the lungs also arise. Professor Heiko Lickert, director of the IDR, in collaboration with Professor Gunnar Schotta of LMU Mnchen, showed that the Wnt/-catenin signaling pathway regulates Sox17, which in turn regulates molecular programs that assign pluripotent cells to the endoderm, thus inducing an initial differentiation of the stem cells.

In another project Professor Lickert and his colleague Professor Fabian Theis, director of the Institute of Computational Biology (ICB) at Helmholtz Zentrum Mnchen, discovered an additional mechanism that influences the progenitor cells. miRNA-335, a messenger nucleic acid, regulates the endodermal transcription factors Sox17 and Foxa2 and is essential for the differentiation of cells within this germ layer and their demarcation from the adjacent mesoderm. The concentrations of the transcription factors determine here whether these cells develop into lung, liver or pancreas cells. To achieve these results, the scientists combined their expertise in experimental research with mathematical modeling.

"Our findings represent two key processes of stem cell differentiation," said Lickert. "With an improved understanding of cell formation we can succeed in generating functional specialized cells from stem cells. These could be used for a variety of therapeutic approaches. In diabetes, we may be able to replace the defective beta cells, but regenerative medicine also offers new therapeutic options for other organ defects and diseases."

Diabetes is characterized by a dysfunction of the insulin-producing beta cells of the pancreas. Regenerative treatment approaches aim to renew or replace these cells. An EU-funded research project ('HumEn'), in which Lickert and his team are participating, shall provide further insights in the field of beta-cell replacement therapy.

The aim of research at Helmholtz Zentrum Mnchen, a partner in the German Center for Diabetes Research (DZD), is to develop new approaches for the diagnosis, treatment and prevention of major common diseases such as diabetes mellitus.

Explore further: Stem cells on the road to specialization

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Insulin-producing beta cells from stem cells: Scientists decipher early molecular mechanisms of differentiation

PUBLIC RELEASE DATE:

22-Jan-2014

Contact: Robin Crawford src@faseb.org 301-634-7010 Federation of American Societies for Experimental Biology

Bethesda, MD This 2014 FASEB Science Research Conference focuses on recent advances in our understanding of the regulatory mechanisms controlling normal and abnormal functions of muscle-resident stem cells in regeneration, muscle homeostasis, hypertrophy, aging and muscle degenerative disease.

Eight plenary sessions and three dedicated poster sessions will encompass the following major themes: transcriptional and posttranscriptional regulation of gene expression in stem cells, satellite cell heterogeneity and potential, stem cell signaling and environmental interactions, satellite cell quiescence, activation and renewal, non-satellite stem cells, satellite cell proliferation, commitment and differentiation, muscle stem cells in growth and hypertrophy, and muscle stem cells in aging, disease and therapeutics.

This FASEB Conference increasingly attracts investigators in related fields who are interested in the rapid advances in muscle stem cell research, and interdisciplinary interactions are an important feature of this meeting. Collectively, this conference, which represents the only international conference that focuses exclusively on muscle satellite and stem cell populations, provides a venue to present cutting edge research, foster discussions, and promote collaborative interactions, with the goal of advancing a fundamental understanding of muscle-resident stem cells, and ultimately, translating this knowledge to the clinic.

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FASEB has announced a total of 35 Science Research Conferences (SRC) in 2014. Registration opens January 17, 2014. For more information about an SRC, view preliminary programs, or find a listing of all our 2014 SRCs, please visit http://www.faseb.org/SRC.

Since 1982, FASEB SRC has offered a continuing series of inter-disciplinary exchanges that are recognized as a valuable complement to the highly successful society meetings. Divided into small groups, scientists from around the world meet intimately and without distractions to explore new approaches to those research areas undergoing rapid scientific changes.

In efforts to expand the SRC series, potential organizers are encouraged to contact SRC staff at SRC@faseb.org. Proposal guidelines can be found at http://www.faseb.org/SRC.

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FASEB announces 2014 Science Research Conference: Skeletal Muscle Satellite and Stem Cells

Researchers at the Universitys Comprehensive Cancer Center, in collaboration with an international cohort, have developed means of identifying two states of breast cancer stem cells, giving them new clues as to how to treat patients with cancer.

By distinguishing the different states, they hope to find more targeted and effective treatments for the disease, which kills over 40,000 people each year in the U.S., according to the American Cancer Society.

What we found is that the stem cells actually are like chameleons that is they can exist in two different states, said Max S. Wicha, M.D., professor of Oncology and director of the University of Michigan Comprehensive Cancer Center.

In breast cancer, a small fraction of cells act as seeds of the tumor, Wicha said. Cells in this state, known as epithelial-mesenchymal transition, are dormant but can spread to other organs in the body.

The process of these cells spreading is called metastasis, and studying this process has been a key component of the research findings. The previous dearth of research on the dormant cells within the process of metastasis has posed a challenge to researchers trying to find new treatment options.

As a matter of fact, in breast cancer, we sometimes have women that go out ten or 15 years and we think are cured, and then the cancer, it turns out, was hiding in the bone, Wicha said.

Moreover, the new findings show that these exact same cells have the capacity to switch states, causing them to not only look different under the microscope, but also turn on different genes in the cell.

When the cells enter the mesenchymal-epithelial transition state, they can no longer invade tissues but they can grow and reproduce into malignant tumors.

The tumor microenvironment enables these cells to flip back and forth between the EMT and MET-states, researchers said. While the cells plasticity seems to be the reason that they are able to flip between two states, the reason for the cells ability to switch states at any given time is unclear.

Were very interested in studying whether things like stress that may change some of the proteins or hormones in your body may actually cause the cells to change their state and come out of dormancy, Wicha said.

Read more:
Study examines stem cell role in breast cancer care