Stimulating Stem Cell Activity to Prevent Aging-Related Mental Decline

Aging tends to rob us of our ability to concentrate, recall facts, and reason, and this decline seems to stem from the fact that older brains generate fewer neurons than they did when they were younger. However, German researchers have discovered a molecule that accumulates with age that inhibits the formation of new neurons. This finding might help scientists design therapies to prevent age-related mental decline.

This molecule, Dkk1 or Dickkopf-1, accumulated in the brains of aged mice. If Dkk1 production was blocked, neurons were born at much higher rates. Dr. Ana Martin-Villalba, the senior author of this work and a member of the German Cancer Research Center in Heidelberg. Said, “We released a brake on neuronal birth, thereby resetting performance in spatial memory tasks to levels observed in younger animals.”

Aged mice that lacked Dkk1 performed just as well in cognitive tests that included memory and recognition tests as younger mice because of the ability of their neural stem cells to self-renew and generate immature neurons.

Younger mice that lacked Dkk1 were less susceptible to developing acute stress-induced depression than normal mice. This seems to indicate that in addition to slowing memory loss during aging, neutralizing Dkk1 could be beneficial in counteracting symptoms of depression.

Martin-Villalba said that there are ongoing clinical trials to test inhibitors of Dkk1 for other medical purposes. “The design of inhibitors that reach the brain might enable the prevention of cognitive decline in the aging population and depression in the general population,” she said.

Modulating Gene Expression to Repair Lungs

According to the American Lung Association and the National Institutes of Health, lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are on the rise. These are chronic ailments that affect the small airways of the lung. Asthma and COPD involve an injury-repair cycle that leads to the destruction of normal airway structure and function. Presently, drug treatments for COPD only treat the symptoms.

“A healthy lung has some capacity to regenerate itself like the liver,” noted Ed Morrisey, professor of Medicine and Cell and Developmental Biology and the scientific director of the Penn Institute for Regenerative Medicine in the Perelman School of Medicine, University of Pennsylvania. “In COPD, these reparative mechanisms fail.”

Morrisey and his colleagues are examining how epigenetic mechanisms control lung repair and regeneration. Epigenetics consists of chemical modifications to DNA and its supporting proteins that affect gene expression. Previous studies have discovered that smokers with COPD had the most significant decrease in one of the enzymes that controls these modifications, called HDAC2.

“HDAC therapies may be useful for COPD, as well as other airway diseases,” he explained. “The levels of HDAC2 expression and its activity are greatly reduced in COPD patients. We believe that decreased HDAC activity may impair the ability of the lung epithelium to regenerate.”

By using genetic and pharmacological approaches, Morrisey and others showed that the development of progenitor cells in the lung is specifically regulated by the combined function of two highly related HDACs, HDAC/1 and /2. Morrisey and his colleagues published their findings in the prestigious journal Developmental Cell.

By studying how HDAC activity and other epigenetic regulators control lung development and regeneration, they hope to develop new therapies to alleviate the unmet needs of patients with asthma and COPD.

HDAC1/2 deficiency leads to a loss of expression of the an essential transcription factor, a protein called Sox2, which in turn leads to disruption of airway epithelial cell development. This is affected in part by increasing the expression of two genes, Bmp4 and the tumor suppressor Rb1, both of which are inhibitors of cell proliferation including the proteins p16, and p21. This results in decreased epithelial proliferation in lung injury and inhibition of regeneration.

Together, these data support a critical role for HDAC-mediated mechanisms in regulating both development and regeneration of lung tissue. Since HDAC inhibitors and activators are currently in clinical trials for other diseases, including cancer, such compounds could be tested in the future for efficacy in COPD, acute lung injury and other lung diseases that involve defective repair and regeneration, said Morrisey.

Making Preneurons from White Blood Cells for ALS Patients

ALS or amyotrophic lateral sclerosis is a disease that results in he death of motor neurons. Motor neurons enable skeletal muscles to contract, which drives movement. The death of motor neurons robs the patient of the ability to move and ALS patients suffer a relentless, progressive, and sad decline that culminates in death from asphyxiation. Treatments are largely palliative, but stem cells treatments might delay the onset of the disease, or even regenerate the dead neurons.

To this end a Mexican group from Monterrey has used a protocol to isolate white blood cells from the circulating blood of ALS patients, and differentiate a specific population of stem cells from peripheral blood into preneurons. Although these cells were not used to treat the patients in this study, such cells do show neuroprotective features and using them in a clinical study does seem to be the next step.

In this study, CD133 cells were isolated from peripheral blood and subjected to a special culture system called a neuroinduction system. After 2-48 hours in this system, the cells showed many features that were similar to those of neurons. The cells express a cadre of neural genes (beta-tubulin III, Oligo 2, Islet-2, Nkx6.1, and Hb9). Some of the ells also grew extensions that resemble the axons of true neurons.

Interestingly, the conversion of the CD133 cells into preneurons showed similar efficiency regardless of the age, sex, or health of the individual. Even those patients with more advanced ALS had CD133 cells that differentiated into preneurons with efficiencies equal to those of their healthier counterparts. While each patient showed variation with regards to the efficiency at which their CD133 cells differentiated into preneurons, these variations could not be correlated with the age, health or sex of the patient.

The fact that these preneurons expressed Oligo2, suggests that they could differentiate into motor neurons. Therefore, even though this study was small (13 patients), it certainly shows that cells that might provide treatment possibilities for ALS patients can be made from the patient’s own blood cells.

See Maria Teresa Gonzalez-Garza et al., Differentiation of CD133+ Stem Cells from Amyotrophic Lateral Sclerosis Patients into Preneuron Cells. Stem Cells Translational Medicine 2013;2:129-35.

Stem Cells as the Target for Antidepressants and Electroconvulsive Therapy

Researchers at Johns Hopkins University have used experiments in mice and humans to determine to target of antidepressant drugs and electroconvulsive therapy. The results of these experiments explain how these therapies work to relieve depression. Apparently, antidepressant drugs and electroconvulsive therapy stimulate stem cells in the brain to grow and mature. These findings also provide a way to determine how well a patient might respond to anti-depression therapies, which will allow fine-tuning of these therapies.

Hongjun Song, Professor of neurology and director of the Stem Cell Program at the John Hopkins University School of Medicine’s Institute or Cell Engineering, main this comment: “Previous studies have shown that antidepressants and electroconvulsive therapy both activate neural stem cells in the adult brain to divide and form new neurons. What were missing were the specific molecules linking antidepressant treatment and stem cell activation.”

Song’s team made this link by assembling evidence from several different experiments. First, they examined gene expression profiles in the brains of mice that had and had not been treated with electroconvulsive therapy. They found that one gene in particular showed decreased expression in mice that had undergone electroconvulsive therapy (ECT), and that gene is called sFRP3 (secreted frizzled-related protein 3). Secreted frizzled-related protein 3 regulates the activity of secreted Wnt signaling proteins. Wnt proteins stimulate neural stem cells growth, but the presence of sFRP3 prevents Wnt proteins from doing so. Since ECT decreases sFRP3 production, Wnt proteins have a freer hand to stimulate neural stem cell proliferation.

Wnt signaling

A second experiment in mice confirmed that antidepressants targeted sFRP3. When knock-out mice were constructed that did not possess a functional copy of the sFRP3 gene, both sFRP3+ and sFRP3- mice were given antidepressants, but neither one showed any difference in behavior. These data strongly suggest that antidepressant treatments blocking the function of the sFRP3 protein, since in the absence of sFRP3, there is nothing to block and the drugs fail to elicit any changes in behavior.

Finally, Song and his collaborators examined sFRP3 genes from 541 patients diagnosed with clinical depression. The response of these patients to antidepressant drugs was tracked and correlated with their DNA sequences of their sFRP3 genes. They discovered that there were three variants of the sFRP3 gene that presaged a stronger response to antidepressant drugs.

A complicating factor is that the levels of sFRP3 are regulated by other factors such as exercise. According to Song, “This gene’s activity is very sensitive to the amount of activity in the brain so that sFRP3 seems to be a gatekeeper that links activity to new neuronal growth.”

This funding has two major near-term implications. First it could lead to genetic tests that enable doctors to predict a patient’s response to antidepressants. Second, it could provide new targets for potential new therapies for clinical depression.

See M-H Jang, Y Kitabatake, E Kang, H Jun, M V Pletnikov, K M Christian, R Hen, S Lucae, E B Binder, H Song and G-I Ming. Secreted frizzled-related protein 3 (sFRP3) regulates antidepressant responses in mice and humans. Molecular Psychiatry , (4 December 2012) | doi:10.1038/mp.2012.158.


Mi-Hyeon Jang, et al., Secreted Frizzled-Related Protein 3 Regulates Activity-Dependent Adult Hippocampal Neurogenesis. Cell Stem Cell, Volume 12, Issue 2, 215-223, 7 February 2013.

Stem Cells in the Epicardium of the Heart

Congestive heart failure is the leading cause of morbidity and mortality worldwide. Implanting stem cells into the damaged heart to regenerate the dead heart cells is a potentially exciting prospect for regenerative medicine. Finding the right cell for the job is the greatest challenge, and to this end the heart itself may provide an interesting source of stem cells for regenerative medicine. This source of cells resides on the outside of the heart, a layer known as the epicardium.

Epicardial cells

After a heart attack, the cells of the epicardium differentiate into smooth muscle cells and heart-specific fibroblasts. They do not form heart muscle cells or blood vessels, but they do secrete a whole cadre of growth factors that encourage the heart to form blood vessels. In mice, preconditioning the heart with a protein called “thymosin beta4” induces the epicardial cells to migrate into the heart and form new heart muscle cells (Smart et al., Nature 2001 474: 640-4). Unfortunately, using thymosin beta4 in human patients who have had heart attacks fails to elicit appropriate changes in the myocardium (Zhou et al., J Mol Cell Cardiol 2012 52: 43-7).

Chong and his colleagues have discovered a new stem cell in the epicardium of mice that can grow for long periods of time in culture and are found near blood vessels. Chong and others call this new epicardial stem cell a “cardiac colony-forming-unit fibroblast” or cCFU-F for short (Chong et al., Cell Stem Cell 2011 9: 527-40).

These cCFU-Fs form from the epicardium, but they do not express heart-specific genes (e.g., c-Kit, CD31, Flk1, CD45, Nkx2-5, NG2). When the gene expression profile of cCFU-Fs was examined in some detail, they expressed the same clusters of genes as bone marrow stem cells (Pelekanos et al., Stem Cell Research 2012 8: 58-73). Are these two cell populations the same? Apparently not. Chong and his crew tried to reconstitute the cCFU-Fs in mice that had had their bone marrow completely replaced with green-glowing bone marrow stem cells. The glowing bone marrow stem cells never contributed to the cCFU-F population.

Therefore, can cCFU-Fs contribute to heart regeneration after a heart attack? Can they be primed to form heart muscle with thymosin beta4? Many questions abound, but these cCFU-Fs seem to represent an easily accessed and robust population for regenerative medicine for the heart after a heart attack.

Using Polycarbonate Plastic Surfaces to Direct Bone Formation by Embryonic Stem Cells

Materials researchers at the University of Southampton, UK, have invented a new plastic that directs pluripotent stem cells to attach and differentiate into bone. This technology could lead to new therapies for people who suffer osteoporosis and osteoarthritis and need hip replacements.

Dr. Emmajayne Kingham has collaborated with University of Glasgow researchers to develop special plastics, grow embryonic stem cells on them, and assess the behavior of the cells on the plastic material. Normally, stem cells require chemicals in order to direct their differentiation. However, in this experiment, the only directing the cells was the microscopic topography of the plastic surface.

This plastic material, polycarbonate, is a very versatile material and is found in substances as hard an inflexible and bullet-proof glass to compact discs. This material is also rather inexpensive and because it can direct the differentiation of embryonic stem cells into bone tissue cells, it can make bone from pluripotent stem cells quite cheaply.

Professor Richard Oreffo, the leader of the Southampton research team said: “To generate bone cells for regenerative medicine and further medical research remains a significant challenge. However, we have found that by harnessing surface technologies that allow the generation and ultimately scale up of human embryonic stem cells to skeletal cells, we can aid the tissue engineering process. This is very exciting.”

Oreffo continued: “Our research may offer a whole new approach to skeletal regenerative medicine. The use of nontopographical patterns could enable new cell culture designs, new device designs, and could herald the development of new bone repair therapies as well as further human stem cell research.”

These data expand on previous work in which the Southampton research group teamed up with another research group from the University of Glasgow to show that plastic surfaces with embossed patterns encouraged the growth and spread of adult stem cells while preventing the stem cells from differentiating. Such a process uses inexpensive polycarbonate plastics that are inexpensive and relatively easy top manufacture.

“Our previous collaborative research showed exciting new ways to control mesenchymal stem cell – stem cells from bone marrow of adults – growth and differentiation on nanoscale patterns,: said Nikolaj Gadegaard from the University of Glasgow.

He continued, “This new Southampton discovery shows a totally different cell source, embryonic, also respond in a similar manner and this really starts to open this new field of discovery up. With more research impetus, it gives us the hope that we can go on to target a wider variety of degenerative conditions than we originally aspired to. This result is of fundamental significance.”

FDA Approves Argus II Retinal Prosthesis

The Food and Drug Administration (FDA) of the United States has approved the first retinal implant for use in the United States. This approval is for Second Sight’s Argus II Retinal Prosthesis System, which provides limited sight to those patients blinded by a rare genetic eye condition called advanced retinitis pigmentosa. This condition damages the light-sensitive cells that line the outer layer of the retina and causes them to die. This severely reduces vision and eventually leads to blindness.

Argus II

Second Sight has devoted more than 20 years of research and development to the development of the Argus II Retinal Prosthesis. It has succeeded in two clinical trials, and the funding for the development of this device – more than $200 million – came from the National Eye Institute, the Department of Energy and the National Science Foundation. The remaining money came from private investors. European regulators approved the Argus II for use in 2011 and it has been used in 30 patients in clinical-trial patients since 2007. The Ophthalmic Devices Advisory Panel of the FDA unanimously recommended approval for the Argus II in September 2012.

The Argus II includes a small video camera, a video processing unit and a 60-electrode implanted retinal prosthesis with a transmitter mounted on a pair of eyeglasses. This device replaces the function of degenerated cells in the retina. It must be stressed that the Argus II does not fully restore vision, but it can improve a patient’s ability to perceive images and movement. It uses the video processing unit to transform images from the video camera into electronic data that is wirelessly transmitted to the retinal prosthesis.

Retinitis pigmentosa affects about one in 4,000 people in the US and about 1.5 million people worldwide. It kills off the retina’s photoreceptors, which convert light into electrical signals that are transmitted by means of the optic nerve to the brain’s visual cortex for processing. Second Sight plans to adapt its technology to assist people afflicted with age-related macular degeneration, which is a similar but more common disease.

Second Sight has plans to make the Argus II available later this year in clinical centers throughout the US. They want to establish a network of surgeons who have the skills to implant the device and, eventually recruit hospitals to offer it.

The Argus II is not the only retinal implant under development. A medical start-up company called Retina Implant AG uses a different approach in its device. In this case, the prosthetic device, the Alpha IMS Implant, is inserted beneath a portion of the retina. The three- by three-millimeter microelectronic chip (0.1-millimeter thick) contains ~1,500 light-sensitive photodiodes, amplifiers and electrodes. The Alpha IMS Implant is surgically inserted beneath a portion of the retina known as the fovea (which contains a rich concentration of particular photoreceptors known as cone cells) in the retina’s macula region. The fovea enables the highest clarity of vision for people to read, watch TV and drive. This chip helps generate at least partial vision by stimulating intact nerve cells in the retina. The nerve impulses from these cells are then fed by means of the optic nerve to the visual cortex where they create impressions of sight. The power source for the chip is implanted under the skin behind the ear and connected by a thin cable to the chip. In May the company announced its first UK patients for its latest trial. To date surgeons have implanted the Alpha IMS Implant prosthetic in 36 patients through two clinical trials over six years.

Alpha IMS Implant

Researchers from Stanford University researchers are developing self-powered retinal implants in which each pixel in the device is fitted with silicon photodiodes. These sensors detect light, and control the output of a pulsed electric current. Patients would be required to wear a set of goggles for these devices that emit near-infrared pulses that transmit power and data directly to the photodiodes. Inductive coils that must be surgically implanted in the patient’s head to power these other retinal prostheses. This design was reported in May 2012 issue of Nature Photonics, and in the article, they described in vitro electrical stimulation of healthy and degenerate rat retina by photodiodes powered by near-infrared light.

Other researchers are utilizing yet another design for retinal prosthesis design. Researchers from Weill Cornell Medical College in New York City have deciphered the neural codes that mouse and monkey retinas use to turn light patterns into patterns of electrical pulses that their brains translate into meaningful images. Next they programmed this information into an “encoder” chip that was combined with a mini-projector to create an implantable prosthetic. This chip converts images that come into the eye into a series of electrical impulses, and the mini-projector then converts the electrical impulses into light impulses that are sent to the brain. With this approach, instead of increasing the number of electrodes placed in an eye to capture more information and send signals to the brain, this approach increases the quality of the artificial signals themselves, which improves their ability to carry impulses to the brain.