Researchers Reprogram Cells from Human Skin into Functional Nerve Cells.

“Transdifferentiation” refers to the conversion of adult cells that are already committed to a particular cell fate to another cell fate. Transdifferentiation is an alternative to the cellular reprogramming that involves converting a mature cell into a pluripotent stem cell — one capable of becoming many types of cell — then coaxing the pluripotent cell into becoming a particular type of cell, such as neurons. In the past year, scientists have been able to convert connective tissue-specific cells called fibroblasts into heart cells (Ieda, M. et al. Cell 142, 375-386 (2010)), blood cells (Szabo, E. et al. Nature 468, 521-526 (2010)), and liver cells (Huang, P. et al. Nature advance online publication doi:10.1038/nature10116 (2011)). Clearly transdifferentiation is a very fast-moving field.

Now researchers have succeeded in converting fibroblasts into neurons, the cells that are responsible for the conduction of nerve impulses. This might generate a model system for nervous-system diseases and even regenerative therapies based on cell transplants.

Stanford University stem-cell researcher Marius Wernig, says that skipping the pluripotency step could avoid some of the problems of making tissues from induced pluripotent stem cells (iPSCs). Also, making iPSCs can also take months to complete. Wernig’s team sparked the imaginations of stem cell scientists last year when he and his research team managed to convert adult mouse cells into iPSCs in only two weeks (Vierbuchen, T. et al. Nature 463, 1035-1041 (2010)). That feat took just three foreign genes that were delivered into tail cells with a virus. “We thought that as it worked so great for the mouse, it should be no problem to work it out in humans,” Wernig says. “That turned out to be wrong.”

Instead those three genes also made human cells that looked like nerve cells but did not fire the electric pulses characteristic of neurons. However, the addition of a fourth virus-delivered gene, found through trial and error, pushed fibroblast cells to become bona fide neurons. After a couple of weeks in culture, many of the neurons responded to electric jolts by pumping ions across their membranes. A few weeks later still, these neurons started to form connections, or synapses, with the mouse neurons they were grown alongside.

This transdifferentiation procedure is rather inefficient. Only 2–4% of the treated fibroblasts became neurons. This is lower than the ~8% efficiency achieved with the mouse tail cells. Also most of the resulting neurons communicated using a chemical called glutamate, which limits their use for understanding or treating neurodegenerative diseases. Given all these caveats, Wernig admits that there are still kinks to work out. However, he and his team are trying to improve the efficiency of transdifferentiation and also to make neurons that communicate using other chemicals.

Evan Snyder, a stem-cell biologist at the Sanford Burnham Medical Research Institute in San Diego, California stated that neurons forged through transdifferentation offer advantages over brain cells made from iPSCs. In addition to being made more quickly, they are less likely to form tumors when they implanted into tissue. There are disadvantages, however. The signs of disease usually appear when a cell develops naturally, from a pluripotent stem cell into a differentiated neuron. Forcing a cell into becoming a neuron could cause scientists to miss aspects of a disease. Also fibroblasts that are the starting material for transdifferentiation do not divide as readily as iPSCs, which limits their use in applications that require lots of cells, such as drug screening, according to Wernig.

Researcher Makes Astrocytes in the Lab from Embryonic Stem Cells

In the brain, star-shaped cells called astrocytes perform a variety of basic housekeeping tasks in the central nervous system. They regulate blood flow, soak up excess chemicals released by interacting neurons, and form a protective filter that keeps dangerous molecules from entering the brain.

Making astrocytes in the laboratory could be used to study a range of central nervous system disorders like dementia and even headaches. Such cells could also be used to test therapeutic drugs and strategies to treat neurological disorders.

Now, a research group from University of Wisconsin-Madison; specifically stem cell researcher Su-Chun Zhang, has differentiated embryonic and induced human stem cells into astrocytes in the lab dish. Zhang said, “Not a lot of attention has been paid to these cells because human astrocytes have been hard to get…But we can make billions or trillions of them from a single stem cell.” Zhang is a researcher at UW-Madison’s Waisman Center and a professor of neuroscience in the UW school of medicine and public health. ”

Some studies suggest astrocytes may even play a role in human intelligence. Their volume in the human brain is much greater than those found in brains from any other species of animal. Without astrocytes, neurons, the cells that actually make and propagate nerve impulses, cannot function. Astrocytes wrap around nerve cells, protect them and keep them healthy. Astrocytes participate in virtually every function or disorder of the brain.

According the Zhang, the ability to make large quantities of astrocytes in the lab has several potential practical outcomes. They could be used as screens to identify new drugs for treating diseases of the brain, to model disease in the lab dish and—in the future—to transplant the cells to treat a variety of neurological conditions, including brain trauma, Parkinson’s disease, and spinal cord injury.

New Lung Stem Cells used to Regenerate Mouse Lungs

Stem cell scientists think that they have discovered stem cells in the lung that are able to make a very wide range of lung-specific cell types.  These stem cells can potentially be used to treat severe lung diseases like emphysema and lung cancers.

In humans, stem cells are found in bone marrow, liver, cornea, ciliary bodies of the eye, hair follicles, and other places.  While several studies have strongly suggested the existence of stem populations in the lung, definitive experiments that demonstrate the existence of lung-specific stem cells have yet to be done.  For example, the airways that bring air to the lung possess so-called basal cells, which are a multipotential stem cell population that replenish and heal the tissues that conduct air to the air sacs of the lung (see JR Rock et al., Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Disease Models and Mechanisms (Sept-Oct 2010), 3(9-10):545-56).  Also, within the air sacs, particular types of “Clara cells” have been recently identified as bronchiolar tissue-specific stem cell (see Susan D. Reynolds and Alvin M. Malkinson, Clara Cell: Progenitor for the Bronchiolar Epithelium.  Int J Biochem Cell Biol. 2010 January; 42(1): 1–4).  However this identification of particular Clara cells as the lung-specific stem cell has several caveats, and doubts remain as to whether or not these cells actually are the lung-specific stem cell.  Also it is not completely clear what the lung stem cell normally does but it might very well be involved in replacing other lung cells lost throughout life.

New work has shown that a lung stem cell can do just that.  The main authors of this work are Piero Anversa and Joseph Loscalzo from Brigham and Women’s Hospital in Boston.  Their results are reported in the New England Journal of Medicine.  In this paper, Anversa, Loscalzo and their colleagues utilized cells from donated, surgical samples of adult lung tissue.  Also, lung tissue from nine fetuses that had died as a result of miscarriages was also used.  After macerating the lung tissue, the researchers isolated lung cells from the lung structural matrices and injected about 20,000 cells, six different times into mice that had experienced lung damage.

The results were astounding.  10 – 14 days after the lung cell injections, all 29 mice showed new airways, blood vessels and air sacs, all of which had been made from the injected human lung cells.  Anversa said, “We had a very large amount of regeneration” involving millions of new cells.  Even more surprising, the new tissue made by the lung stem cells showed “seamless” connection to the rest of the lung.

This study is fascinating and extremely hopeful, but it does not answer a question central to the study of lung-based stem cells.  There is a raging debate as to whether or not a single-lung-based stem cell could produce the more than 40 different cell types in the lung.  Some of the cells in the lung protect the body from inhaled germs, while others exchange oxygen for carbon dioxide.  This is still an open question.  If these new results can be confirmed, they represent a significant advance that will help sort out normal lung repair and how that repair goes awry in lung diseases.

Joseph Loscalzo said it’s too early to tell what lung diseases might be treated someday by using the cells. He said researchers are initially looking at emphysema and high blood pressure in the arteries of the lungs, called pulmonary hypertension. Emphysema is a progressive disease that destroys key parts of the lung, leaving large cavities that interfere with the lung’s function.

This new lung stem cell would be an “adult” stem cell, like others found in the body.  Adult stem cells maintain and repair the tissues where they’re found.  The bone marrow cells, for example, give rise to various kinds of blood cells, and they’ve been used for years in transplants to treat leukemia and other blood diseases.

Anversa said the cells may also prove useful to build up lungs after lung cancer surgery. It’s not clear whether they could be used in treating asthma, he said.

While a lung stem cell theoretically could be used to grow a lung in a lab for transplant, Loscalzo said that would be very difficult because the lung is so complex. Instead, he said, scientists will first look at isolating the cells from a patient, multiplying them in the laboratory, and then injecting them back into the patient’s lung.