Archive for ‘Stem cells’

November 20, 2011

Researchers Create a Pituitary Gland from Scratch

The development of a complex multicellular organism from a single-cell zygote into a complete animal (or plant) is somewhat of a neat trick. It’s impressive that from the zygote perhaps a couple hundred different types of cells can emerge, with each of the trillions of final cells at the right time and place. What’s just as surprising is that the whole process is so neatly programmed by evolution into an organism’s genome that it happens automatically as the appropriate set of genes gets turned on at just the right time.

Developmental biologists have been studying the process for decades. What they’ve found is that cells at any particular stage not only make up specific types of embryonic tissue, but are also programmed to turn on genes for the next generation of cells based on the types of tissue and nearby tissue they occur in.

Biologists have now learned enough about the details of this program that they can make it work – for certain tissues and organs – in a lab dish instead of a complete embro, starting from pluripotent stem cells.

In research just published, the organ was a mouse pituitary gland, a very small organ, but with complex function. In humans it’s about the size of a pea and weighs only half a gram. But it secretes dozens of different endocrine hormones.

It’s particularly important that the gland has a 3-dimensional structure that’s essential to its function. Being able to grow a pituitary gland from stem cells is a very significant achievement towards eventual regenerative medicine, in which larger and more complex organs such as kidneys or even hearts can be grown from stem cells.

Self-organized pituitary-like tissue from mouse ES cells

The possibility that functional, three-dimensional tissues and organs may be derived from pluripotent cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), represents one of the grand challenges of stem cell research, but is also one of the fundamental goals of the emerging field of regenerative medicine. Developmental biology has played a central role in informing such efforts, as it has been shown that stem cell differentiation can be directed to follow a given lineage pathway by culturing stem cells in conditions that recapitulate the specific cellular and molecular environment from which such cells normally emerge during embryogenesis. Intriguingly, recent work has shown that when ES cells are cultured under the appropriate conditions, they can be driven to self-organize into complex, three-dimensional tissue-like structures that closely resemble their physiological counterparts, a remarkable advance for the field.

New work by Hidetaka Suga of the Division of Human Stem Cell Technology, Yoshiki Sasai, Group Director of the Laboratory for Organogenesis and Neurogenesis, and others has unlocked the most recent achievement in self-organized tissue differentiation, steering mouse ESCs to give rise to tissue closely resembling the hormone-secreting component of the pituitary, known as the adenohypophysis, in vitro.

Not only did the lab-grown pituitary tissue have much of the appropriate physiological activity, but when transplanted into mice whose pituitary gland had been removed, the mice survived much better than controls.

Further reading:

A Gland Grows Itself

Researchers Create a Pituitary Gland from Scratch

Pituitary glands from stem cells

Self-formation of functional adenohypophysis in three-dimensional culture

November 7, 2011

Erasing the Signs of Aging in Human Cells Is Now a Reality

Human induced pluripotent stem cells (iPSCs) are adult body cells that have been treated in vitro to revert to a pluripotent state very close to embryonic stem cells. They were first produced in 2007, and the process of generating them has become progressively faster and more efficient. The resulting iPSCs now also have fewer defects and are less susceptible to becoming cancerous.

Although iPSCs are not precisely the same as embryonic stem cells, they share the property of lacking all traces of cellular aging, such as shortened telomeres and altered metabolism. In other words, they have been rejuvenated, having full-length telomeres and normal mitochondrial metabolism, gene expression profiles, and levels of oxidative stress.

Like other pluripotent cells, iPSCs can in principle differentiate into any type of body cell. Progress is being made in figuring out the exact recipe needed to actually produce cells that are equivalent to any adult cell type – some types are easier to make than others.

Given adult cells, of any particular type, derived from iPSCs, the natural question is whether such cells are also free of traces of aging that existed in the original adult cells from which the iPSCs were derived. The answer is that they are rejuvenated in comparison to the cells they were originally derived from – even if those original cells came from human centenarians, and (surprisingly) even if the original cells had entered the senescent stage in which they could no longer divide.

Of course, all this work was accomplished in vitro. There’s no obvious way to apply it to the whole body of an older person, or even to a complex organ. Perhaps such cells can eventually be used as a therapy for patients with Parkinson’s disease or to grow replacement arteries or tracheas. But that kind of development is still somewhere in the future.

Erasing the Signs of Aging in Human Cells Is Now a Reality

[S]enescent cells, programmed into functional iPSC cells, re-acquired the characteristics of embryonic pluripotent stem cells.

In particular, they recovered their capacity for self-renewal and their former differentiation potential, and do not preserve any traces of previous aging. To check the “rejuvenated” characteristics of these cells, the researchers tested the reverse process. The rejuvenated iPSC cells were again differentiated to adult cells and compared to the original old cells, as well as to those obtained using human embryonic pluripotetent stem cells (hESC).

“Signs of aging were erased and the iPSCs obtained can produce functional cells, of any type, with an increased proliferation capacity and longevity,” explains Jean-Marc Lemaitre who directs the Inserm AVENIR team.

The key to this new development was finding an improved recipe for the transcription factors used to effect reprogramming. In addition to the usual four factors (OCT4, SOX2, c-MYC and KLF4), the researchers included NANOG and LIN28 to erase traces of cell senescence.

Further reading:

Ageing stem cells from centenarian rejuvenated

‘Rejuvenated’ stemcells coaxed from centenarian

Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state

October 14, 2011

Researchers demonstrate that iPS stem cells may be used for gene therapy

Gene therapy sounds good, in principle, as a means of treating diseases that result from genetic defects. But there have been at least two major practical problems in making use of gene therapy in the clinic. First, it’s very important for the safety of the procedure to make changes only to the defective gene (or even just the critical part of the gene) and no other portion of the DNA. Second, there needs to be an effective way to deliver the therapy, in whatever form it takes, to exactly the right tissues in the body that are affected by the defective gene.

Solving these two problems simultaneously is especially difficult. There are a variety of techniques for modifying DNA in specific ways, using a number of specialized enzymes. But these techniques are actually usable only in a test tube. Simply setting the enzymes loose in a patient’s body doesn’t work. The usual way to get around this is by preparing the appropriate modified DNA segments and incorporating them into “vectors”, such as some sort of virus, and introducing the vector into a patient’s body, in the hope that it will reach the right tissues to deliver the DNA, without causing any other problems. That hasn’t worked very well, so far, despite a large number of attempts.

What about taking some cells from the patient, modifying their DNA in vitro and then putting them back in the body? The problem there is being able to produce enough cells with good DNA, either before or after reintroduction to the patient’s body, to make a significant difference. Most human cells just don’t reproduce very prolifically outside the body, or even inside for that matter.

At this point you should be thinking, “stem cells!” They are specialized to reproduce quickly, when needed. Up until now, there have been practical problems here, too. Adult stem cells capable of differentiating into the specific type of cell needed in a given tissue may be difficult or impossible to find in useful quantities. And embryonic stem cells, well, even any other problems aside, there’s the problem of avoiding rejection by the patient’s immune system.

The potential solution: induced pluripotent stem cells (iPSCs), made from any convenient cell type of the actual patient. It’s only been five years since iPSCs were first produced. Various practical problems have arisen along the way since then. Some have been mostly overcome; some haven’t. But progress seems to be occurring steadily – including very recently. The application to gene therapy involves making appropriate corrections to the DNA, producing a sufficient number of differentiated cells of the required type from the “fixed” iPSCs, and finally reintroducing them into the patient.

Alpha 1-antitrypsin deficiency is a genetic disorder caused by a point mutation that results in inadequate production of the alpha 1-antitrypsin (A1AT) enzyme in liver cells. The disease affects functioning of the lungs, as well as the liver. Research just published has shown that gene therapy to correct the mutation, applied to iPSCs, is successful at treating the condition in a mouse model.

Researchers demonstrate that iPS stem cells may be used for gene therapy

Researchers from the University of Cambridge, directed by Ludovic Vallier and David Lomas, and from the Sanger Institute, coordinated by Allan Bradley, began by sampling patients’ skin cells, which were then cultured in vitro for “differentiation” before applying the properties of the pluripotent stem cells: this is the “iPS cells” stage. Through genetic engineering, scientists were then able to correct the mutation responsible for the disease. They then engaged the now “healthy” stem cells in the maturation process, leading them to differentiate to liver cells.

Scientists from the Institut Pasteur and Inserm, led by H-l-ne Strick-Marchand in the mixed Institut Pasteur/Inserm Innate Immunity unit (directed by James Di Santo), then tested new human hepatic cells thus produced on an animal model afflicted with liver failure. Their research showed that the cells were entirely functional and suited to integration in existing tissue and that they may contribute to liver regeneration in the mice treated.

Further reading:

Liver-disease mutation corrected in human stem cells

Spell-Checked Stem Cells Show Promise Against Liver Disease

Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells

October 14, 2011

Seeking superior stem cells

The first research reporting the productions of induced pluripotent stem cells (iPSCs) was announced five years ago. Since then, the field has made significant progress, encouraging high hopes that iPSCs could be so similar to embryonic stem cells (ESCs) that they could eventually replace ESCs in research and therapeutic applications.

However, as with almost any new technology, there have been various problems along the way. These include incomplete reproduction of all important characteristics of ESCs, alterations of cell DNA that might cause cancer, and susceptibility of iPSCs to rejection by the immune system even of the donor of the reprogrammed cells.

Further progress depends on being able to deal with these problems. In addition, depending on the method used to produce iPSCs, the process may be too slow and inefficient for practical use. The latest research demonstrates what appears to be an effective technique to significantly improve speed and efficiency of reprogramming.

Seeking superior stem cells – Wellcome Trust Sanger Institute

Researchers from the Wellcome Trust Sanger Institute have today (10/10/2011) announced a new technique to reprogramme human cells, such as skin cells, into stem cells. Their process increases the efficiency of cell reprogramming by one hundred-fold and generates cells of a higher quality at a faster rate.

Until now cells have been reprogrammed using four specific regulatory proteins. By adding two further regulatory factors, Liu and co-workers brought about a dramatic improvement in the efficiency of reprogramming and the robustness of stem cell development. The new streamlined process produces cells that can grow more easily.

read more »

September 24, 2011

Stems cells are potential source of cancer-fighting T cells

The human immune system is, in principle, capable of killing cancer cells all by itself, without need for any extra drugs or doses of radiation. But that supposes the immune system is able to distinguish cancer cells from healthy body cells, since it’s not a good thing when the immune system targets healthy cells.

Stems cells are potential source of cancer-fighting T cells

Adult stem cells from mice converted to antigen-specific T cells — the immune cells that fight cancer tumor cells — show promise in cancer immunotherapy and may lead to a simpler, more efficient way to use the body’s immune system to fight cancer, according to Penn State College of Medicine researchers.

“Cancer immunotherapy is a promising method to treat cancer patients,” said Jianxsun Song, assistant professor of microbiology and immunology. “Tumors grow because patients lack the kind of antigen-specific T cells needed to kill the cancer. An approach called adoptive T cell immunotherapy generates the T cells outside the body, which are then used inside the body to target cancer cells.”

read more »

September 21, 2011

Scientists Turn Back the Clock on Adult Stem Cells Aging

The main function of adult stem cells is to enable the replacement of old or damaged cells of most types, from neurons to skin to the liver. One of the main reasons that organisms as a whole suffer from aging is that their adult stem cells do too, almost like any other cell type.

An important differences between stem cells and other types of cells is that there is a limit to how often an ordinary cell can divide (to create new cells of the same type). This limit is controlled by telomeres – structures on the ends of chromosomes that are gradually shortened every time a cell divides, in part because DNA copying mechanisms cannot accurately copy the ends of DNA strands. In stem cells, however, a mechanism is active that can rebuild shortened telomeres. (This also happens in cancer cells, unfortunately.)

However, in spite of telomere repair in stem cells, they still experience aging, so there must be more to aging than telomeres. One factor is the accumulation of DNA damage due to the inherent imperfections in DNA repair mechanisms.

The research in question here compared young adult stem cells with cells of the same type that had been allowed to divide repeatedly in cultures, in order to determine what changed. One important difference found was the accumulation of DNA segments called Alu element retrotransposons. This type of noncoding DNA is common in primate genomes. However, the accumulation that occurs in aging stem cells appears to be toxic to the cells and eventually forces them into a senescent state.

The good news is that when copying of these Alu elements is suppressed, stem cells are able to regain their self-renewing properties. Naturally, this is being investigated further for possible applications in slowing the overall aging process.

Scientists Turn Back the Clock on Adult Stem Cells Aging

The regenerative power of tissues and organs declines as we age. The modern day stem cell hypothesis of aging suggests that living organisms are as old as are its tissue specific or adult stem cells. Therefore, an understanding of the molecules and processes that enable human adult stem cells to initiate self-renewal and to divide, proliferate and then differentiate in order to rejuvenate damaged tissue might be the key to regenerative medicine and an eventual cure for many age-related diseases. A research group led by the Buck Institute for Research on Aging in collaboration with the Georgia Institute of Technology, conducted the study that pinpoints what is going wrong with the biological clock underlying the limited division of human adult stem cells as they age.

“We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional ‘genomic junk’,” said Victoria Lunyak, associate professor at the Buck Institute for Research on Aging.

Further reading:

Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal

September 17, 2011

Researchers discover a switch that controls stem cell pluripotency

Stem cell scientists are continuing to turn up new information on how embryonic (and other) stem cells work. Embryonic stem cells are pluripotent, meaning they can transform into any other cell type. But what determines when and how this happens? The latest research reveals one particular process, probably out of many.

The FOXP1 gene codes for a transcription factor that regulates the expression of other genes important in embryonic development. As it turns out, very slightly different proteins can be produced from FOXP1, depending on a process, alternative splicing, that affects the derived messenger RNA. In one form of the final transcription factor, genes that maintain pluripotency are expressed: OCT4, NANOG, NR5A2, and GDF3. But in the alternative form, genes are expressed that cause the cell to differentiate into a non-pluripotent cell. The question remains as to what causes splicing to take one path or the other.

Researchers discover a switch that controls stem cell pluripotency

Scientists have found a control switch that regulates stem cell “pluripotency,” the capacity of stem cells to develop into any type of cell in the human body. The discovery reveals that pluripotency is regulated by a single event in a process called alternative splicing.

Alternative splicing allows one gene to generate many different genetic messages and protein products. The researchers found that in genetic messages of a gene called FOXP1, the switch was active in embryonic stem cells but silent in “adult” cells—those that had become the specialized cells that comprise organs and perform functions.

Further reading:

An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming

September 15, 2011

Gene therapy kills breast cancer stem cells, boosts chemotherapy

Gene therapy has had a somewhat tortuous history – as well as some fairly recent successes. The key issue is being able to deliver appropriate genes to exactly the cells where they are needed.

The way this therapy works is somewhat complicated. The agent is targeted to cells, such as cancer cells, that overexpress a gene called claudin4, which encodes a cell membrane protein. Cancer therapies such as chemotherapy and radiation therapy work by causing apoptosis (programmed cell death). But some types of cancer overexpress genes for certain members of the Bcl-2 family of proteins, which inhibit apoptosis. Another protein, BIK counteracts the effects of these Bcl-2 proteins, but it falls short if they are overexpressed. However, BIKDD is a mutant form of BIK that is better at the same task. The experimental therapy delivers BIKDD genes to targeted cancer cells, and pre-clinical tests show that it improves the anti-cancer activity of the lapatinib chemotherapy drug.

Gene therapy kills breast cancer stem cells, boosts chemotherapy

Gene therapy delivered directly to a particularly stubborn type of breast cancer cell causes the cells to self-destruct, lowers chance of recurrence and helps increase the effectiveness of some types of chemotherapy, researchers at The University of Texas MD Anderson Cancer Center reported in the Sept. 13 edition of Cancer Cell.

In cellular and mouse studies, scientists found the gene mutation BikDD significantly reduced treatment-resistant breast-cancer initiating cells (BCICs), also known as breast cancer stem cells, by blocking the activity of three proteins in the Bcl-2 family. This genetic approach increased the benefits of lapatinib, one of the most common chemotherapy drugs for breast cancer.

Further reading:

BikDD Eliminates Breast Cancer Initiating Cells and Synergizes with Lapatinib for Breast Cancer Treatment

September 15, 2011

Obscure Organelle in Stem Cells and Cancer

Stem cells and cancer cells seem to have more in common besides an ability to divide much more freely than normal adult cells – the persistence of structures called midbodies that are, as currently understood, important only in cell division. This raises the question of whether midbodies have functions, besides helping in cell division, that are common to both stem cells and cancer cells.

Obscure Organelle in Stem Cells and Cancer – The Scientist

Cellular structures known as midbodies, formed during cell division, appear to accumulate in stem cells and cancer cells, hinting at a potential function for these once-disregarded organelles.

Midbodies, once considered the rubbish of cell division, might have a function beyond their role in getting daughter cells to separate. Researchers show in today’s Nature Cell Biology that stem cells and cancer cells collect used midbodies, whereas differentiated cells digest the organelle through autophagy.

Further reading:

Midbody accumulation through evasion of autophagy contributes to cellular reprogramming and tumorigenicity

September 15, 2011

Skipping Pluripotency

When the production of induced pluripotent stem cells (iPSCs) was achieved about five years ago, it seemed they might provide a good alternative to working with embryonic stem cells, in both research and clinical applications. Then problems showed up, such as potential tumorigenicity, inadvertent DNA damage, and incompatibilities with the source’s immune system. More recently, the alternative of “reprogramming” adult cells directly from one type (such as skin) to another type (such as neurons) has been achieved. But this newer technique has problems of its own.

Skipping Pluripotency – The Scientist

The discovery of induced pluripotent stem cells (iPSC) in 2006 opened the door to promising research and therapeutic techniques, such as the generation of disease models and the potential to replace cells damaged by neurodegenerative diseases like Parkinson’s. Derived from fetal or adult cells, iPSC strategies avoided the ethical issues surrounding embryonic stem cells. But they retained one critical drawback—the propensity for tumor formation. In the last 18 months, however, researchers have discovered a new reprogramming technique that could avoid that problem altogether: the direct conversion of one differentiated cell type to another.

read more »