Category Archives: Stem Cells

Public release date: 23-Jan-2013 [ | E-mail | Share ]

Contact: Jim Fessenden james.fessenden@umassmed.edu 508-856-2600 University of Massachusetts Medical School

WORCESTER, MA A retrovirus called HERV-H, which inserted itself into the human genome millions of years ago, may play an important role in pluripotent stem cells, according to a new study published in the journal Retrovirology by scientists at UMass Medical School. Pluripotent stem cells are capable of generating all tissue types, including blood cells, brain cells and heart cells. The discovery, which may help explain how these cells maintain a state of pluripotency and are able to differentiate into many types of cells, could have profound implications for therapies that would use pluripotent stem cells to treat a range of human diseases.

"What we've observed is that a group of endogenous retroviruses called HERV-H is extremely busy in human embryonic stem cells," said Jeremy Luban, MD, the David L. Freelander Memorial Professor in HIV/AIDS Research, professor of molecular medicine and lead author of the study. "In fact, HERV-H is one of the most abundantly expressed genes in pluripotent stem cells and it isn't found in any other cell types."

In the study, Dr. Luban and colleagues describe how RNA from the HERV-H sequence makes up as much as 2 percent of the total RNA found in pluripotent stem cells. The HERV-H sequence is controlled by the same factors that are used to reprogram skin cells into induced pluripotent stem (iPS) cells, a discovery that garnered the 2012 Nobel Prize in Physiology or Medicine. "In other words, HERV-H is a new marker for pluripotency in humans that has the potential to aid in the development of iPS cells and transform current stem cell technology," said Luban.

When a retrovirus infects a cell, it inserts its own genes into the chromosomal DNA of the host cell. As a result, the host cell treats the viral genome as part of its own DNA sequence and begins making the proteins required to assemble new copies of the virus. And because the retrovirus is now part of the host cell's genome, when the cell divides, the virus is inherited by all daughter cells.

In rare cases, it's believed that retroviruses can infect human sperm or egg cells. If this happens, and if the resulting embryo survives, the retrovirus can become a permanent part of the human genome, and be passed down from generation to generation. Scientists estimate that as much as 8 percent of the human genome may be comprised of extinct retroviruses left over from infections that occurred millions of years ago. Yet these sequences of fossilized retrovirus were thought to have no discernible functional value.

"The human genome is filled with retrovirus DNA thought to be no more than fossilized junk," said Luban. "Increasingly, there are indications that these sequences might not be junk. They might play a role in gene expression after all."

An expert in HIV and other retroviruses, Luban and his colleagues were seeking to understand if there was a rationale behind where, in the expansive human genome, retroviruses inserted themselves. Knowing where along the chromosomal DNA retroviruses might attack could potentially lead to the development of drugs that protect against infection; better gene therapy treatments; or novel biomarkers that would predict where a retrovirus would insert itself in the genome, said Luban.

Turning these same techniques on the retrovirus sequences already in the human genome, they discovered a sequence, HERV-H, that appeared to be active. "The sequences weren't making proteins because they had been so disrupted over millions of years, but they were making these long, noncoding RNAs," said Luban.

Continue reading here:
Retrovirus in the human genome is active in pluripotent stem cells

Researchers in Japan said Wednesday they have succeeded in growing human kidney tissue from stem cells for the first time in a potential breakthrough for millions with damaged organs who are dependent on dialysis.

Kidneys have a complex structure that is not easily repaired once damaged, but the latest findings put scientists on the road to helping a diseased or distressed organ fix itself.

Kenji Osafune of Kyoto University said his team had managed to take stem cells -- the "blank slates" capable of being programmed to become any kind of cell in the body -- and nudge them specifically in the direction of kidney tissue.

"It was a very significant step," he told AFP.

Osafune said they had succeeded in generating intermediate mesoderm tissue from the stem cells, a middle point between the blank slate and the finished kidney tissue.

"There are about 200 types of cells in the human body, but this tissue grows into only three types of cells," namely adrenal cells, reproductive gland cells and kidney cells, he said, adding that as much as 90 percent of cultures in their research developed into viable mesoderm tissue.

This embryonic intermediary can be grown either in test tubes or in a living host into specific kidney cells.

Osafune and his team created part of a urinary tubule, a small tube in the kidney that is used in the production of urine.

While the research is not aimed at growing an entire working kidney, he said the method his team had developed would help scientists learn more about intermediate mesoderm development and may provide a source of cells for regenerative therapy.

"I would say that we have arrived at the preliminary step on the road to the clinical level," he said.

See the original post here:
Japan researchers grow kidney tissue from stem cells

In this week's issue of Science Signaling (22 January, 2013), Danen and colleagues of the Division of Toxicology of LACDR report novel insights into the question how stem cells decide to commit suicide when their DNA is damaged.

It is known that damaged DNA, especially in stem cells can lead to accumulation of potentially dangerous mutations that may be a source for cancer. To prevent this, evolution has provided our cells with the ability to recognize damaged DNA and to rapidly respond to it. This so-called "DNA damage response" activates repair mechanisms, and, if damage is too severe to repair, turns on a cascade of events leading to cell death.

All cells in our body are constantly experiencing small injuries in their DNA, for instance due to UV light or chemicals. It is important that cells first try to repair damaged DNA and only decide to commit suicide if damage is beyond repair. If suicide signals would be turned on too fast, stem cells in our tissues might be depleted causing premature aging. The discovery published in this week's Science Signaling is a new mechanism that acts as a break on the suicide signals.

In collaboration with colleagues from the Department of Toxicogenetics of the LUMC and from the University of Copenhagen, Danen et al. have been able to integrate several large-scale analyses to unravel the events that make up the DNA damage response. Genome-wide changes in gene activity and protein modifications, as well as genome-wide "gene silencing" screens were integrated with bioinformatics tools to create signaling networks. This was possible through extensive collaboration within the NGI-funded, "Netherlands Toxicogenomics Center".

The signaling networks point to novel methods to recognize chemicals or drugs that activate a DNA damage response and hence, might be dangerous for human exposure. At the same time, the networks provide new clues for why cancer cells are often able to avoid activation of suicide signals when exposed to radiotherapy or chemotherapy. The publication in Science Signaling is one of the outcomes of this project; additional publications will come out this year.

Journal reference: Science Signaling

Provided by Leiden University

More:
Stem cells: Tuning the death sentence

Human life is dependent on the constant growth of plants, and it is the job of stem cells to see to it that this occurs. They are found at the tips of the shoots and roots, the so-called meristems. Stem cells can transform themselves into other types of cells and develop new organs, such as leaves, fruits, and twigs, throughout the entire lifespan of the plant. However, in order for the plant to continue growing and developing organs, several cells at the tips of the shoots and roots have to remain stem cells. In order to ensure that this is the case, the cells need signals to help them identify their position in the plant and trigger the appropriate developmental program.

A team led by Prof. Dr. Thomas Laux from the Institute of Biology III of the University of Freiburg has succeeded in confirming that plants need a micro-RNA at the tip of their shoots to prevent all of the stem cells from transforming themselves into other cell types. The Freiburg researchers used thale cress as a model organism for their studies. Their findings have now been published in the renowned journal Developmental Cell.

Micro-RNAs are very small molecules of ribonucleic acid (RNA) that do not encode any proteins themselves but rather prevent proteins from being generated from other RNAs. Thanks to their diminutive size, micro-RNAs can move from one cell to the next in plants.

Scientists are already familiar with one micro-RNA that informs meristem cells that they should specialize. However, this micro-RNA needs to be neutralized in the area where stem cells need to be preserved. Thomas Laux, member of the Cluster of Excellence BIOSS Centre for Biological Signalling Studies, has now succeeded in demonstrating that there is a second micro-RNA that serves precisely this function, thus preventing the stem cells from transforming.

The newly discovered micro-RNA, the stem cell preserver, is only produced in one particular cell layer, the epidermis of the tip of the shoot. The micro-RNA only reaches several underlying layers of cells near its home in the epidermis, all of which become stem cells. The more distant areas do not receive enough stem cell preservers, and the cells there transform themselves into other cell types. In this way, the plant can preserve the stem cells at the tip of its shoots and thus develop leaves, blossoms, or fruits regardless of environmental influences.

Journal reference: Developmental Cell

Provided by Albert Ludwigs University of Freiburg

Excerpt from:
Tiny molecules preserve stem cells: Researchers shows what makes constant plant growth possible

Jan. 22, 2013 Human life is dependent on the constant growth of plants, and it is the job of stem cells to see to it that this occurs. They are found at the tips of the shoots and roots, the so-called meristems. Stem cells can transform themselves into other types of cells and develop new organs, such as leaves, fruits, and twigs, throughout the entire lifespan of the plant. However, in order for the plant to continue growing and developing organs, several cells at the tips of the shoots and roots have to remain stem cells. In order to ensure that this is the case, the cells need signals to help them identify their position in the plant and trigger the appropriate developmental program.

A team led by Prof. Dr. Thomas Laux from the Institute of Biology III of the University of Freiburg has succeeded in confirming that plants need a micro-RNA at the tip of their shoots to prevent all of the stem cells from transforming themselves into other cell types. The Freiburg researchers used thale cress as a model organism for their studies. Their findings have now been published in the journal Developmental Cell.

Micro-RNAs are very small molecules of ribonucleic acid (RNA) that do not encode any proteins themselves but rather prevent proteins from being generated from other RNAs. Thanks to their diminutive size, micro-RNAs can move from one cell to the next in plants.

Scientists are already familiar with one micro-RNA that informs meristem cells that they should specialize. However, this micro-RNA needs to be neutralized in the area where stem cells need to be preserved. Thomas Laux, member of the Cluster of Excellence BIOSS Centre for Biological Signalling Studies, has now succeeded in demonstrating that there is a second micro-RNA that serves precisely this function, thus preventing the stem cells from transforming.

The newly discovered micro-RNA, the stem cell preserver, is only produced in one particular cell layer, the epidermis of the tip of the shoot. The micro-RNA only reaches several underlying layers of cells near its home in the epidermis, all of which become stem cells. The more distant areas do not receive enough stem cell preservers, and the cells there transform themselves into other cell types. In this way, the plant can preserve the stem cells at the tip of its shoots and thus develop leaves, blossoms, or fruits regardless of environmental influences.

Share this story on Facebook, Twitter, and Google:

Other social bookmarking and sharing tools:

Story Source:

The above story is reprinted from materials provided by Albert-Ludwigs-Universitt Freiburg.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

See more here:
Tiny molecules preserve stem cells: Research shows what makes constant plant growth possible

Cancer stem cells (CSCs) are an important population of tumour cells. They can self-renew, are thought to contribute to metastasis and are resistant to chemo- and radiotherapy. CSCs’ specific properties mean that new cancer treatments are required to target these cells. This article reviews some recent developments in the field including new therapeutic strategies and techniques that researchers are using to overcome some of the main challenges they face. These studies are proving vital in understanding the biology of CSCs and tumour survival.

Cancer was first suggested to originate from adult stem cells in the nineteenth century. This theory acquired credibility in the twentieth century when acute myeloid leukaemia cells were shown to be able to give rise to new tumours [Bonnet and Dick, 1997]. The ‘cancer stem cell’ theory, as it is now known [reviewed by Behbod and Rosen, 2004], suggests that adult stem cells may play an important part in cancer due to their association with tumour initiation, maintenance and metastasis [Reya et al. 2001; Zhao et al., 2012].  All tumours are thought to contain populations of cancer stems cells (CSCs) that undergo asymmetric division to form phenotypically distinct cells within the same tumour cell population [Castano et al. 2012].

Research has demonstrated that CSCs behave differently from normal stem cells. Their molecular regulation is disrupted, which induces changes in their phenotype. CSCs have deregulated cell cycles, which result in DNA damage, and are suggested to play a key role in the tumour, contributing to its survival through unlimited self-renewal capacity [Baccelli and Trumpp, 2012].

Clinical challenges of cancer stem cells

The CSC concept has accumulated credibility over the past fifteen years or so. However, recent research has also emphasised the clinical challenges provoked by this theory. For example, genetically and phenotypically distinct sub-populations of CSCs can exist within the same tumour. Despite this, non-CSCs have been shown to form the main bulk of the tumour, prompting debate on the roles of the different cell types within a tumour [Zhao, 2012]. CSC phenotypes also vary between individuals [Baccelli and Trumpp, 2012].

An important discovery is that CSCs are resistant to current standard therapies that are used to treat patients. CSCs are not killed by chemotherapy, radiotherapy or surgery. In fact, it has been shown that chemotherapy increases the ability of CSCs to survive [Zhao et al., 2012]. These cells are also capable of entering a dormant or quiescent state before re-entering the cell cycle and rebounding to form new tumours when their environment is more favourable [Castano et al., 2012].

CSCs have also been suggested to originate from progenitors that undergo reverse phenotypic changes due to an accumulation of genetic and epigenetic abnormalities [Baccelli and Trumpp, 2012]. These re-generated stem cells may go on to form CSCs that can differentiate into any cell type the tumour may require [Baccelli and Trumpp, 2012], forming a hierarchy within the tumour’s multiple cell populations.

 The Challenges of working with CSCs

One main hypothesis for treatment is the ‘dandelion phenomenon’ insomuch as treating the visible ‘flower’ (tumour growth) does not treat the underlying problem and you need to aim for the ‘roots’ (CSCs) [Zhao et al., 2012]. Targeting the root of the problem, however, means finding new drug therapies to specifically eradicate CSCs and this has challenged researchers due to the difficulties experienced in culturing CSCs and performing assays. The large quantities of cells required for assays are hard to cultivate. New drugs are routinely screened using high throughput assays that allow thousands of compounds to be tested simultaneously in a small timeframe. Each test requires the use of microtitre plates that contain 1,536 or 3,456 wells. Robotic instruments are usually used for the assay testing due to their reliability and rapidity in dispensing the small volumes needed for these assays. However, cells and especially stem cells are very delicate and require specific growth media, rendering them difficult to work with using laboratory equipment, notably causing blockages in robotic instruments. Due to their fragility and specific growth requirements for culture, all stem cells are very precious and waste needs to be kept to a minimum. To resolve these assay problems, innovative microplate dispensers have been developed, which enables reliable stem cell dispensing.

New therapeutic targets

Recent research has identified new potential targets in CSCs. These include targeting specific receptors and specific molecular pathways. It has been reported that breast CSCs can be selectively eradicated by salinomycin [Gupta et al., 2009]. An important mechanism of CSC drug resistance involves ABC-transporters and in human myeloid leukemia stem cells, salinomycin is thought to overcome ABC-transporter-mediated multidrug resistance. This drug may also prevent apoptosis resistance [Naujokat and Steinhart, 2012]. Recently, salinomycin has also been shown to target CSCs in other types of human cancers including gastric and prostate cancers [Zhi et al., 2011; Ketola et al., 2012].

It has also been shown that microRNAs (miRNAs) are frequently deregulated in human cancer, suggesting that they could be a new means of testing for and diagnosing the disease [Ali et al. 2012]. Research has also targeted molecular pathways used by CSCs. By targeting the functional pathways that CSCs rely upon, it is hoped that CSCs can be eradicated. One problem with this method is that normal stem cells and CSCs share many pathways so any drug would have to be very selective. One main target is the Wnt signalling pathway, which is thought to play a role in self-renewal of mammary tumour stem cells [Behdod and Rosen, 2004]. The hedgehog, notch and hox family pathways have also been successfully inhibited by researchers, eradicating CSCs in some tumour types [Zhao et al., 2012].

In conclusion, current cancer therapies have proved unsuccessful in eliminating CSCs, thought to be the main cause of metastasis and tumour regrowth following treatment. Our understanding of CSCs has improved greatly since the beginning of the century, enabling scientists to explore potential new cancer cures. As explained by the dandelion phenomenon, much research is going into eradicating CSCs as an integral part of cancer therapies. A combination of therapies, which target the tumour as well as the CSCs, could lead to dramatic improvements in cancer therapies and survival rates.

References

Ali AS, Ahmad A, Ali S, Bao B, Philip PA, Sarkar FH (2012). The role of cancer stem cells and miRNAs in defining the complexities of brain metastasis, Journal of Cellular Physiology 228: 36-42

Baccelli I, Trumpp A (2012). The evolving concept of cancer and metastasis stem cells. Journal of Cell Biology 198(3): 281-293.

Behbod F, Rosen JM (2004). Will cancer stem cells provide new therapeutic targets? Carcinogenesis 26(4): 703-711.

Bonnet D, Dick JE. Human acute myeloid leukemia is organised as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine 3(7): 730-737

Castano Z, Fillmore CM, Kim CF, McAllister SS (2012). The bed and the bugs: Interactions between the tumor microenvironment and cancer stem cells, Seminars in Cancer Biology 22:462-470

Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138: 645-659.

Ketola K, Hilva M, Vuoristo A, Ruskeepaa AL, Oresic M, Kallioniemi O, Iljin K (2012). Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress, British Journal of Cancer 106(1): 99-106

Naujokat C and Steinhart R (2012). Salinomycin as a drug for targeting human cancer stem cells, Journal of Biomedicine and Biotechnology 2012 doi: 10.1155/2012/950658

Reya T, Morrison SJ, Clarke MF, Weissman IL (2001). Stem cells, cancer, and cancer stem cells. Nature 414(6859): 105-111.

Zhao L, Zhao Y, Bao Q, Niess H, Jauch K-W, Bruns CJ (2012). Clinical implications of targeting of stem cells. European Surgical Research 49: 8-15.

Zhi QM, Chen XH, Ji J, Zhang JN, Li JF, Cai Q, Lui BY, Gu QL, Zhu ZG, Yu YY (2011). Salinomycin can effectively kill ALDHhigh stem-like cells on gastric cancer, Biomedicine and Pharmacotherapy 65(7): 509-515