Cell Transplantation Treatments for Amyotrophic Lateral Sclerosis (ALS)


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.

Heart Muscle Cells from Mature Fat Cells


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.

Mesenchymal stem cells used to treat Acute Respiratory Distress


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.

Making Older Mice Younger with Stem Cell Injections


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.

Rick Santorum on the Dignity of Human Life


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.

Bone Marrow Stem Cells Differentiate into Brain-Specific Cell Types in Laboratory Animals


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.

Using Nanoparticles to Successfully Deliver Stem Cells


Getting healthy cells to a damaged tissue might be much easier than previously thought if a new cell delivery technology pans out. A recent report in the American Chemical Society’s journal “Langmuir” described a technique for delivering normal cells to a diseased tissue that makes use of a simple magnetic effect.

Rawil Fakhrullin and colleagues explain that the goal of cell therapy is to replace damaged or diseased cells in the human body with normal cells or cultured stem cells. In order to do this, physicians need techniques that can target these cells to diseased organs or tissues. A technique called “superparamagnetic iron oxide nanoparticles” or SPIONS can be attached to therapeutic cells and help deliver them to the diseased site. Magnetic devices can move SPION-labeled cells to diseased areas of the body. Currently, the protocols for attaching SPIONs to therapeutic cells are difficult to use and may potentially damage the therapeutic cells. Thus, researchers set out to develop a better process for attaching SPIONs to human cells.

In their Langmuir paper, Fakhrullin and colleagues describe a new process for making “stabilized” SPIONs in the laboratory and successful attaching them to the surfaces of human cells without damaging them. They found that the SPIONs were not toxic to cells, and they moved in response to a magnet. Fakhrullin commented: “Our current results, as we believe, will inspire scientists to apply the simple and direct technique reported here in tissue engineering and cell-based therapies.” SPIONs might be the delivery method of the future for some stem cell-based regenerative therapies.