A research team led by Raymond Lund, Ph.D., Professor Emeritus of Ophthalmology, and Trevor McGill, Ph.D., Research Assistant Professor at the Casey Eye Institute, Oregon Health and Science University have made a remarkable discovery using proprietary stem cells from StemCells, Inc. These results await publication in the European Journal of Neuroscience, and constitute positive preclinical data for StemCells, Inc. proprietary Human Central Nervous System Stem Cells (HuCNS-SC).
For these experiments, the team used Royal College of Surgeons (RSC) rats. RCS rats have an inherited form of retinal degeneration. Although the genetic defect that causes retinal regeneration was not known for many years, it was identified in the year 2000 to be due to a mutation in the Merkt gene. Mutations in the Merkt gene prevent the retinal pigment epithelium cells from scooping up outer segments of photoreceptor cells. As photoreceptor cells respond to light, their outer membrane proteins suffer photo-oxidation. Retinal pigment epithelial cells phagocytose these defective photoreceptor outer membrane segments and recycle them, which maintains photoreceptor health and function. When retinal pigment epithelium cells are unable to phagocytose photoreceptor out membrane segments, the photoreceptors accumulate photo-damage and eventually die.
To test the efficacy of HuCNS-SCs in preserving photoreceptor health, Lund and his colleagues injected HuCNS-SCs into the subretinal space of 21-day old RCS rats. They found that photoreceptors, the key cells of the eye involved in vision were protected from degeneration. Additionally, the density of healthy cone photoreceptors (those photoreceptors that help in color perception) remained relatively constant over several months. Visual acuity and luminance sensitivity tests in the injected RCS rats further corroborated the results of observed in the retinas. Apparently, the donor cells remained immature and did not differentiate throughout the seven-month experiment. However, the transplanted HuCNS-SCs underwent very little proliferation, and produced no tumors or abnormal growths. The ability of these transplanted cells to protect photoreceptors and preserve vision when injected into the retinas of RCS rats is important to human disorders of vision loss such as dry age-related macular degeneration (AMD).
Lund excitedly noted: “These results are the most robust shown to date in this animal model. One of the more striking findings is that the effect on vision was long-lasting and correlated with the survival of HuCNS-SC cells more than seven months after transplantation, which is substantially longer than other cell types transplanted into this same model. Also important, particularly for potential clinical application was that the cells spread from the site of initial application to cover more of the retina over time. These data suggest that HuCNS-SC cells appear to be a well-suited candidate for cell therapy in retinal degenerative conditions.”
Another investigator in this study, Alexandra Capela, Ph.D., a senior scientist at StemCells, commented, “This study showed that the HuCNS-SC cells persisted and migrated throughout the retina, with no evidence of abnormal cell formation, which supports our hypothesis of a single transplant therapeutic. With this research, then, we have shown that vision can be positively impacted with a simple approach that does not require replacing photoreceptors or the RPE cells. We look forward to investigating this promising approach in the clinic later this year.”
Wesley Smith at his blog notes that the California Stem Cell Report, which will include public testimony to the Institute of Medicine (IOM), an arm of the National Institutes of Health (NIH), will include scientists who were awarded lucrative grants by the California Institute for Regenerative Medicine (CIRM), but no critics of the program. His source is a very critical Los Angeles Timesarticle.
The critics of CIRM are not pro-life advocates who oppose embryonic stem cell research on principle. Instead critics include the Little Hoover Commission, which issued this blistering report of CIRM, and the Oakland-based Center for Genetics and Society. These organizations were afraid that there were too many conflicts of interest on the grant-awarding panel. In the words of the Little Hoover Commission:
CIRM’s 29-member oversight committee includes representatives from institutions that have benefitted from grants the committee approved. This structure, along with overly long terms and the inability to nominate its own leaders or hold them accountable, fuels concerns that the committee never can be entirely free of conflict of interest or self-dealing, notwithstanding a court ruling that established the legality of such a structure. Legal is not necessarily optimal, however, and litigation over this issue delayed CIRM from beginning its work. As long as the board remains in its present form, its structure will draw scrutiny, diverting CIRM resources.
No representatives from either of these critical institutions are on the witness list. Why aren’t members of the public allowed to address the IOM? According to the LA Times, the proprietor of the California Stem Cell Report, David Jensen, says he asked the IOM why no objective witnesses were on the hearing list, and an IOM public relations person directed him to a survey form members of the public could fill out (though the link for the form on the IOM’s website was dead when I checked it). Apparently, members of the public will also be permitted to address the IOM panel at Tuesday’s hearing. They’ll each get up to five minutes.
CIRM is selling the people of California a bill of goods. In 2014, CIRM will be back to the people of California with their hand out for more money. If the process is so objective, then what do they have to hide? 3 billion dollars later and little to show for it except for lots of dead human embryos. People will be more than a little miffed; and they should be.
The APOLLO Clinical trial is derived from its longer title: A Randomized Clinical Trial of Adipose-derived Stem cells in the Treatment of Patients with ST-elevation myocardial Infarction. The APOLLO trial is being funded by the National Institutes of Health and Cytori Therapeutics. The study participants are Alexander Milstein MD at Cytori Therapeutics, Patrick Serruys MD PhD at Erasmus University Medical Centrum in Rotterdam, Netherlands, and Hospital General Universitario Gregorio Maranon in Madrid, Spain. Goal of this clinical trial is to test the efficacy and safety of adipose tissue-derived stem cells to improve the heart function of patients that have experienced a heart attack.
14 patients were initially enrolled in the APOLLO trial and it is a randomized, placebo-based, double-blind safety and feasibility trial (Phase I/IIA) that uses a patient’s own fat-based stem cells that have been isolated from liposuction aspirates. Recently, the six-month outcomes of this experiment were published in Journal of the American College of Cardiology.
All patients in the APOLLO trial had experienced a heart attack and underwent liposuction of abdominal fat. Each patient’s fat cells were processed by the Celution System. This system extracted the stem cells from the surrounding fat cells and concentrated them into a syringe of clinical grade cells. All patients were treated within 36 hours after the heart attacks and 10 patients received an injection of 20 million Adipose-Derived Regenerative Cells and 4 of them received a placebo.
The findings are encouraging. There were no side effects from the stem cell treatments, and no increase in cardiac arrhythmias. Patients that had received the stem cells showed improvement in cardiac function as ascertained by single-photon emission computed tomography SPECT, Furthermore, stem cell-treated patients showed improved blood flow into the heart, and an 11% decrease in the size of the heart scar. Also, these positive results were also seen in the 18-month examination as well. Those patients that received the placebo showed no such improvements.
Cytori CEO, Christopher J. Calhoun said, “Based on both the six and 18-month outcomes, which showed continued safety and sustained long-term benefits, we initiated ADVANCE, a pivotal, prospective, randomized, double-blind, European heart attack trial in up to 360 patients. The goal of our ADRC therapy is to reduce scarring, preserve heart muscle beyond what can be salvaged with current treatments, minimize harmful remodeling, and ultimately protect patients from advancing into heart failure.”
Dr. Henricus J. Duckers, lead author of the paper, added, “The advantage of adipose tissue as a cell source is that it allows physicians to get a meaningful dose of a patient’s own cells at the point-of-care when using the Celution System without cell culture or use of donor cells. We believe delivering cells within the first 24 to 36 hours takes advantage of the body’s signaling and initiates the repair process before irreparable damage occurs.”
Scientists from the University of California, San Diego School of Medicine, have created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer’s, using induced pluripotent stem cells from patients with the neurodegenerative disorder. This experiment provides the ability to study the precise abnormalities present in neurons that cause the pathology of this neurodegenerative disease.
Senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute investigator and director of the UC San Diego Stem Cell Program, noted that the production of highly purified, functional human Alzheimer’s neurons in culture has never been done before. Goldstein said: “It’s a first step. These aren’t perfect models. They’re proof of concept. But now we know how to make them.”
This experiment represents a new method for studying the causes of Alzheimer’s disease. These living cells provide a tool for developing and testing drugs to treat the disorder. According to Goldstein, “We’re dealing with the human brain. You can’t just do a biopsy on living patients. Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”
Goldstein and colleagues extracted skin cells called fibroblasts from skin tissues from two patients with familial Alzheimer’s disease. They also used fibroblasts from two patients with sporadic Alzheimer’s disease, and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated them into working neurons. These iPSC-derived neurons from the Alzheimer’s patients exhibited normal electrophysiological activity, formed functional synaptic contacts and displayed tell-tale indicators of Alzheimer’s disease. Also, they possessed higher-than-normal levels of proteins associated with Alzheimer’s disease.
With cultured neurons from Alzheimer’s patients, scientists can more deeply investigate how Alzheimer’s disease begins and chart the biochemical processes that eventually destroy brain cells and produce degeneration of elemental cognitive functions like memory. Currently, Alzheimer’s research depends heavily upon autopsies performed after the patient has died and the damage has been done. Goldstein added, “The differences between a healthy neuron and an Alzheimer’s neuron are subtle. It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”
Neurons derived from one of the two patients with sporadic Alzheimer’s disease showed biochemical changes possibly linked to the disease. Thus there may be sub-categories of the disorder and, in the future, potential therapies might be targeted to specific groups of Alzheimer’s patients.
Laboratory research needs tissue as a model system. Smooth muscle is found in the urogenital system, circulatory system, digestive system, and respiratory systems of the human body. Various diseases affect smooth muscle and being able to work on cultured smooth muscle would greatly advance the ability of medical researchers to find treatments for smooth muscle disorders.
To address this need, Cambridge University scientists have devised a protocol for generating different types of vascular smooth muscle cells (SMCs) using cells from patients’ skin. This work could lead to new treatments and better screening for cardiovascular disease.
The Cambridge group used embryonic stem cells and reprogrammed skin cells. Skin cells were turned into induced pluripotent skin cells (iPSCs), which were then differentiated into SMCs. They found that they could create all the major vascular smooth muscle cells in high purity using iPSCs. This technique can also be scaled up to produce clinical-grade SMCs.
The scientists created three subtypes of SMCs from these different types of stem cells. They also showed that various SMC subtypes responded differently when exposed to substances that cause vascular diseases. They concluded that differences in the developmental origin play a role in the susceptibility of SMCs to various diseases. Furthermore, the developmental origin of specific SMCs might part some role in determining where and when common vascular diseases such as aortic aneurysms or atherosclerosis originate.
Alan Colman MD, Principle Investigator of the Institute of Medical Biology at Cambridge University, said: “This is a major advance in vascular disease modeling using patient-derived stem cells. The development of methods to make multiple, distinct smooth muscle subtypes provides tools for scientists to model and understand a greater range of vascular diseases in a culture dish than was previously available.”
Human stem cells capable of giving rise to any fetal or adult cell type are known as pluripotent stem cells. It is hoped that such cells, the most well-known being human embryonic stem cells (hESCs), can be used to generate cell populations that can be used in therapeutic regiments. Presently, neural derivatives of embryonic stem cells are being tested in clinical trials.
Nathalie Lefort and colleagues at the Institute for Stem cell Therapy and Exploration of Monogenic Diseases (France) have shown that neural derivatives of human embryonic stem cells frequently acquire extra material from the long arm of chromosome 1 (1q). This particular chromosomal defect is sometimes seen in some blood cell cancers and pediatric brain tumors that have a rather poor clinical prognosis. Fortunately, when Lefort and her colleagues implanted these abnormal neural cells into mice, they were unable to form tumors in mice.
Neil Harrison of the University of Sheffield (U.K.) has commented on Lefort’s work in an accompanying article that these data raise safety issues relevant for the therapeutic use of embryonic stem cell derivatives. The fact that the same chromosome was affected in all cases suggests that it should be possible to design a screen that can effectively detect and remove genetically abnormal cells.
Huntington’s disease is an inherited brain disorder that causes progressive uncontrolled movements, dementia and culminates in death. The symptoms of Huntington’s disease are involuntary jerking or writhing movements (chorea), involuntary, sustained contraction of muscles (dystonia), muscle rigidity, slow, uncoordinated fine movements, slow or abnormal eye movements, impaired gait, posture and balance, difficulty with the physical production of speech, and difficulty swallowing.
More than a quarter of a million Americans are affected by Huntington’s disease. Huntington’s disease is passed through families even if only one parent has the abnormal huntingtin gene, since it is inherited as an autosomal dominant. The huntingtin gene is found on the fourth chromosome, and Huntington’s disease-causing mutations result from the expansion of a trinucleotide (CAG) repeat (Jones L, Hughes A. Int Rev Neurobiol.2011;98:373-418 & Reiner A, Dragatsis I, Dietrich P. Int Rev Neurobiol. 2011;98:325-72). This trinucleotide repeat is normally repeated up to 28 times on the chromosome, but polymerase slip during DNA replication can expand the number of these repeats so that an abnormal form of the Huntingtin protein to be made. The abnormal Huntingtin protein accumulates in the brain and this cause the disease’s devastating progression. Individuals usually develop symptoms in middle age if there are more than 35 copies of the CAG repeats. A more rare form of the disease occurs in youth when the number of CAG repeats occurs many more times.
Huntington’s disease can be managed with medications. For example Terabenazine (Xenazine) suppresses the involuntary jerking and writhing movements associated with Huntington’s diseases. Antipsychotic drugs such as Haloperidol (Haldol) and Clozapine (Clozaril) can suppress movements but they can also increase muscle rigidity and involuntary contractions. Other medications like clonazepam (Klonopin) and diazepam (Valium) can suppress the chorea, dystonia and muscle rigidity.
Even though brain grafts in laboratory animals have shown some promise, these experiments used a chemically induced form of Huntington’s disease. Because the surrounding tissue was genetically normal, implanted brain tissue simply integrated into the damaged brain tissue and healed it. However, clinical Huntington’s disease is due to mutations in the huntingtingene, and the surrounding brain tissue is not genetically normal. Therefore grafted stem cells are killed off by the toxic environment in the brain (Clelland CD, Barker RA, Watts C. Neurosurg Focus.2008;24(3-4):E9 & Dunnett SB, Rosser AE. Exp Neurol. 2007 Feb;203(2):279-92). To overcome this problem, researchers have developed a technique for that used stem cells to deliver therapeutic agents that specifically target the genetic abnormality found in Huntington’s disease.
Scientists at the UC Davis Institute for Regenerative Cures have developed a novel, and promising approach that might prevent the disease from advancing. Jan A. Nolta, principal investigator of the study and director of the UC Davis stem cell program and the UC Davis Institute for Regenerative Cures, thinks that the best chance to halt the disease’s progression will be to reduce or eliminate the mutant Huntingtin (Htt) protein found in the neurons of those with the disease. RNA interference (RNAi) technology has been shown to be highly effective at reducing Htt protein levels and reversing disease symptoms in mouse models.
Nolta said: “For the first time, we have been able to successfully deliver inhibitory RNA sequences from stem cells directly into neurons, significantly decreasing the synthesis of the abnormal Huntingtin protein. Our team has made a breakthrough that gives families affected by this disease hope that genetic therapy may one day become a reality.” She continued: “Our challenge with RNA interference technology is to figure out how to deliver it into the human brain in a sustained, safe and effective manner,” said Nolta. “We’re exploring how to use human stem cells to create RNAi production factories within the brain.”
The research team from UC Davis showed for the first time that inhibitory RNA sequences are directly transferable from donor cells into target cells to greatly reduce unwanted protein synthesis from the mutant huntingtin gene. To transfer these inhibitory RNA sequences into their targets, Nolta’s team genetically engineered mesenchymal stem cells (MSCs) from bone marrow that had been collected from unaffected human donors. Over the past two decades, Nolta and her colleagues have shown MSCs are safe and effective vehicles for the transfer of enzymes and proteins to other cells. According to Nolta, MSCs can also transfer RNA molecules directly from cell to cell, in amounts sufficient to reduce levels of a mutant protein by over 50% in the target cells. This discovery has never been reported before and offers great promise for a variety of disorders.
Nolta has recently received a Transformative Research Grant from the National Institutes of Health (NIH) to study how MSCs can transfer microRNA and other factors into the cells of damaged tissues, and how that process can be harnessed to treat injuries and disease. Nolta said: “Not only is finding new treatments for Huntington’s disease a worthwhile pursuit on its own, but the lessons we are learning are applicable to developing new therapies for other genetic disorders that involve excessive protein development and the need to reduce it. We have high hopes that these techniques may also be utilized in the fight against some forms of amyotrophic lateral sclerosis (Lou Gehrig’s disease) as well as Parkinson’s and other conditions.”
Published – Scott D. Olson, Jan Nolta et al.; Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington’s disease affected neuronal cells for reduction of huntingtin;” Molecular and Cellular Neuroscience,2011; DOI: 10.1016/j.mcn.2011.12.001.
A fascinating paper published in the journal Lasers in Surgery and Medicine shows that low-level laser treatment of bone marrow can have profound effects on the ability of bone marrow stem cells to repair a heart after a heart attack.
The paper’s authors are H Tuby, L Maltz, and Uri Oron, who are members of the Zoology department at Tel-Aviv University, Tel-Aviv, Israel. The title of the paper is “Induction of autologous mesenchymal stem cells in the bone marrow by low-level laser therapy has profound beneficial effects on the infarcted rat heart,” and it was published in the July edition ofLasers in Surgery and Medicine, 2001;43(5):401-109.
Oron and his co-workers have been studying the effects of photobiostimulation with low-level lasers on injured tissues. Their recent work established that application of low energy laser irradiation (LELI) to the site of injury in muscles, bone marrow or heart is beneficial. This irradiation does not heat the tissue and has not been found to cause adverse side effects.
The strategy of this study is rather simple: LELI on bone marrow stem cells after an laboratory animal has suffered a heart attack. The stimulated bone marrow stem cells might migrate to the injured heart and repair it. They used Sprague-Dawley rats, and induced heart attacks in those rats. Then they subjected the bone marrow of those rats to LELI 20 minutes or four hours after the heart attack. They also had rats that had not experienced heart attacks but were operated on as controls, and rats that had suffered heart attacks but were not treated with LELI. For those interested, they used a Ga-Al-As diode laser, power density 10 mW/cm², for 100 seconds.
The results were astounding. The size of the infarction was reduced by 75% and dilation of the ventricle was reduced 75% in those animals treated with LELI 20 minutes after the heart attack. There was also a 25-fold increase in the density of bone marrow-derived cells in the heart relative to the non-LELI-treated controls. This indicates that LELI offers a new approach to induce bone marrow stem cells to move into the blood stream, arrive at the damaged heart and repair it. This mobilization of bone marrow stem cells great shrinks the scar caused by a heart attack in laboratory animals. Maybe it’s time for trials in larger animals and then a phase I clinical trial in humans?
Several different diseases cause deterioration of the eye and plunge aging or even young men and women into a life of blindness. Several of these genetic diseases affect the tissues that reside at the back of the eye, which is collectively called the retina. The retina contains two main layers; an inner neural retina and an outer pigmented retina.
The neural retina is filled with photoreceptors and cells that process the outputs from the photoreceptor cells and send them to the brain. The pigmental retina contains the retinal pigmented epithelium, which plays a central role in retinal physiology. The retinal pigmented epithelium or RPE forms the outer blood-retinal barrier and supports the function of the photoreceptors. Many diseases the adversely affect the retina called “retinopathies” involve a disruption of the epithelium’s interactions with the neural retina. Other types of retinopathies are caused by uncontrolled proliferation of the RPE cells.
Transplantation of RPE cells can help treat patients that have various types of retinopathies (see Lund RD et al.,Cloning Stem Cells.2006 Fall;8(3):189-99). However, embryonic stem cells can be made into copious quantities of RPEs rather easily (Huang Y, Enzmann V, Ildstad ST. Stem Cell Rev. 2011 Jun;7(2):434-45). Therefore, it was only a matter of time before clinical trials were instigated with embryonic stem cell-derived RPEs.
In recent edition of the journal The Lancet, Steven Schwartz and colleagues have reported the first clinical results from patients treated with embryonic stem cell-derived RPEs. A patient with “Stargardt’s macular dystrophy,” which is the most common form of pediatric macular degeneration, and a patient with dry age-related macular degeneration, the leading cause of blindness in the developed world, each received a subretinal injection of RPEs derived from embryonic stem cells (ESCs). Both of these disorders are not treatable at present, but both also result from degeneration of the RPE. Loss of RPE cells causes photoreceptor loss and progressive vision deficiency.
Schwartz and colleagues differentiated the hESCs into RPE cultures that showed greater than 99% purity. Then they injected 50,000 RPE cells into the subretinal space of one eye in each patient. Each patient received anti-rejection drugs (low-dose tacrolimus and mycophenolate mofetil) just in case the immune system tried to attack the transplanted RPE cells.
There results are hopeful, since, after 4 months, both patients show no sign of retinal detachment, hyperproliferation, abnormal growths, intraocular inflammation, or teratoma formation. Anatomical evidence of the injected cells was difficult to confirm in the patient with age-related macular degeneration, but was present in the patient with Stargardt’s macular dystrophy.
Both patients showed some visual improvements. The patient who suffers from age-related macular degeneration improved in visual acuity, since she was able to recognize 28 letters in a visual acuity chart, whereas before he procedure, she was able to identify only 28 (improvement from 20/500 vision to 20/320). The patient with Stargardt’s macular dystrophy went from counting fingers and seeing only one letter in the eye chart by week 2, and to a stable level of five letters (20/800) after 4 weeks. This patient also showed subjective improvement in color vision, contrast, and dark adaptation in the treated eye.
These results are highly preliminary and the improvements are slight, but the progressive nature of these eye diseases suggests that the injections largely worked. Before we can crack our knuckles for joy, we will need to see improvements with more than two patients. But the fact that the treated eye showed improvements not seen in the untreated eye is highly suggestive that the transplanted RPEs are improving the health of the photoreceptors in the neural retina. The eye is an ideal place to do such research because it is one place in the body that is not regularly patrolled by the immune system, and foreign cells placed in the eye tend to receive far less scrutiny from the immune system than other parts of the body.
I am glad for these patients, but I am troubled by this experiment. Other types of stem cells can be converted into RPEs (Uygun BE, Sharma N, Yarmush M. Crit Rev Biomed Eng. 2009;37(4-5):355-75.). Also, there are other stem cells in the eye that, if properly investigated might possess the ability to form RPEs (Bhatia B, et al.,Exp Eye Res. 2011 Dec;93(6):852-61). Why was this experiment first done with cells that require the death of early human embryos? The safety concerns with ESCs makes the clinical trial far more expensive and slower. While the embryos sacrificed to make these RPEs have long since died, the ESC culture is doing some clinical good. However, how would we feel about cell lines made from children who were murdered by a sadistic scientist? Would you receive treatments from them given what you know about their origin? So while this experiment shows hope, it also leads to controversy as well that is not being discussed as deeply as it should.
Tomorrow (Wednesday, January 25th, 2012), the popular TV show “The Doctors” will feature the Centeno/Schultz clinic and their orthopedic stem cell treatment known as “Regenexx.” On hand will be Dr. Hanson from the Centeno clinic (unfortunately Dr. Centeno was in China for the studio taping), and a former Regenexx patient named Barbee James. Ms. James had knee cartilage breaks and received the Regenexx-C knee stem cell procedure in 2008. The stem cell-treated knee is doing quite well, but the other knee, which was surgically treated with a failed micro fracture procedure, is now in need of a stem cell treatment. See a preview of the show here.
Republican presidential candidate Rick Santorum has written another eloquent defense of human life at all stages of development. This is in the form of an op-ed piece that was published at the Wall Street Journal. Unfortunately, you need a subscription to the newspaper to read it here. Fortunately, Santorum has a free copy of it on his Twitter page here.
Our country’s Declaration of Independence stated: “We hold these truths to be self-evident, that all men are created equal, that they are endowed by their Creator with certain unalienable Rights, that among these are Life, Liberty and the pursuit of Happiness.–That to secure these rights, Governments are instituted among Men, deriving their just powers from the consent of the governed.” Unfortunately, we did not live by those words consistently when our fore-bearers agreed to let some enslave their African brothers. Nevertheless, if the principles of freedom are morally praiseworthy, they must apply to all of us no matter what our age.
Umbilical cord stem cells (UCSCs) have been differentiated into clinically significant cell types that might, potentially, lead to new treatment options for spinal cord injuries, multiple sclerosis, and other nervous system diseases.
James Hickman, a University of Central Florida bioengineer and leader of the research group that accomplished this work, said, “This is the first time this has been done with non-embryonic stem cells. . . . We’re very excited about where this could lead because it overcomes many of the obstacles present with embryonic stem cells.” Hickman’s work and that of his colleagues was published in the Jan. 18 issue of the journal ACS Chemical Neuroscience.
UCSCs do not pose the ethical dilemma represented by embryonic stem cells (ESCs). ESC lines are made from 5-day old human embryos and in order to derive them, the inner cell mass cells are extracted from the embryo by means of destroying the embryo. Destruction of a human embryo ends the life of a very young human person. UCSCs, however, come from a source that would otherwise be discarded, and the acquisition of UCSCs do not compromise the life of a human person. Another major benefit is that umbilical cells generally are not rejected by the immune system, and this simplifies their potential use in medical treatments.
The Menlo, California-based pharmaceutical company, Geron, developed a treatment protocol for spinal cord repair that utilized oligodendrocyte precursor cells that were derived from embryonic stem cells. However, it took Geron scientists 18 months to secure approval from the Food & Drug Administration (FDA) for human clinical trials. This is due, largely, to the ethical and public concerns attached to human ESCs. These concerns, in addition to anxieties over ESC-caused tumors, led the company to shut down its ESC division. This highlights the need for other stem cell alternatives.
One of the greatest challenges in working with any kind of stem cell is determining the precise chemical or biological cues that trigger them to differentiate into the desired cell type. The lead author on this paper, Hedvika Davis, a postdoctoral researcher in Hickman’s lab, transformed UCSCs into oligodendrocytes (those structural cells that surround and insulate nerves in the brain and spinal cord). Davis learned from research done by other groups that surface proteins on the surfaces of oligodendrocytes bind the hormone/neurotransmitter norepinephrine. This suggests that cells normally interact with this chemical and that it might be one of the factors that stimulates oligodendrocyte production. Therefore Davis decided to treat USCSs with epinephrine as a starting point.
In early tests, Davis found that norepinephrine, plus several other stem cell growth promoters, caused the UCSCs to differentiate into oligodendrocytes. However, that conversion was incomplete, since the cells grew but stopped short of becoming completely mature oligodendrocytes. Clearly something else was needed to push UCSCs completely into mature oligodendrocytes.
Many stem cells differentiate into particular cell types only if the appropriate environment is offered to them. For example, mesenchymal stem cells can form cartilage, but cartilage formation is extremely sensitive to environmental factors like cell density, and the matrix in which cells are embedded. Thus, Davis decided that, in addition to chemistry, the physical environment might be critical. In order to more closely approximate the physical restrictions cells face in the body, Davis constructed a more confined, three-dimensional environment. She grew the cells on a microscope slide, covered by a glass cover slip. Once the UCSCs had the proper confined environment and norepinephrine plus the appropriate growth factors, they differentiated into completely mature oligodendrocytes. Davis noted, “We realized that the stem cells are very sensitive to environmental conditions.”
The use of these differentiated oligodendrocytes is exciting. There are two main options for the use of these cells. First, the cells could be injected into the body at the point of a spinal cord injury to promote repair. Another intriguing possibility for the Hickman team’s work relates to multiple sclerosis and similar conditions. Hickman explained, “Multiple sclerosis is one of the holy grails for this kind of research.” Hickman’s research group is collaborating with Stephen Lambert at UCF’s medical school, another of the paper’s authors, to explore biomedical possibilities.
Oligodendrocytes produce a protein called myelin, which insulates nerve cells. Myelin sheaths make is possible for neurons in the central nervous system to conduct those nerve impulses that guide movement and other functions. Myelin loss is responsible for conditions like multiple sclerosis, and is also observed in other related conditions such as diabetic neuropathy.
The injection of new, healthy oligodendrocytes might improve the condition of patients suffering from such neurological diseases. These research teams are also hoping to develop the techniques needed to grow oligodendrocytes in the lab and use them a model system to better understand the loss and restoration of myelin, and for testing potential new treatments. Hickman enthusiastically said, “We want to do both. We want to use a model system to understand what’s going on and also to look for possible therapies to repair some of the damage, and we think there is great potential in both directions.”
Wesley Smith at his blog “Secondhand Smoke” has an excellent article on the Canadian Medical Association Journal‘s proposal to ban disclosing the sex of a baby to the parents, until the baby is 30 weeks old. This proposal is hypocritical, since the CMAJ has no problem with abortion for purposes of eugenics, in vitro fertilization, or lifestyle choices. In all those cases, at least 50% of the babies whose lives are terminated are female, but for some reason, CMAJ thinks that termination of a female baby’s life just because the parents want a boy rather than a girl is illicit. The journal even calls it “feticide.”
Well, so now abortion is feticide. That’s what I’ve been saying all along. Read Smith’s article here.
A developer of innovative stem cell technologies, BrainStorm Cell Therapeutics Inc. has developed a stem cell treatment called NurOwn for central nervous system-based disorders. NurOwn™ is a product derived from human bone marrow mesenchymal stem cells. After these cells are collected from a patient by means of a bone marrow aspiration (which not nearly as invasive as a bone marrow biopsy), they are differentiated into nerve-like cells that can release the neurotransmitter dopamine and a nervous system-specific growth factor called glial-derived neurotrophic factor (GDNF). Dopamine cell damage and death is the hallmark of Parkinson’s Disease (PD), and GDNF-producing cells can protect healthy dopamine-producing cells and repair degenerated cells. This halts the progression of PD and other neurodegenerative diseases. BrainStorm’s NurOwn™ therapy for PD replaces degenerated dopamine-producing nerve cells and strengthens them with GDNF.
BrainStorm has just announced patient data from its ALS combined phase I & II human clinical trial. ALS patients who were treated with NurOwn, a stem cell-based product that BrainStorm had developed, did not show any significant side effects to the NurOwn treatment. Therefore, so far, NurOwn seems to be safe.
The leader of this clinical trial at Hadassah Medical Center, Prof. Dimitrios Karussis, stated, “There have been no significant side effects in the initial patients we have treated with BrainStorm’s NurOwn technology. In addition, even though we are conducting a safety trial, the early clinical follow-up of the patients treated with the stem cells shows indications of beneficial clinical effects, such as an improvement in breathing and swallowing ability as well as in muscular power. I am very excited about the safety results, as well as these indications of efficacy, we are seeing. This may represent the biggest hope in this field of degenerative diseases, like ALS.”
The Hadassah Medical Center ethics committee reviewed the safety data from the first four patients who were implanted with NurOwnTM, and concluded that the clinical trial should proceed with implanting the next group of ALS patients.
BrainStorm’s President, Chaim Lebovits, remarked: “We are happy to report that the first patients treated with our NurOwn technology did not present any significant side effects. This supports and strengthens our belief and trust in our technology. Based on the interim safety report, the hospital ethical and safety committee granted the company approval to proceed with treating the next patients. We are pleased with the progress we are making and look forward to continuing to demonstrate the safety of NurOwn in the future.”
This study is headed by Prof. Karussis, MD, PhD, head of Hadassah’s Multiple Sclerosis Center and a member of the International Steering Committees for Bone Marrow and Mesenchymal Stem Cells Transplantation in Multiple Sclerosis (MS), and a scientific team from BrainStorm headed by Prof. Eldad Melamed. This clinical trial is being conducted at Hadassah Medical Center in Israel in collaboration with BrainStorm and utilizes BrainStorm’s NurOwn technology for growing and modifying autologous adult human stem cells to treat ALS, which is often referred to as Lou Gehrig’s Disease. The initial phase of the study is designed to establish the safety of NurOwn, but will also be expanded later to assess efficacy of the treatment.
Because so many of you commented on the ALS entry, I decided to write more about stem cell treatments for this disease.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results from death of so-called “upper” and “lower” motor neurons. Motor neurons enervate skeletal muscles, and the activity of motor neurons allows those muscles to contract. Without contraction of skeletal muscles, the skeleton cannot move and ambulatory movement as we know it, becomes impossible.
There is only one treatment for ALS and that is a drug called riluzole (Rilutek). When neurons start to die, they dump enormous quantities of neurotransmitters into the spaces surrounding the cells, and this neurotransmitter dump causes nearby neurons to die from neurotransmitter overdose. Blocks the glutamate receptor and prevents large quantities of glutamate from binding to the surfaces of neurons en mass and killing them. Riluzole, however, only buys ALS patients time and increases survival by a matter of months (3-5 months). ALS patients die approximately within three-to-five years after receiving their diagnosis. Death typically results from the weakness of those skeletal muscles that are responsible for airway and respiratory control (See Borasio, G. & Miller, R. Clinical characteristics and management of ALS. Semin. Neurosci. 2002;21:155–166).
As you can see, better treatment options are required, and cell transplantation has recently been proposed as a treatment for various neurological disorders (see Miller, R. H. The promise of stem cells for neural repair. Brain Res. 2006;1091:258–264). In 2009, the FDA approved the first phase I trial of intraspinal stem cells as a treatment of ALS. This trial is ongoing, with completion anticipated sometime in 2012.
What causes motor neurons to all of a sudden start dying off? In a small subset of cases, genetic mutations in genes such as super¬oxide dismutase 1 are the reason for motor neuron die-off (see Rothstein, J. D. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann. Neurol. 2009;65(Suppl. 1):S3–S9 & Ilieva, H., Polymenidou, M. & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 2009;187:761–772). In the vast majority of cases, the exact mechanisms of motor neuron degeneration in ALS are poorly understood. ALS pathogenesis involves multiple cell types and many mechanisms. The events that cause neuronal death in ALS patients include inflammation, oxidative stress, overdose of the neurotransmitter glutamate, and loss of neurotrophic support. Therefore, the spinal is converted into a toxic waste dump that is completely inhospitable for the survival of neurons. The best way to treat this disease is to maintain or restore motor neuron function and roll back the toxic environment in the spinal cord. Also replacing dead neurons is the goal of cell transplantation therapies.
Cell transplantation strategies come in two forms: A) transplantation of neurons (the conductive cells in the nervous system; and B) transplantation of glial cells (the support cells in the nervous system). Neuron transplantation is possible, since neurons can be derived from embryonic stem cells or from existing neural stem cell lines. Neuron transplantation has been studied in an ALS model in rodents. See the following papers: a) Bonner, J. F., Blesch, A., Neuhuber, B. & Fischer, I. Promoting directional axon growth from neural progenitors grafted into the injured spinal cord. J. Neurosci. Res. 88, 1182–1192 (2010). b) Silani, V., Calzarossa, C., Cova, L. & Ticozzi, N. Stem cells in amyotrophic lateral sclerosis: motor neuron protection or replacement? CNS Neurol. Disord. Drug Targets 9, 314–324 (2010). c) Xu, L., Ryugo, D. K., Pongstaporn, T., Johe, K. & Koliatsos, V. E. Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. J. Comp. Neurol. 514, 297–309 (2009). d) Yan, J. et al. Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med. 4, e39 (2007). Unfortunately, when it comes to transplanting motor neurons, there are some daunting practical issues: grafted neurons must receive functional synapses, send axons through inhibitory white matter, and direct axons over long distances to the target muscles in order to retain neuromuscular function. Given these limitations, direct replacement of motor neuron populations is unlikely to provide a viable treatment option for ALS.
Transplantation of glial cells, such as astrocytes and microglia is a much more practical possibility for ALS treatment. Astrocytes and microglia contribute to ALS pathology by impaired metabolic support, compromised neuron–glia crosstalk, or release of toxic metabolites. By replacing diseased glia cells, the pathology of ALS can be effectively short-circuited and the environment of the spinal cord is ameliorated. Experiments, once again in rodents, have shown that transplantation of astrocytes that express the wild-type SOD1 allele can reduce the degeneration and death of motor neurons expressing mutant SOD1 (see Boucherie, C., Schafer, S., Lavand’homme, P., Maloteaux, J. M. & Hermans, E. Chimerization of astroglial population in the lumbar spinal cord after mesenchymal stem cell transplantation prolongs survival in a rat model of amyotrophic lateral sclerosis. J. Neurosci. Res. 2009;87:2034–2046; & Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 2003;302:113–117). Other experiments that transplanted glial-restricted progenitor (GRP) cells into the spinal cords of mutant SOD1 rats showed that such GRPs differentiates into astrocytes that restored the levels of astrocyte physiology, decreased glutamate levels in the spinal cord and extended the survival of the transplanted rats (Lepore, A. C. et al. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat. Neurosci. 2008;11:1294–1301). These experiments indicate that cellular replacement therapies might support motor neurons in ALS by maintaining a more hospitable microenvironment in the spinal cord.
Another therapeutic strategy for ALS patients is to use growth factors to protect the axons that extend from the motor neurons in the spine to the skeletal muscles in the limbs and body wall. Axonal defects that include degeneration of the neuromuscular junction and distal axon are some of the earliest hallmarks of ALS. Degeneration of axons occurs before the onset of symptoms and the death of the motor neurons (Fischer LR & Glass JD. Axonal degeneration in motor neuron disease. Neurodegener. Dis. 4, 431–442 (2007). This suggests that axonal dysfunction is a consequence of a loss of trophic support. To understand trophic support, consider that you have to take a very long trip to bring something to a client. Without gas stations along the way, you would never make it to your destination, since your care would run out of gas. Axons that extend from neurons are the same way. In order to make it all the way to their target muscle, they need gas stations along the way. Once they attach to their target muscle, the muscle secreted molecules that allows the axon to survive. However, glial cells along the way provided molecules that helped the axon survive as well. Without this constant input of pro-survival molecules (so-called “trophic factors”), the axons retract and lose their neuromuscular junction with the muscle. This is what is meant by trophic support.
Transplanted stem cells that secrete neurotrophic factors might provide a strategy to protect the diseased neurons. Trophic support of axons by growth factors and insulin-like growth factor I (IGF‑I) have been shown to provide neuroprotection in both in vitro and in vivo models of ALS and reduce motor neuron degeneration (see Sakowski, S. A. et al. Neuroprotection using gene therapy to induce vascular endothelial growth factor‑A expression. Gene Ther. 16, 1292–1299 (2009) & Sakowski, S. A., Schuyler, A. D. & Feldman, E. L. Insulin-like growth factor‑I for the treatment of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 10, 63–73 (2009). Unfortunately, recent clinical trials showed that subcutaneous delivery of IGF‑I had no therapeutic benefit in ALS, since the growth factor could not reach the motor neurons in the spinal cord (Sorenson, E. J. et al. Subcutaneous IGF‑1 is not beneficial in 2‑year ALS trial. Neurology 71, 1770–1775 (2008). Intraspinal transplantation of stem cells that are capable of secreting IGF‑I could potentially overcome this limitation and provide therapeutic levels of IGF‑I directly to motor neurons.
More and more data point to the efficacy of treatments that improvement the spinal cord environment. Transplantation of stem cells that secrete growth factors might do exactly this task. Cortical human neural progenitor cells engineered to secrete glial cell-derived neurotrophic factor (GDNF) provide protection for motor neurons after transplantation into the spinal cords of SOD1G93A transgenic rats (which develop a rodent form of ALS; see Suzuki, M. et al. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS ONE 2, e689 (2007). These cells also rapidly differentiated into astrocytes and replaces diseased glial cells. Therefore, transplanted stem cells provided multiple therapeutic benefits. Similarly, transplantation of neural progenitor cells producing either GDNF or IGF‑I into SOD1G93A mice decreases loss of motor neuron loss (Park, S. et al. Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice. Exp. Mol. Med. 41, 487–500 (2009). Intramuscular delivery of GDNF-producing mesenchymal stem cells in a rat model of ALS also increases neuromuscular contacts, motor neuron survival and lifespan (Suzuki, M. et al. Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS. Mol. Ther. 16, 2002–2010 (2008). Cellular therapies might, therefore, represent a source of neurotrophic support for diseased motor neurons in ALS.
Human spinal stem cells are derived from spinal cord progenitors and differentiate into both neurons and glia. Several rodent studies have confirmed the therapeutic potential of intraspinal HSSC transplantation. Following transplantation, these cells express excitatory amino acid transporters that can restore functional glutamate reuptake around vulnerable motor neurons. Additionally, HSSCs also release neurotrophic factors (Yan, J. et al. Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med. 4, e39 (2007). Grafted HSSCs express several growth factors, including GDNF and brain-derived neurotrophic factor, and also form synaptic contacts with host motor neurons (Xu, L., Ryugo, D. K., Pongstaporn, T., Johe, K. & Koliatsos, V. E. Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. J. Comp. Neurol. 514, 297–309 (2009). Several publications show that transplantation of Intraspinal HSSCs delays symptom onset and extends the lifespan in rodent ALS models (see following papers: a) Xu, L. et al. Human neural stem cell grafts ameliorate motor neuron disease in SOD‑1 transgenic rats. Transplantation 82, 865–875 (2006); b) Yan, J. et al. Combined immunosuppressive agents or CD4 antibodies prolong survival of human neural stem cell grafts and improve disease outcomes in amyotrophic lateral sclerosis transgenic mice. Stem Cells 24, 1976–1985 (2006); c) Xu, L., Shen, P., Hazel, T., Johe, K. & Koliatsos, V. E. Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats. Neurosci. Lett. 494, 222–226 (2011). Thus, transplanted HSSCs differentiate into multiple cell types, improve the spinal cord milieu, provide neurotrophic support, and form functional synaptic contacts with motor neurons in the spinal cord, forming a multifaceted attack on ALS progression. HSSCs are the ideal stem cell for ALS treatment.
Since cellular therapies have the ability to improve survival and motor function of ALS rodents, the next stop is human trials. In 2009, the FDA approved a human trial that involved intraspinal injection of HSSCs. Choosing the right stem cell for ALS patients will require several clinical trials, but with this trial, HSSCs were chosen. They were injected at two levels in the spinal cord; lumbar and cervical levels. Some patients were injected at both levels and others were injected at one but not the other level. Injections were performed with a special device designed specifically for stabilized injection into the spinal cord at specific locations.
a | Platform anchored to patient’s spine consists of two bridge rails (blue), one of which is scored at 2-mm intervals to aid regular positioning of injections. Gondola (green) compensates for slight movements in the platform application. Mechanical Z drive (orange) allows precise raising and lowering of a floating cannula. b | Cannula tip is positioned 1 mm medial to dorsal root entry zone. c | Needle penetrates into spinal cord ~4 mm from pial surface. d | Once needle tip is positioned at the target, metal outer sleeve is pulled up, leaving flexible tubing exposed.
This figure comes from Nicholas M. Boulis, Thais Federici, Jonathan D. Glass, J. Simon Lunn, Stacey A. Sakowski & Eva L. Feldman. Translational stem cell therapy for amyotrophic lateral sclerosis. Nature Reviews Neurology, advance online publication, Published online 13 December 2011 | doi:10.1038/nrneurol.2011.191.
The clinical trial will be completed in 2012 and the data should be published soon thereafter. A new era in ALS treatment is dawning and stem cells are leading the way.
Humans store excess dietary fat in specialized called “adipocytes.” Adipocytes are found underneath the skin and deep within the core of our bodies, and this excess fat is a source of health problems. However when placed in artificial culture, adipocytes do something completely unexpected and remarkable.
Cultured human adipocytes dump their fat globules and begin to dedifferentiate. Such cells are called “dedifferentiated fat ” cells or DFAT cells for short. DFAT cells result from the subjection of mature adipocytes to a so-called “ceiling culture,” and these DFAT cells can revert to a more primitive phenotype and gain the ability to divide in culture and expand (see Matsumoto T, et al, J Cell Physiol. 2008;215(1):210-22). DFAT cells can be subjected to differentiation protocols and can produce skeletal muscle (Kazama T et al Biochem Biophys Res Commun. 2008;377(3):780-5), bone cells (Oki Y et al Cell Struct Funct. 2008;33(2):211-22), smooth muscle cells that can be used to repair a laboratory animal’s bladder (Sakuma T et al J Urol. 2009l;182(1):355-65), and beating heart muscle cells (Jumabay M et al Cardiovasc Res. 2010;85(1):17-2). Heart muscle cells made from DFAT cells can even treat the hearts of laboratory animals that have had a heart attack (Jumabay M, et al J Mol Cell Cardiol. 2009;47(5):565-75).
Gene expression studies of DFAT cells have shown that they no longer express the genes particular to adipocytes, and also express many new genes necessary for cell growth and division. Thus DFAT have truly undergone a significant change (Ono H et al Biochem Biophys Res Commun. 2011;407(3):562-7).
DFAT cells have yet to be used in a clinical trial, but several preclinical trials have been conducted with them, and phase I clinical trials are certainly not far away.
Acute Respiratory Distress Syndrome (ARDS) describes a spectrum of increasingly severe acute respiratory failure events. ARDS results from multiple causes that include infections, trauma and major surgery. Clinically, ARDS is the leading cause of death and disability in the critically ill.
The characteristics of ARDS includes a somewhat sudden onset, severe oxygen depletion or hypoxia, stiff lungs that do not expand or contract properly, and the presence of an inflammation in the lungs that results in pulmonary swelling (edema; see Ware LB, Matthay MA. N Engl J Med. 2000, 342:1334–49.). In the US, there are 200,000 new cases each year, and carries a mortality rate of 40%. This is a mortality rate that is comparable to that seen from HIV infections and breast cancer. The prognosis of ARDS survivors is also somewhat poor. ARDS sufferers can also find themselves fighting with cognitive impairment, depression and muscle weakness. Also ARDS can saddle patients with substantial financial burdens (see Herridge MS, et al. N Engl J Med. 2003, 348:683–93 & Hopkins RO, et al. Am J Respir Crit Care Med. 2005, 171:340–7).
Despite decades of research on ARDS, there are no therapies for it and management of the disease remains supportive. But now stem cells called “mesenchymal stem cells” offer a potentially successful treatment of ARDS. Mesenchymal stem cells (MSCs) are multipotent cells stem cells that are derived from adult tissues and capable of self-renewal and can differentiate into cartilage-making cells (chondrocytes), bone-making cells (osteocytes), and fat cells (adipocytes). Friedenstein and colleagues were the first to isolate MSCs from rodent bone marrow in 1976 ()m the bone marrow in 1976 (see Friedenstein AJ, Gorskaja JF, Kulagina NN. Exp Hematol. 1976, 4:267–74). Since their discovery, MSCs have been isolated from many other tissues, including fat, muscle, dermis, placenta, umbilical cord, peripheral blood, liver, spleen, and lung. The fact that MSCs come from adult tissue, are relatively easy to isolate, and are capable of robust growth in culture, males them attractive candidates for regenerative medicine (see Prockop DJ, et al. J Cell Mol Med. 2010, 14:2190–9). Additionally, MSCs are usually tolerated by the immune system, which means that they can be transplanted from one individual to another.
Earlier studies provided data that suggested that MSCs actually might differentiate into lung epithelial cells and directly replace the damaged and destroyed lung cells. For example, Kotton et al. demonstrated that bone marrow-derived cells could engraft into pulmonary epithelia and acquire the specific characteristics typical to lung epithelial cells (Kotton DN, et al. Development. 2001, 128:5181–8). Krause and colleagues showed that transplantation of a single bone marrow-derived blood-cell making (hematopoietic) stem cell could give rise to cells of different organs, including the lung, and demonstrated that up to 20% of lung alveolar cells were derived from this single bone marrow stem cell (Krause DS, et al. Cell. 2001, 105:369–77). Finally, Suratt and co-workers examined female patients who had received bone marrow transplants from male donors, and found that significant numbers of male bone marrow stem cells, which were detected by the presence of the Y chromosome, had formed cells that engrafted in the lungs of the female patients (Suratt BT, et al. Am J Respir Crit Care Med. 2003, 168:318–2). Unfortunately, more recent studies have clearly demonstrated that even though MSCs definitely reduce experimental lung injury, engraftment rates are low (see Mei SH, et al. PLoS Med. 2007, 4:e269; & Ortiz LA, et al. Proc Natl Acad Sci U S A. 2007, 104:11002–7). This suggests that direct engraftment of mesenchymal stem cells in the lung is unlikely to be of large therapeutic significance.
Several experiments have suggested many different mechanisms by which MSCs might help injured lungs. First, MSCs seem to slow down the immune response to lung injury (see Gupta N, et al. J Immunol. 2007, 179:1855–63 & Mei SH, et al. Am J Respir Crit Care Med. 2010, 182:1047–57). However, instead of acting like classic “anti-inflammatory” drugs might work, MSCs actually decrease host damage that arises from the inflammatory response, but also enhance host resistance to bacterial infections (sepsis). MSCs decrease the expression of small molecules called “cytokines” that encourage inflammation (see Danchuk S, et al. Stem Cell Res Ther. 2011, 2). Conversely, they also produce a host of anti-inflammatory molecule (e.g., interleukin 1 receptor antagonist, interleukin-10, and prostaglandin E2; see Németh K, et al. Nat Med. 2009, 15:42–9). Because of these activities, MSCs reduced the recruitment of white blood cells to the lung during episodes of lung damage. This is important because when white blood cells are recruited to a damaged area, they act as though they are ticked off and damaged not just the invading bacteria, but anything that stands in their and that includes innocent bystanders. Thus by keeping ticked off white bloods away from lung tissue, the lung is spared extensive damage.
Secondly, MSCs seem to increase the immune response to sepsis, and reduce lung-damage-induced systemic sepsis. Sepsis refers to the colonization of the bloodstream by infecting microorganisms. Damage to the lung epithelium and provide a door from the air we breathe and the bacteria that contaminate it to our bloodstream. MSCs mitigate lung damage, and therefore, reduce lung-induced sepsis, MSCs secrete prostaglandin-E2, and this molecule stimulates resident white blood cells in the lung, known as “alveolar macrophages” to produce a molecule called “IL-10.” IL-10 prevents potentially damaging activated white blood cells from being summoned to the lung (see Németh K, et al. Nat Med. 2009, 15:42–9). Additionally, MSCs secrete anti-microbial peptides such as LL-37 and tumour-necrosis-factor-alpha-induced-protein-6 that retard bacterial growth (Krasnodembskaya A, et al. Stem Cells. 2010, 28:2229–3). When given to mice with lung damaged-induced sepsis, transplanted MSCs increased clearance of bacteria from the lung anf enhanced destruction of the bacteria by resident white blood cells (Mei SH,et al. Am J Respir Crit Care Med. 2010, 182:1047–57).
Thirdly, MSCs aid lung regeneration following injury. They do this by secreting molecules that protect cells and promote cell survival (so-called “cytoprotective agents”). MSCs also secrete “angiopoeitin” and “keratinocyte growth factor,” which restore the growth and health of the lung alveolar epithelial and endothelial permeability. These molecules enhance lung healing in ARDS animals (see Lee JW,et al. Proc Natl Acad Sci U S A. 2009, 106:16357–6Mei SH, et al. PLoS Med. 2007, 4:e269 & Fang X, et al. J Biol Chem 2010. 285:26211–2).
Clearly MSCs show a very diverse cadre of mechanisms that favorably modulate the immune response, which reduces inflammation and inflammation injury, without compromising the integrity of the immune response. They also hasten healing of damaged lung tissue. These features make MSCs attractive therapeutic candidates for ARDS.
Preclinical have proven extremely hopeful. Human trials are currently in the planning and early stages. It is not clear what the right dosages of MSCs might be or what is the best way to administer them (intravenous, intra-tracheal, or intra-peritoneal). Another hurdle is that MSCs are a very heterogeneous population once they are isolated. Which cells in this mixed population are them best for helping ARDS patients? All these questions much be addressed before human trials can definitively test MSC treatments for ARDS.
University of Pittsburgh scientists have used stem cells derived from younger young mice to revitalize older mice. They used mice that were bred to age quickly, but after these stem cell injections, they seemed to have sipped from the fountain of youth. These stem cells were derived from muscles of young, healthy animals, and instead of becoming infirm and dying early as untreated mice did, the injected animals improved their health and lived two to three times longer than expected. These findings were published in the Jan. 3 edition of Nature Communications.
Previous research has revealed stem cell dysfunction, such as poor replication and differentiation, in a variety of tissues in old age. However it is not clear whether that loss of function contributes to the aging process or is a result of it. Senior investigators in this work were Johnny Huard, Ph.D., professor in the Departments of Orthopaedic Surgery and of Microbiology and Molecular Genetics, Pitt School of Medicine, and director of the Stem Cell Research Center at Pitt and Children’s Hospital of PIttsburgh of UPMC, and Laura Niedernhofer, M.D., Ph.D. associate professor in Pitt’s Department of Microbiology and Molecular Genetics and the University of Pittsburgh Cancer Institute (UPCI).
Niedernhofer explained: “Our experiments showed that mice that have progeria, a disorder of premature aging, were healthier and lived longer after an injection of stem cells from young, healthy animals. That tells us that stem cell dysfunction is a cause of the changes we see with aging.”
The research team examined a stem/progenitor cell population derived from the muscle of mice engineered to suffer from a genetic disease called progeria. Progeria is a genetic disease that causes premature aging. Human patients with progeria age extremely quickly and die at a very young age from old age. Muscle-derived stem cells from progeria mice were fewer in number, did not replicate as often, didn’t differentiate as readily into specialized cells and were impaired in their ability to regenerate damaged muscle in comparison to those found in normal rodents. The same defects were discovered in the stem/progenitor cells isolated from very old mice.
Dr. Huard said: “We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice. Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer – some even lived beyond 66 days. They also were in better general health.”
As the progeria mice age, they lose muscle mass in their hind limbs, hunch over, tremble, and move slowly and awkwardly. Affected mice received an injection of stem cells just before showing the first signs of aging were more like normal mice, and they grew almost as large. Closer examination showed new blood vessel growth in the brain and muscle, even though the stem/progenitor cells weren’t detected in those tissues. However, the injected cells didn’t migrate to any particular tissue after injection into the abdomen.
Niedernhofer noted: “This leads us to think that healthy cells secrete factors to create an environment that help correct the dysfunction present in the native stem cell population and aged tissue. In a culture dish experiment, we put young stem cells close to, but not touching, progeria stem cells, and the unhealthy cells functionally improved.”
Animals that age normally were not treated with stem/progenitor cells, but these provocative findings urge further research. They hint that it might be possible one day to forestall the biological declines associated with aging by delivering a shot of youthful vigor, particularly if specific rejuvenating proteins or molecules produced by the stem cells could be identified and isolated.
Republican candidate for president Rick Santorum provides a beautiful, terse defense of the sanctity of human life. Finally a politician who is willing to articulate a clear commitment to the sanctity of human at all stages of life. Read it here.
Spanish researchers have observed the ability of bone marrow-derived stem cells (BMDC) to contribute to a several different neural cell types in other areas of the brain besides the cerebellum, including the olfactory bulb, because of a mechanism of “plasticity”. BMDCs have been recognized as a source for transplantation because they have the capacity to contribute to different cell populations in several different organs under both normal and pathological conditions. Many BMDC studies have aimed at repairing damaged brain tissue or helping to restore lost neural function, and much of that research has focused on BMDC transplants to the cerebellum, which is located at the back of the brain.
Eduardo Weruaga of the University of Salamanca, Spain commented, “To our knowledge, ours is the first work reporting the BMDC’s contribution to the olfactory neurons, We have shown for the first time how BMDCs contribute to the central nervous system in different ways in the same animal depending on the region and cell-specific factors.”
Weruaga and his group grafted bone marrow cells into mutant mice that suffered from degeneration of specific neuronal populations at different ages. Then they compared these mice to similarly transplanted healthy controls, and they found that increased numbers of transplanted BMDCs did increase the number of bone marrow-derived stem cells in the experimental groups. However, six weeks after transplantation, more bone marrow-derived microglial cells were observed in the olfactory bulbs of the test animals even though degeneration of mitral cells was still in progress. Such a difference was not observed in the cerebellum where cell degeneration had been completed.
Weruaga noted: “Our findings demonstrate that the degree of neurodegenerative environment can foster the recruitment of neural elements derived from bone marrow. But we also have provided the first evidence that BMDCs can contribute simultaneously to different encephalic areas through different mechanisms of plasticity: cell fusion for Purkinje cells, which are among the largest and most elaborately dendritic neurons in the human brain, and differentiation for olfactory bulb interneurons.”
The Salamanca group also confirmed that BMDCs fuse with Purkinje cells in the cerebellum, but they also found that the neurodegenerative environment had no effect on the behavior of the BMDCs. “Interestingly, the contribution of BMDCs occurred through these two different plasticity mechanisms, which strongly suggests that plasticity mechanisms may be modulated by region and cell type-specific factors,” he said.
Paul R. Sanberg, distinguished professor of Neuroscience at the Center of Excellence for Aging and Brain Repair, University of South Florida made this observation about Weruaga’s study: “This study shows a potential new contribution of bone marrow derived cells following transplantation into the brain, making these cells highly versatile, in their ability to both differentiate into and fuse with endogenous neurons.” Bone marrow stem cells continue to surprise researchers with their plasticity and ability to become other cell types.
Beyond the Dish 