Stem Cells

Our friends over at California’s stem cell agency yesterday shared the story of one of the speakers at the annual meeting of the International Society for Stem Cell Research (ISSCR), taking place now in Boston. The speaker was Andres Trevino, father of a little boy who was born with an extremely rare life-threatening disease and successfully treated using his sister’s cord blood stem cells.

Trevino’s story is a dramatic one, and I quite liked what Kevin McCormack wrote of such stories at the end of his post:

At CIRM we know how important it is to engage patients and patient advocates in everything we do (see our Stories of Hope page). Their voices, their stories, are a constant reminder why we do the work we do, to find treatments and cures for diseases and conditions that are currently incurable. At ISSCR, Andres’ voice rang out clear and strong, reminding everyone that even the best research is just a means to an end, and that end is saving lives.

Photo courtesy of Children’s Hospital Boston

Alan Trounson, PhD, president of the California Institute for Regenerative Medicine, co-authored a comment piece published yesterday in Nature discussing the issues surrounding therapeutic human cloning. The comments were sparked by last month’s announcement by researchers at Oregon Health and Science University of the successful derivation of embryonic stem cells from cloned human embryos. Although problems with the original research article have since surfaced, the crux of the finding remains unchanged. The article explains:

This formidable technical feat is potentially a key step towards developing replacement tissues to treat disease. Media coverage of the paper has also rekindled long-standing controversies about human cloning, the use of human eggs and the destruction of human embryos. The achievement is a timely reminder that scientists must remain actively engaged in discussions about the ethics of using human embryos for research in cell biology and regenerative medicine.

The researchers used a technique called somatic cell nuclear transfer, or SCNT, to create the embryonic stem cells. In SCNT, the nucleus of a mature, donated human egg is replaced with the nucleus from a cell from another individual. The egg is then stimulated to divide and become an embryo carrying the genetic information from the donor nucleus. The process would conceivably allow researchers or clinicians to create unique embryonic stem cell lines to match individual patients and would avoid issues of immune rejection that could arise with non-genetically matched ES cells. But it’s also the first step in potentially cloning a human for reproductive purposes.

In the article, Trounson and his co-author, Martin Pera, PhD, from the University of Melbourne, urge caution and proactive consensus building to address the many complex ethical and biological issues surrounding this type of work. It’s a very interesting read. They conclude:

The potential benefits of stem-cell research are immense. Prospects for transformative treatments for conditions such as macular degeneration, type 1 diabetes or Parkinson’s disease are now on the horizon. But without first convincing governments, the public, and funding and regulatory bodies that all the possibilities have been thought through and evaluated, headline-catching results could create a backlash that unnecessarily delays the tremendous potential benefits of cell therapies.

Previously: Stem cell guidelines under fire and New York Stem Cell Foundation researchers create human stem cell lines from SCNT

Embryonic stem cells (or ESCs) and their younger cousins the induced pluripotent stem cells (iPSCs) are prized because they can, alternatively, replicate themselves indefinitely in a dish or differentiate into every cell type in the body. This makes them potentially valuable tools for regenerative medicine.

And because iPSCs can be made from a person’s skin cells, manipulating their differentiated progeny lets investigators study disease processes at the cellular level, in a dish and in a personalized way. By custom-producing, for example, a given individual’s nerve cells,  researchers can study the specific defects of those cells in a dish, without having to first perform the ethically unthinkable – and, therefore, purely hypothetical – act of slicing chunks of tissue out of that person’s brain in order to do so. The researchers can, further, toss thousands of different compounds into thousands of tiny “wells” containing these nerve cells to see which ones might restore those cells’ proper function. (Different drugs are likely to work better with different individuals’ defective cells, depending on the nature of the cell’s defining defect.)

Scientists have successfully coaxed both ESCs and iPSCs down the developmental pathway to become nerve cells. They’ve even generated nerve cells directly from skin cells. But up to now, the procedures they’ve used have been plagued by two problems. First, quality assurance: The extent to which nerve cells generated by these methods actually look and act like nerve cells are supposed to look and act varies a lot, depending on which particular ESC line, or which iPSC line, was used to generate them. Second, the process is slow and the yield is low (it typically takes months to get from the beginning to the end, and many of the “starter” ESCs or iPSCs don’t successfully convert to decently functioning nerve cells).

But in a recently published paper in Neuron,  a team under the direction of Stanford cell physiologist and neuroscientist Tom Sudhof, PhD, has showed that just boosting the level, in human ESCs or iPSCs, of one single substance (a type known as a transcription factor) results in an abundant and quite pure population of nerve cells within as little as two weeks. And unlike previous methods, this one seems to generate nerve cells of equally high functional quality regardless of which “starter” cell line was used to get the process underway.

Clearly, if you’re doing regenerative medicine for a stroke or brain-trauma victim etc., you’re going to need a lot of nerve cells, and time is of the essence. So the new method represents a major forward step toward the realization of the dream of personalized regenerative medicine.

Previously: Revealed: the likely role of Parkinson’s protein in the healthy brain, Nervous breakdown: Preventing demolition of faulty proteins counters neurodegeneration in lab mice and Human neurons from skin cells without pluripotency?
Photo by Crystalline Radical

The growth of hair on your head (and elsewhere on your body, for that matter) is a tightly regulated and fascinating biological activity. Researchers are particularly interested in understanding how the stem cells in the hair follicles, which are called bulge cells, know how and when to cycle in and out of dormancy. Learning more about this process, they believe, may provide the insight necessary to harness the regenerative capacity of many types of stem cells for tissue repair and renewal.

This week, Stanford dermatologist Anthony Oro, MD, PhD, and colleagues published a study (subscription required) in Genes and Development of a mouse model they developed of a human condition called Timothy syndrome. Patients with Timothy syndrome are born bald and often take months or years to develop any hair. They also suffer from cardiac abnormalities and physical malformations and usually die at a tragically young age. But they have a very interesting genetic mutation. As Oro explained to me:

Stem cells exhibit the ability to cyclically regenerate organs, but what controls the timing of activation remains a puzzle. Timothy syndrome (TS) patients carry mutations in a calcium channel called Cav1.2 that controls the timing of the heartbeat. TS patients exhibit both cardiac arrhythmia and a significant delay in the activation of the hair cycle.

Oro and his colleagues, including Stanford postdoctoral scholar and the study’s first author Gozde Yucel, PhD, were puzzled as to why bulge cells, which (they showed in their study) don’t respond to or rely on the electrical and molecular pulses that drive cardiac cells, would even have a calcium channel. They used mouse genetics and pharmacology to investigate the abnormality in hair stem cell timing in the animals with a similar mutation. They found that, in the mice, the channel functions to control the levels of stem cell regulators responsible for tissue regeneration. According to Oro:

These surprising results demonstrate a wider function for pacemaker channels in tissue stem cells, and suggest the existence of channel ligands that have therapeutic applications in regenerative medicine.

Previously New skin cancer target identified by Stanford researchers, The secret life of hair follicles, revealed by Stanford researchers and Examining the role of genetics in hair loss

Interesting stem cell news today. A blog post from the California Institute for Regenerative Medicine describes research published in Cell Stem Cell by researchers at Stanford and the VA Palo Alto Health Care System. The study investigates the relative difficulty reprogramming adult cells from fully developed tissues like skin into what are known as induced pluripotent stem cells, or iPS cells. The technique was first described in 2006 by Nobel Prize recipient Shinya Yamanaka, MD, PhD (now at the Gladstone Institutes in San Francisco). As the blog post describes:

And yet seven years after the initial breakthrough, reprogramming is still very inefficient: less than 99 percent of treated cells actually get reprogrammed into embryonic-like stem cells. Many researchers are trying to better understand what goes on inside cells during the reprogramming process to help increase this efficiency and ultimately help accelerate disease research.

The researchers, including CIRM grant recipient Ji-Fan Hu, MD, PhD, and Stanford endocrinologist Andrew Hoffman, MD, found that chromosomal looping is a critical step in reprogramming. And not all would-be-iPS cells do it. From CIRM’s blog post:

During the reprogramming process, scientists activate a handful of genes that act as master control switches: they produce proteins that bind to specific spots on the cell’s DNA. This DNA binding then activates a cascading set of genes that ultimately re-sets the skin cells’ properties to the stem cell-like state of iPSC. It turns out that those cascading events only happen if the string-like DNA loops around, bringing proteins bound to distant parts of the DNA together (see the simplified illustration above).

Hu and his colleagues showed that those loops were only present in the cells that did get reprogrammed. The other 99% that don’t get reprogrammed into stem cells lacked the DNA loops.

Previously: Nobel Prize-netting iPS-cell discovery was initially a tough sell (for me, anyway) and The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors

What if it were possible, when faced with a devastating neurological disease like multiple sclerosis, to coax the brain to heal itself? Unfortunately, we’re probably still years away from any kind of quick fix for these conditions (if, in fact, one exists at all). But recent research by Stanford geneticist Anne Brunet, PhD, describes an intriguing way to delay the onset of a multiple-sclerosis-like disease in laboratory mice. The study is published in the most recent issue of Nature Cell Biology.

We’re excited by the potential implications our study has on demyelinating diseases and injuries

Specifically, the researchers created a type of mouse in which they could turn the expression of a protein called SIRT1 on and off in the neural stem cells in the animals’ brains. (They wanted to investigate SIRT1′s involvement in the disease because it appears to be highly expressed in the brains of mice with multiple sclerosis.) They found that animals in which the protein’s expression was blocked developed the characteristic paralysis of the disorder more slowly than their peers with normal levels of SIRT1 expression.

From our article:

Blocking SIRT1 expression appears to work by promoting the development of neural stem cells in the brain into a type of cell called an oligodendrocyte precursor. These cells, in turn, become the mature oligodendrocytes that wrap the long arms of neurons with myelin — a fatty material necessary to facilitate the transmission of the electrical impulses from one nerve cell to another. In humans, most myelination occurs during infancy and adolescence.

Diseases such as multiple sclerosis wreak havoc in the central nervous system by damaging this protective myelin coating and impeding communication between nerve cells.

Brunet, who last year received a Pioneer Award from the National Institutes of Health for her work in studying the inheritance of longevity, worked with Stanford neurologist and noted multiple sclerosis researcher Lawrence Steinman, MD, to conduct the study. She told me:

We are excited by the potential implications our study has on demyelinating diseases and injuries… It’s intriguing because activating SIRT1 is typically considered to be beneficial for metabolism and health, but in this case, inactivating SIRT1 can provide protection against a demyelinating injury.

Previously: NIH awards nine Stanford faculty funding for innovative research, Black hat in Alzheimer’s, white hat in multiple sclerosis? and Amyloid, schmamaloid: Stanford MS expert finds dreaded proteins may not be all bad.

I was so happy to learn that Stanford stem cell researcher Marius Wernig, MD, (here describing his research as part of the California Institute for Regenerative Medicine’s recent Elevator Pitch competition) has been selected by the International Society for Stem Cell Research to receive its Outstanding Young Investigator of the year at the organization’s annual meeting in June in Boston.

My colleagues at CIRM beat me to the punch yesterday (Wernig is a CIRM grant recipient) with a nice blog post about the award.

I’ve written several times (here and elsewhere) about Wernig’s research as part of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. Essentially, he’s shown that it’s possible to directly convert adult, terminally differentiated cells directly into other types of cells like neurons, without first having to force the cells through a stage called induced pluripotency. It’s exciting stuff.

Wernig, who was in a former life a composer of classical music,  joins Stanford researcher Joanna Wysocka, PhD, in the ISSCR hall of fame. She won the award in 2010.

Previously: Stanford scientists turn human skin cells directly into neurons, skipping iPS stage, The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors and Stanford researcher wins Outstanding Young Investigator Award from international stem cell society.
Video courtesy of the California Institute for Regenerative Medicine

Really. Come on. Who isn’t interested in hair? Hair growth, hair loss, hair thickness, hair shape, hair location. I’d bet that everyone of us spends at least a minute or two each day thinking about (or, if you’re like me, futilely plucking and prodding at) the state of our locks.

Now Stanford researchers have delved deep into the cells surrounding our hair follicles to better understand what makes them grow and maintain hair. Perhaps not surprisingly, the answer lies in the stem cells (here, called ‘bulge cells’) within the follicle.

Specifically, research associate Yiqin Xiong, PhD, and associate professor of medicine Ching-Pin Chang, MD, PhD, have identified a signaling circuit that controls the cells’ activity. The research was published yesterday in Developmental Cell (subscription required). As Chang explained in an e-mail to me:

By promoting self-renewal of stem cells, this circuit maintains a healthy pool of bulge cells for repeated cycles of hair growth and regeneration. Each cycle of hair regeneration is initiated by the activation of this circuit in those bulge cells, and subsequent growth of the hair is sustained by the circuit in hair matrix cells.  Besides hair regeneration, the circuit is triggered by skin injury to stimulate migration of the bulge cells to the wounded area to differentiate into epidermal cells, thereby regenerating epidermis over the wounded skin.

In the past, news about hair growth (and how to stimulate it) has been a trigger for a deluge of interest from media and individuals struggling with… (how shall we say it?) ‘hair problems.’ But the research has many implications beyond hair, or the lack thereof. For example, the presence or absence of hair follicles on the skin affect how the skin heals after a wound, and whether a scar remains. According to Chang:

This molecular circuit in the hair follicle can be targeted for therapeutic purposes. Because of its activity in hair regeneration, inhibition of this circuit can reduce hair growth in patients with excessive hairiness (hirsutism), whereas activation of this pathway can promote hair growth for people with baldness (alopecia). Also, for its activity during epidermal regeneration, activation of the circuit can facilitate wound healing for patients receiving surgery and for diabetic patients who have wounds that are difficult to treat. The activity of the circuit in both hair follicle and epidermal regeneration may have additional therapeutic benefit. Lack of hair follicles in a wounded area is a hallmark of scar formation. Targeting this pathway has the advantage of promoting both hair follicle formation and wound repair, thus reducing scar formation in the wound.

Interestingly, one of the key molecules, called Brg1, involved in this regulatory circuit has also been implicated in previous work from Chang’s lab in the enlargement of the heart and in fetal heart development. It’s apparent this story has many layers, some more than skin deep.

Previously:  Examining the role of genetics in hair loss and Epigenetics: the hoops genes jump through,
Photo by Furryscaly

Hot on the heels of my Friday post about the elevator-pitch throwdown organized by the California Institute for Regenerative Medicine comes news that Stanford postdoc and clinical instructor Michael Rothenberg, PhD, was awarded third place in the organization’s “non-lead scientist” category. (Awards were given in two categories – non-lead scientist and lead scientist – to acknowledge the vast range of experience and training of the scientists who chose to compete. )

Rothenberg works in the laboratory of Michael Clarke, MD, at Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, and he studies… well, why don’t I let him tell you himself? Watch the video above to see how winning science communication is done. And then check out a few more of the winners (links in the CIRM announcement).

Videos longer than 35 seconds lost points. All had to clearly explain in plain language what their CIRM-funded research was about. Humor helped, but it wasn’t necessary. And although the contest was lighthearted, the purpose was serious. From CIRM’s release:

The goal of the Elevator Pitch Challenge was to help researchers who get funding from the stem cell agency, the California Institute for Regenerative Medicine (CIRM), do a better job of communicating with the public. After all, we are a publicly funded agency and the money we use to fund research comes from the people of California, so it’s only reasonable to expect researchers to be able to explain the importance of what they do to Californians, and anyone else they might meet.

Congratulations Michael!

Previously: Learning and laughing: CIRM’s elevator pitch contest and A call to fix the “crisis of communication” in science

Stem cells in the laboratory lead a seemingly idyllic life, spending most of their time being gently sloshed around in a warm bath of yummy nutrients. But this pampered, directionless lifestyle presents a problem for scientists trying to understand how the cells organize themselves in the body. In “real life” it matters quite a lot who your neighbors are and from what direction the various messages and signals that guide cellular life originate. Until now, however, it’s been nearly impossible for scientists to study how such localized signals affect stem cells.

Now developmental biologist Roeland Nusse, PhD, and Shukry Habib, PhD, a research associate and Siebel Scholar, have devised an ingenious way to mimic localized signals by binding a signaling molecule (in this case, a protein called Wnt3a) to an inert microscopic bead. They then traced the actions of individual mouse embryonic stem cells bound to only one bead–meaning the cell was receiving the Wnt3a signal from only one location on its membrane. The research was published yesterday in Science (subscription required). From our release:

The effect of the localized signal was clear. In 75 percent of cases, the stem cell began to divide in a very specific orientation, with the plane of division occurring perpendicularly to the location of the incoming signal. In contrast, only 12 percent of cells exposed to beads bound to a control protein exhibited similar patterns of division.

Habib and his colleagues also found that the daughter cell closest to the Wnt3a signal expressed proteins showing it was maintaining its pluripotency, or ability to function as a stem cell like its parent. The one farthest from the signal, however, expressed proteins indicating that it was beginning to differentiate.

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