Reversing Lung Diseases By Directing Stem Cell Differentiation


Lung diseases can scar the respiratory tissues necessary for oxygen exchange. Without proper oxygen exchange, our cells lack the means to make the energy they so desperately need, and they begin to shut down or even die. Lung diseases such as asthma, emphysema, chronic obstructive pulmonary disease and others can permanently diminish lung capacity, life expectancy and activity levels.

Fortunately, a preclinical study in laboratory animals has suggested a new strategy for treating lung diseases. Carla Kim and Joo-Hyeon Lee of the Stem Cell Research Program at Boston Children’s have described a new lung-specific pathway that is activated by lung injury and directs a resident stem cell population in the lung to proliferate and differentiate into lung-specific cell types.

When Kim and Lee enhanced this pathway in mice, they observed increase production of the cells that line the alveolar sacs where gas exchange occurs. Alveolar cells are irreversibly damaged in emphysema and pulmonary fibrosis.

Inhibition of this same pathway increased stem cell-mediated production of airway epithelial cells, which line the passages that conduct air to the alveolar sacs and are damaged in asthma and bronchiolitis obliterans.

For their experiments, Kim and Lee used a novel culture system called a 3D culture system that mimics the milieu of the lung. This culture system showed that a single bronchioalveolar stem cell could differentiate into both alveolar and bronchiolar epithelial cells. By adding a protein called TSP-1 (thrombospondin-1), the stem cells differentiated into alveolar cells.

Next, Kim and Lee utilized a mouse model of pulmonary fibrosis. However, when they cultured the small endothelial cells that line the many small blood vessels in the lung, which naturally produce TSP-1, and directly injected the culture fluid of these cells into the mice, the noticed these injections reverse the lung damage.

When they used lung endothelial cells that do not produce TSP-1 in 3D cultures, lung-specific stem cells produce more airway cells. in mice that were engineered to not express TSP-1, airway repair was enhanced after lung injury.

Lung Stem Cell Repair of Lung Damage

Lee explained his results in this way: “When the lung cells are injured, there seems to be a cross talk between the damaged cells, the lung endothelial cells and the stem cells.”

Kim added: “We think that lung endothelial cells produce a lot of repair factors besides TSP-1. We want to find all these molecules, which could provide additional therapeutic targets.”

Even though this work is preclinical in nature, it represents a remarkable way to address the lung damage that debilitates so many people. Hopefully this work is easily translatable to human patients and clinical trials will be in the future. Before that, more confirmation of the role of TSP-1 is required.

When Is the Best Time to Treat Heart Attack Patients With Stem Cells?


Several preclinical trials in laboratory animals and clinical trials have definitively demonstrated the efficacy of stem cell treatments after a heart attack. However, these same studies have left several question largely unresolved. For example, when is the best time to treat acute heart attack patients? What is the appropriate stem cell dose? What is the best way to administer these stem cells? Is it better to use a patient’s own stem cells or stem cells from someone else?

A recent clinical trial from Soochow University in Suzhou, China has addressed the question of when to treat heart attack patients. Published in the Life Sciences section of the journal Science China, Yi Huan Chen and Xiao Mei Teng and their colleagues in the laboratory of Zen Ya Shen administered bone marrow-derived mesenchymal stromal cells at different times after a heart attack. Their study also examined the effects of mesenchymal stem cells transplants at different times after a heart attack in Taihu Meishan pigs. This combination of preclinical and clinical studies makes this paper a very powerful piece of research indeed.

The results of the clinical trial came from 42 heart attack patients who were treated 3 hours after suffering a heart attack, or 1 day, 3 days, 2 weeks or 4 weeks after a heart attack. The patients were evaluated with echocardiogram to ascertain heart function and magnetic resonance imaging of the heart to determine the size of the heart scar, the thickness of the heart wall, and the amount of blood pumped per heart beat (stroke volume).

When the data were complied and analyzed, patients who received their stem cell transplants 2-4 weeks after their heart attacks fared better than the other groups. The heart function improved substantially and the size of the infarct shrank the most. 4 weeks was better than 2 weeks,

The animal studies showed very similar results.

Eight patients were selected to receive additional stem cell transplants. These patients showed even greater improvements in heart function (ejection fraction improved to an average of 51.9% s opposed to 39.3% for the controls).

These results show that 2-4 weeks constitutes the optimal window for stem cell transplantation. If the transplant is given too early, then the environment of he heart is simply too hostile to support the survival of the stem cells. However, if the transplant is performed too late, the heart has already experiences a large amount of cell death, and a stem cell treatment might be superfluous. Instead 2-4 weeks appears to be the “sweet spot” when the heart is hospitable enough to support the survival of the transplanted stem cells and benefit from their healing properties. Also, this paper shows that multiple stem cell transplants a two different times to convey additional benefits, and should be considered under certain conditions.

Cord Blood Stem Cells to Treat Acquired Hearing Loss


The Cord Blood Registry has announced the beginning of an FDA-regulated study at the Florida Hospital for Children in Orlando to investigate the potential of a child’s umbilical cord stem cells to treat acquired sensorineural hearing loss.

In the United States, about 15% of children suffer from low or high frequency hearing loss. Sensorineural hearing loss is the most common type of hearing loss, especially at high frequencies. Acquired sensorineural hearing loss results from damage to hair cells in the inner ear (cochlea) and can be caused by illness, medication, noise exposure, birth injury or head trauma. Because the ability to hear affects language development, hearing impairments can lead to poor academic and social development.

This particular study is a Phase I clinical trial, which will determine the safety and efficacy of using cord blood stem cells in children to improve inner ear function, and speech and language development.

In this study, the research group will follow 10 children who range in age from 6 weeks to 6 years, who have been diagnosed with acquired hearing loss for less than 18 months and who have had their own umbilical cord blood processed and stored.

Unfortunately, children who have a known genetic cause of deafness are ineligible for study participation. Patients will receive one intravenous infusion of their own umbilical cord blood stem cells. All patients will be tested at 1 month after the infusion, 6 months, and 1 year post-treatment.

As usual, this clinical trial is inspired by positive results in preclinical tests in laboratory animals.

Adult Stem Cells Used for Spinal Disc Repair


The Australian regenerative medicine company Mesoblast Limited announced the results of their 12-month clinical trial that examined the use of their “off-the-shelf” product to treat patients with disc-related low back pain.

This phase 2 clinical trial enrolled 100 patients with chronic moderate to severe “discogenic low back pain” and tested the ability of “mesenchymal precursor cells” to shore up degenerating intervertebral discs.

Intervertebral discs

Intervertebral discs sit between each vertebra and act as shock absorbers. Each disc consist of an outer layer called the “annulus fibrosus.” The annulus fibrosus consists of several layers of fibrocartilage. The annulus fibrosus surrounds an inner layer called the nucleus pulposus, which contains loose fibers suspended in a mucoprotein gel with the consistency of jelly. This jelly-like center distributes pressure evenly across the disc. These discs absorb the impact of the body’s daily activities and keep the two vertebrae separated. The development of a prolapsed disc results when the jelly in the nucleus pulposus is forced out of the doughnut/disc, which may put pressure on the nerve located near the disc.

Intervertebral structure

More than six million people in the United States alone deal with chronic back pain that has persisted for at least three months, and 3.5 million people are affected by moderate or severe degenerative intervertebral disc disease.

In this clinical trial, Mesoblast Limited injected their mesenchymal precursor cells (MPCs) into the degenerating intervertebral discs of patients suffering from moderate to severe back pain. When compared with a control group, patients who received the MPC injections used less pain killers, went through fewer surgeries and non-surgical interventions, and had greater disc stability as ascertained by X-rays. MPC injections also were well tolerated and produced few side effects.

This phase 2 clinical trial extends earlier observations by Mesoblast Limited on laboratory animals. In preclinical trials, purified MPCs increased the quality of the jelly content of the nucleus pulposus and improved disc structure in sheep.

This present study enrolled 100 patients at 13 different sites across Australia and the United States with early disc degeneration and randomly assigned the subjects to one of four groups: 1) those who received saline injections; 2) those who received hyaluronic acid injections; 3) those who received low-dose MPCs in hyaluronic acid; and 4) those who received high-dose injections of MPCs in hyaluronic acid.

All patients received their injections in an outpatient procedure, and are being evaluated for safety and efficacy to evaluate long-term treatment effects.

At 12 months, the key findings were improvement in chronic low back pain, function, and disc stability. Also, no safety concerns emerged as a result of the treatment.

As this trial proceeds, more data should be forthcoming.

Umbilical Cord Stem Cells Preserve Heart Function After a Heart Attack in Mice


A consortium of Portuguese scientists have conducted an extensive examination of the effects of mesenchymal stromal cells from umbilical cord on the heart of mice that have suffered a massive heart attack. Even more remarkable is that these workers used a proprietary technique to harvest, process, and prepare the umbilical cord stem cells in the hopes that this technique would give rise to a commercial product that will be tested in human clinical trials,

Human umbilical cord tissue-derived Mesenchymal Stromal Cells (MSCs) were obtained by means of a proprietary technology that was developed by a biomedical company called ECBio. Their product,, UCX®, consists of clean, high-quality, umbilical cord stem cells that are collected under Good Manufacturing Practices. The use of Good Manufacturing Practice means that UCX is potentially a clinical-grade product. Thus, this paper represents a preclinical evaluation of UCX.

This experiments in this paper used standard methods to give mice heart attacks that were later received injections of UCX into their heart muscle. The same UCX cells were used in experiments with cultured cells to determine their effects under more controlled conditions.

The mice that received the UCX injections into their heart muscles after suffering from a large heart attack showed preservation of heart function. Also, measurements of the numbers of dead cells in the heart muscle of heart-sick mice that did and did not receive injections of umbilical cord cells into their hearts showed that the umbilical cord stem cells preserved heart muscle cells and prevented them from dying. Additionally, the implanted umbilical cord MSCs induced the growth and formation of many small blood vessels in the infarcted area of the heart. This prevented the heart from undergoing remodeling (enlargement), and preserved heart structure and function.

When subjected to a battery of tests on cultured cells, UCX activated cardiac stem cells, which are the resident stem cell population in the heart. Implanted UCX cells activated the proliferation of cardiac stem cells and their differentiation into heart muscle cells. There was no evidence that umbilical cord MSCs differentiated into heart muscle cells and engrafted into the heart. Rather UCX seems to help the heart by means of paracrine mechanisms, which simply means that they secrete healing molecules in the heart and help the heart heal itself.

In conclusion, Diana Santos Nascimento, the lead author of this work, and her colleagues state that, “the method of UCX® extraction and subsequent processing has been recently adapted to advanced therapy medicinal product (ATMP) standards, as defined by the guideline on the minimum quality data for certification of ATMP. Given that our work constitutes a proof-of-principle for the cardioprotective effects UCX® exert in the context of MI, a future clinical usage of this off-the-shelf cellular product can be envisaged.”

Preclinical trials with larger animals should come next, and after that, hopefully, the first human clinical trials will begin.

Stimulus-Triggered Acquisition of Pluripotency Cells: Embryonic-Like Stem Cells Without Killing Embryos or Genetic Engineering


Embryonic stem cells have been the gold standard for pluripotent stem cells. Pluripotent means capable of differentiating into one of many cell types in the adult body. Ever since James Thomson isolated the first human embryonic stem cell lines in 1998, scientists have dreamed of using embryonic stem cells to treat diseases in human patients.

However, deriving human embryonic stem cell lines requires the destruction or molestation of a human embryo, the smallest, youngest, and most vulnerable member of our community. In 2006, Shinya Yamanaka and his colleges used genetic engineering techniques to make induced pluripotent stem (iPS) cells, which are very similar to embryonic stem cells in many ways. Unfortunately, the derivation of iPSCs introduces mutations into the cells.

Now, researchers from Brigham and Women’s Hospital (BWH), in Boston, in collaboration with the RIKEN Center for Developmental Biology in Japan, have demonstrated that any mature adult cell has the potential to be converted into the equivalent of an embryonic stem cell. Published in the January 30, 2014 issue of the journal Nature, this research team demonstrated in a preclinical model, a novel and unique way to reprogram cells. They called this phenomenon stimulus-triggered acquisition of pluripotency (STAP). Importantly, this process does not require the introduction of new outside DNA, which is required for the reprogramming process that produces iPSCs.

“It may not be necessary to create an embryo to acquire embryonic stem cells. Our research findings demonstrate that creation of an autologous pluripotent stem cell – a stem cell from an individual that has the potential to be used for a therapeutic purpose – without an embryo, is possible. The fate of adult cells can be drastically converted by exposing mature cells to an external stress or injury. This finding has the potential to reduce the need to utilize both embryonic stem cells and DNA-manipulated iPS cells,” said senior author Charles Vacanti, MD, chairman of the Department of Anesthesiology, Perioperative and Pain Medicine and Director of the Laboratory for Tissue Engineering and Regenerative Medicine at BWH and senior author of the study. “This study would not have been possible without the significant international collaboration between BWH and the RIKEN Center,” he added.

The inspiration for this research was an observation in plant cells – the ability of a plant callus, which is made by an injured plant, to grow into a new plant. These relatively dated observations led Vacanti and his collaborators to suggest that any mature adult cell, once differentiated into a specific cell type, could be reprogrammed and de-differentiated through a natural process that does not require inserting genetic material into the cells.

“Could simple injury cause mature, adult cells to turn into stem cells that could in turn develop into any cell type?” hypothesized the Vacanti brothers.

Vacanti and others used cultured, mature adult cells. After stressing the cells almost to the point of death by exposing them to various stressful environments including trauma, a low oxygen and acidic environments, researchers discovered that within a period of only a few days, the cells survived and recovered from the stressful stimulus by naturally reverting into a state that is equivalent to an embryonic stem cell. With the proper culture conditions, those embryonic-like stem cells were propagated and when exposed to external stimuli, they were then able to redifferentiate and mature into any type of cell and grow into any type of tissue.

To examine the growth potential of these STAP cells, Vacanti and his team used mature blood cells from mice that had been genetically engineered to glow green under a specific wavelength of light. They stressed these cells from the blood by exposing them to acid, and found that in the days following the stress, these cells reverted back to an embryonic stem cell-like state. These stem cells then began growing in spherical clusters (like plant callus tissue). The cell clusters were introduced into developing mouse embryos that came from mice that did not glow green. These embryos now contained a mixture of cells (a “chimera”). The implanted clusters were able to differentiate into green-glowing tissues that were distributed in all organs tested, confirming that the implanted cells are pluripotent.

Thus, external stress might activate unknown cellular functions that set mature adult cells free from their current commitment to a particular cell fate and permit them to revert to their naïve cell state.

“Our findings suggest that somehow, through part of a natural repair process, mature cells turn off some of the epigenetic controls that inhibit expression of certain nuclear genes that result in differentiation,” said Vacanti.

Of course, the next step is to explore this process in more sophisticated mammals, and, ultimately in humans.

“If we can work out the mechanisms by which differentiation states are maintained and lost, it could open up a wide range of possibilities for new research and applications using living cells. But for me the most interesting questions will be the ones that let us gain a deeper understanding of the basic principles at work in these phenomena,” said first author Haruko Obokata, PhD.

If human cells can be made into embryonic stem cells by a similar process, then someday, a simple skin biopsy or blood sample might provide the material to generate embryonic stem cells that are specific to each individual, without the need for genetic engineering or killing the smallest among us. This truly creates endless possibilities for therapeutic options.

New Analysis of Stem Cell Treatments for Spinal Cord Injury in Laboratory Animals


A host of preclinical studies have examined the ability of stem cells to improve the condition of laboratory animals that have suffered a spinal cord injury. While these studies vary in their size, design, and quality, there has been little cumulative analysis of the data generated by these studies.

Fortunately, there is a powerful analytical tool that can examine data from many studies and this type of analysis is called a “meta-analysis.” Meta-analyses use sophisticated statistical packages to systematically reassess a compilation of the data contained within these papers. Meta-analyses are exhausting, but potentially very useful. Such a meta-analysis is also very important because it provides researchers with an indication of what problems must be worked out before these treatments advance to human clinical trials and what aspects of the treatment work better than others.

A recent meta-analysis of stem cell therapy on animal models of spinal cord injury has been published by Ana Antonic, MSc, David Howells, Ph.D., and colleagues from the Florey Institute and the University of Melbourne, Australia, along with Malcolm MacLeod and colleagues from the University of Edinburgh, UK in the open access journal PLOS Biology.

The goal of regenerative spinal cord treatments is to use stem cells to replace dead cells within damaged areas of the spinal cord. Such treatments would be given to spinal cord injury patients in the hope of improving the ability to move and to feel below the site of the injury. Many experiments that utilize animal models of spinal cord injury have used stem cells to treat laboratory animals that have suffered spinal cord injury, but, unfortunately, these studies are limited in scale by size (as a result of financial considerations), practical and ethical considerations. Such limitations hamper each individual study’s statistical power to detect the true effects of the stem cell implantation. Also, these studies use different types of stem cells in their treatment scenarios, inject those cells differently induce spinal cord injuries differently, and test their animals for functional recovery differently.

To assess these studies, this new paper examined 156 published studies, all of which tested the effects of stem cell treatments on about 6,000 spinal cord-injured animals.

Overall, they found that stem cell treatment results in an average improvement of about 25 percent over the post-injury performance in both sensory (ability to feel) and motor (ability to move) outcomes. Unfortunately, the variation from one animal to another varied widely.

For sensory outcomes the degree of improvement tended to increase with the number of cells implanted. Such dose-responsive results tend to indicate that the improvements are actually due to the stem cells, and therefore, this stem cell-mediated effect represents a genuine biological effect.

The authors also measured the effects of bias. Simply put, if the experimenters knew which animals were treated and which were untreated, then they might be more likely to report improvements in the stem cell-treated animals. They also examined the way that the stem cells were cultured, the way that the spinal injury was generated and the way that outcomes were measured. In each case, important lessons were learned that should help inform and refine the design of future animal studies.

The meta-analysis also revealed some surprises that should provoke further investigations. For example, there was little evidence that female animals showed any beneficial sensory effects as a result of stem cell treatments. Also, the efficacy of the stem cell treatment seemed to not depend on whether immunosuppressive drugs were administered or not.

The authors conclude, “Extensive recent preclinical literature suggests that stem cell-based therapies may offer promise; however the impact of compromised internal validity and publication bias means that efficacy is likely to be somewhat lower than reported here.”

Even though human clinical trials are in the works, such trials will continue to be informed by preclinical studies on laboratory animals.