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STANFORD RESEARCHERS ISOLATE SKELETAL STEM CELLS THAT GIVE RISE TO BONES AND CARTILAGE

Cartilage and bone deterioration are a common consequence of aging, but poor diet, sedentary lifestyle, excess weight or injury can also result in damaged tissue. Unlike bone tissue, mature cartilage is avascular and doesn’t heal well after injury. Replacement or augmentation surgery is one way to fix a torn joint, but the costs are high and there are also several risks involved in the procedure, such as transplant rejection and infection [1].

In January 2015, scientists at the Stanford University School of Medicine published a paper regarding their latest findings in tissue engineering. With the use of skeletal stem cells (myoblasts), they have been able to give rise to bone and cartilage in mice. In addition, they mapped out the chemical signals which can create skeletal muscle stem cells, directing their development into specialized types of cells [2].

To better understand the medical significance of these findings, we are going to take a closer look at stem cells and their role in bone and cartilage regeneration.

HOW SKELETAL STEM CELLS ARE OBTAINED

Stem cells (or blank cells) are undifferentiated cells that can divide or differentiate into specialized cells, replacing dying cells or damaged tissues. There are two broad types of stem cells: embryonic stem cells (ESCs) and adult stem cells (somatic stem cells).

ESCs are harvested from embryos 4-5 days post-fertilization, at each time they consist of 50-150 cells. Embryonic stem cells are pluripotent and can repair damaged tissue or stimulate the regeneration of diseased cells. However, due to ethical controversy, the study of ESCs is a slow process.

In humans, bone marrow, peripheral blood and adipose tissue are rich sources of adult stem cells, but these can be also harvested from some brain areas, skin, liver and even teeth. Until recent years, it was thought that adult stem cells differentiate only as the type of tissue they originate from. Emerging studies suggest that just like ESCs, these cells can specialize in unrelated cell types, as well.

The study conducted at the Stanford University School of Medicine supports these claims. The research focused on groups of cells with a fast division rate, located at the ends of mouse bones. Human skeletal muscle-derived cells were transplanted into host mice.

Prior to the procedure, the targeted host tissues were modulated by irradiation and cryoinjury, to allow the observation of the transplanted cells in mice. After four weeks of observation it was discovered that these isolated collections of cells were able to reconstruct all parts of the mouse bone.

Through further investigation, scientists were able to map the developmental tree of skeletal stem cells, which provided great insight on how to give rise to more specific types of cells. Irving Weissman, MD professor of pathology and of developmental biology, who directs the Stanford Institute for Stem Cell Biology and Regenerative Medicine, hopes that once these findings are translated into humans, the odds of rescuing cartilage and bone from wear and aging will increase significantly [3].

DIFFERENTIATION OF SKELETAL STEM CELLS AND THERAPEUTIC APPLICATIONS

Skeletal muscle is a dynamic tissue, capable of a regenerative response within a couple of weeks. This ability is primarily due to its satellite cells populations, a type of cells that are located peripheral to the myofiber.

When injury or disruption occurs, these satellite cells become activated and either fuse together to replace the damaged myofiber or multiply at an increased rate, supporting additional rounds of regeneration. In addition, skeletal stem cells can also give rise to blood derivatives, vascular components, osteoblasts (bone formation cells), adipocytes (fat cells) and cartilage [4].

The use of skeletal stem cells for therapeutic purposes brings hope to patients who suffer from muscular conditions, including muscular dystrophy. Joint pain, dislocations and arthritis are also on the list of potential stem cell therapy. Rheumatoid arthritis, Osteoarthritis and even Multiple Sclerosis patients could also benefit from these findings in the not-too-distant future.

The main challenge of using myoblasts for cell therapy remains, for now, harvesting and culturing them up to the numbers required.

References
[1] David King – Development and remodeling of skeletal tissue, School of Medicine, Southern Illinois University, 2009 http://www.siumed.edu/~dking2/ssb/skeleton.htm#development
[2] Christopher Vaughan – Researchers isolate stem cell that gives rise to bones, cartilage in mice, Stanford Institute for Stem Cell Biology and Regenerative Medicine, 2015 https://med.stanford.edu/news/all-news/2015/01/researchers-isolate-stem-cell-that-gives-rise-to-bones-cartilage.html
[3] http://www.stemcellclinic.net/tag/stanford
[4] http://genesdev.cshlp.org/content/20/13/1692.long

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PROTEINS PRODUCED BY STEM CELLS, USED IN BONE REGENERATION

The loss of bone mass and the weakening of the bones are natural consequences of aging, but this process starts around the age of 30, so it’s not only the elderly that are at risk for falls and fractures due to bone resorption.

Some of the factors that cause the decrease in bone mass density can be controlled, but others are out of one’s control. Smoking for example can be avoided, and one can practice strength exercises to keep their bones strong, but an inadequate intake of calcium, the use of asthma medications, as well as the changes in hormone levels that occur in older adults can speed up the weakening of bones.

Also, this process is accelerated by an inadequate intake of vitamin D, the lack of exposure to gravity and hypoparathyroidism, all these factors favoring the resorption of bone. When the tissue is broken down faster than it can be renewed, the density of bones starts to decrease and they become more porous, fragile and prone to fractures.

Although there are a series of conventional treatments that can help in improving bone density in osteoporotic patients, people who suffer multiple fractures, major bone trauma or individuals injured during natural disasters may require a different approach. In such cases, the use of stem cells could speed up bone repair and eliminate the risk of tumor formation.

STEM CELLS FROM BONES AND SKIN, USED FOR BONE RECONSTRUCTION

Scientists from the Gladstone Institutes have discovered a way to stimulate bone reconstruction using proteins produced by stem cells. Instead of grinding up bones from cadavers in order to extract the proteins and growth factors needed for stimulating the growth of new tissue, the researchers have extracted bone-forming proteins from stem cells.

After they treated the proteins in the lab, they injected the substances into muscle tissue of mice, in order to facilitate bone growth. The injected proteins were effective in creating new bone tissue, so there is hope that this method may be a good solution for humans as well. Unlike current treatments, the use of stem cells is safer as it doesn’t involve the transplant of cells or tissues from cadavers or other donors, so the risk for these cells to be rejected is much lower and the risk for tumor formation is very low also.

The study published in Scientific Reports concluded that proteins extracted from stem cells could be a consistent and reproducible source material for tissue regeneration [1]. This isn’t the first study to support the use of stem cells for orthopedic purposes. In 2001, another paper published by Dr. Ranieri Cancedda in the New England Journal of Medicine described the use of autologous bone marrow cells in the repairing of large bone defects.

The research showed that the osteoprogenitor cells derived from stem cells were effective in supporting the integration of macroporous hydroxyapatite scaffolds in damaged bones. Three patients were treated using this method and CT scans taken 6 months afterwards showed good callus formation and integration of the interfaces in all patients [2].

Even more interesting were the results obtained by a team of scientists from the National Institutes of Health, Bethesda, USA, who managed to grow new bone from stem cells harvested from skin cells. The paper was published in the Cell Reports journal, the harvested skin cells being reprogramed into equivalents of embryonic stem cells [3]. The obtained iPSCs were treated in lab conditions to differentiate into precursors of bone cells, then transplanted the obtained cells into monkeys, on a ceramic scaffold.

The implanted cells grew new bone on top of the scaffolds, researchers finding no sign of tumor. According to the researchers, this technique has two great advantages: the stem cells harvested from patient’s own cells are less likely to be attacked by one’s immune system, and iPSCs can be generated from any individual.

Although the use of stem cells for speeding up the integration of implants in damaged bones is not new, scientists are now looking to develop these methods further, so as to obtain stem cells that can promote bone regeneration and regrowth once transplanted to humans.

References:

[1] http://gladstoneinstitutes.org/pressrelease/2015-05-11/scientists-regenerate-bone-tissue-using-only-proteins-secreted-by-stem-cells
[2] http://www.healio.com/orthopedics/biologics/news/print/orthopedics-today/%7B45aecb5d-a1c0-4e13-8bf7-607f32a812bf%7D/bone-regeneration-is-possible-using-stem-cells
[3] www.cell.com/cell-reports/abstract/S2211-1247%2814%2900306-4

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A Good Night's Sleep Protects Stem Cells From Premature Aging

If you’re one of those people who is really fond of their beauty sleep, or who never compromises when it comes to getting their full eight hours per night, now you have one more reason to make a full night’s sleep a priority .

A study by scientists at the German Cancer Research Center have found that while environmental stress can damage the DNA in adult hematopoietic stem cells, a good night’s sleep can keep these cells young, contributing to a youthful appearance and preventing cancer.

Healthy sleep patterns lower the risk of DNA damage in stem cells 

According to German researchers, under normal conditions a high number of different types of adult stem cells exists in a state of dormancy inside the human body, but they cannot divide, therefore cannot be used for tissue regeneration. This state of dormancy protects the stem cells from DNA damage, keeping us younger and preventing premature aging [1].

Yet, increased levels of stress in all its forms—from chronic infections to environmental stress—can trigger a rapid division of stem cells, kicked into gear as the body needs to repair its damaged tissues. In such conditions, the dormant stem cells go from no activity to very high activity in a short interval, and this rapid change forces them to increase their metabolic rate and synthesize new DNA.

Doctor Michael Milsom, who coordinated the German study, says that having to simultaneously execute such complicated functions increases the risk of DNA damage in the stem cells, reducing the ability of tissues to repair themselves and speeding up aging [1, 3].

Moreover, scientists believes that the accumulation of stress-induced damage in the stem cells can make one more prone to cancer. Experiments conducted in this study showed that cell division that takes place under stress leads to an increased production of reactive metabolites. These substances can damage DNA, causing the death of stem cells or leading to mutations that can contribute to cancer.

Understanding how to prevent the aging of stem cells or DNA mutations and damage could be the key to delaying the aging process and reducing the risk of developing certain forms of cancer, concludes Dr. Trumpp, co-author of the study’s research paper.

Protect your stem cells for healthy skin and a youthful appearance  

The study is not the only one to prove a connection between sleep and the health of stem cells. Another paper, published in the journal of Cell Research by scientists from the University of California Irvine, showed that circadian rhythms regulate the metabolism of skin stem cells, and that getting enough sleep during the night can maintain healthy cell division, nurturing stem cell differentiation [2].

Although the study was conducted on mice, the findings are worth exploring further to determine whether a disruption in the healthy circadian rhythm can alter the normal function of stem cells, leading to accelerated aging.

Professors Andersen and Gratton, who conducted the Irvine study, focused on the effects stem cells have on the skin, already knowing that stem cells found in the dermal layers protect the skin and help in the repairing the epidermis after injuries.

Using innovative technologies, the two researchers measured the metabolic state of stem cells, discovering that the circadian clock does regulate one form of intermediary metabolism in target cells. According to researchers, it’s the same component of metabolism that creates oxygen radicals, harmful substances that can cause DNA damage.

The results of this study suggest that maintaining healthy sleep patterns can prevent DNA-damage in skin stem cells, while an altered internal clock could lead to the accumulation of damage in these cells, accelerating aging.

References:

[1] http://www.sciencedaily.com/releases/2015/02/150218122951.htm
[2] http://www.cell.com/cell-reports/abstract/S2211-1247%2814%2901018-3
[3] http://en.wikipedia.org/wiki/DNA_damage_theory_of_aging

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Using Bone Marrow Stem Cells to Treat Heart Disease

What seemed an impossible medical challenge a few years ago might turn into a do-able task with the help of bone marrow stem cells. Several trials are testing the use of adult stem cells in heart disease, hoping to identify a viable solution for repairing the cardiac tissue damaged by heart attacks, coronary artery disease and other similar ailments.

<h1>Obtaining cardiac muscle cells in the lab</h1>

Despite the huge amount of information available out there and the numerous health programs that aim to prevent heart diseases, these conditions remain the most common cause of death in Europe, with heart attacks dominating the list. According to statistics, around 7 million people worldwide suffer from heart attacks each year, the damage being in lots of cases irreversible.

Given the amazing results obtained with stem cell therapies in conditions like leukemia or lymphoma, it was natural for scientists to intensify their research efforts in this niche, in order to see whether the potent stem cells can also be used for repairing damaged hearts. While some studies have showed promising results, others have found no improvement after transplanting stem cells to patients with heart conditions.

The biggest challenge in these cases seems to be the reprograming of stem cells obtained from other tissues into cardiomyocytes. Cardiomyocites are the cells that form the cardiac muscle, and although for a very long time scientists believed that the heart does not produce any stem cells, it’s been shown that the body does produce new cardiomyocytes each year, but the number decreases with age.

The discovery that the human heart produces new cells each year has created hope and encouraged researchers to try to find out where the new cardiac cells come from and how this process is controlled inside the body. The ultimate goal was to identify those mechanisms that could be replicated in lab conditions, so as to obtain new heart cells viable for transplantation in patients with heart diseases.

Although the existence of heart stem cells has not been confirmed yet, it is possible to obtain cardiomyocytes in the lab, from stem cells obtained either from embryos or from iPS cells (induced pluripotent stem cells). The latter can be obtained by reprogramming skin cells that are taken directly from the patient, reducing the risk of transplant rejection.

One of the biggest problems here comes from the fact that bone marrow cells and other adult stem cells can be reprogramed to repair a specific tissue, but if they are treated in lab conditions until they differentiate to specific cells like those in the cardiac tissue, the risk of tumors and rejection increases.

On the other hand, if the pluripotent stem cells from embryos or the iPS cells are transplanted into the heart, they might differentiate and give birth to a multitude of cells. It is impossible for one to control the type of cells formed by stem cells in the body once transplanted, if those cells were transplanted before specializing.

Stem cell studies on the damaged heart show mixed results

Existing studies show that treating heart conditions with stem cells is more difficult than using stem cells therapies for other tissues and organs. A trial done in Belgium, Switzerland and Serbia on 45 patients aimed to treat heart attack victims with stem cells. The injected cells led to no complications and were guided to become cardiac cells, scientists highlighting the safety and feasibility of the procedure [1].

Other studies showed little to no effect after the transplantation of stem cells. Cardiologist Darrel Francis at Imperial College London published a review study in BMJ, examining 133 reports of 49 randomized clinical trials that aimed to treat heart attack or heart failure patients with stem cells. According to his paper, more than 600 discrepancies were found in these trials, so the results cannot be considered relevant [2].

Francis’ study showed that the 5 trials that had no discrepancies reported no improvement in the left ventricular ejection fraction (LVEF) after stem cell treatment, while the 5 trials with the most numerous discrepancies reported a significant improvement (+7.7%) of LVEF after stem cell therapy.

While scientists are still trying to answer whether stem cells are a solution for damaged heart tissue, some stories report that patients who received this treatment after a heart attack saw a clear and dramatic improvement in their health state and heart function. One of these patients is Jim Dearing of Louisville, who was among the first patients to receive heart stem cells after suffering two heart attacks and heart failure. His heart was functioning normally one year post treatment [3].

What’s certain for now is that results of these studies are mixed, and researchers will need to further investigate the use of stem cells from bone marrow in patients with heart diseases.

References:

[1] https://beyondthedish.wordpress.com/2014/12/03/mayo-clinic-uses-reprogrammed-stem-cells-to-heal-the-heart/
[2] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002982/
[3] http://www.webmd.com/heart/features/stem-cells-heart-failure-heart-disease

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The different types of stem cells and their current uses

Stem cells offer great potential for use in clinical applications thanks to their ability to specialize into different cell types and to renew themselves. Although some of them have limitations, stem cells are still an amazing resource for the medical world, as no other cell inside the human body has the ability to generate new cell types with a more specific function that the source.

Stem cells can be considered the body’s raw building blocks, as all the other cells with specialized functions result from stem cells that divide and give birth to daughter cells. These cells, at their turn, divide or differentiate and become specialized, giving birth to muscle, bone, blood, brain or other specific cell types.

The characteristics and applications of stem cells vary not only depending on the type of cells they differentiate into, but also on the nature of the tissue they are derived from. From this point of view, stem cells can be classified into three main groups: embryonic, adult and induced pluripotent stem cells.

Types of stem cells depending on origin

Embryonic stem cells (ESCs) come from embryos of up to 5 days old, and are pluripotent, meaning that they can divide into several stem cells and specialize into any type of cell. This property allows embryonic stem cells to repair damaged tissues and organs and to stimulate the regeneration of diseased tissues. Researchers can grow and induce the differentiation of ESCs in the lab, but the use of embryonic stem cells is often avoided due to ethical considerations.

Adult stem cells, the second type, are found in adult tissues inside the human body and they can also differentiate into various cell types, but their ability to give birth to new cells is limited. Although until recently it’s been thought that an adult stem cells can only differentiate into the same type of cell as the tissue it comes from, emerging studies suggest that these cells, just like ESCs, can create unrelated cell types.

In other words, just like an embryonic stem cell derived from bone marrow can give birth to liver or muscle cells, adult stem cells taken from bone marrow can create bone or skin cells. There’s a limit though, as adult stem cells can’t be manipulated as efficiently as ESCs, and they’re not as versatile and the ones derived from embryos.

The third type of stem cells is somewhere in between the adult and embryonic stem cells, and it’s called induced pluripotent stem cells (iPSCs). These are highly versatile, similarly to ESCs, but are made from adult specialized cells through laboratory techniques (genetic reprogramming). iPSCs have two main advantages: first one’s that they do not create any ethical debate, as they don’t come from embryos, and the second one is that the risk of rejection is lower than in adult stem cells, thanks to the fact that iPSCs are reprogrammed to act as ESCs.

Current applications of stem cells by type

We won’t discuss the ESCs here as the tendency is to not use embryonic stem cells, and opt for adult or induced pluripotent stem cells instead.

Perhaps the most used of all adult stem cells are those obtained from the bone marrow (mesenchymal stem cells), which can be differentiated into bone, cartilage and fat cells, and can encourage the production of new blood cells. These were not proven to be able to differentiate in any type of cell inside the human body, but existing research suggests mesenchymal stem cells may be useful in bone and cartilage repair or blood vessel repair after a heart attack [5].

In lab studies, bone marrow stem cells from adult rats were able to partially regrow the damaged liver, and to have beneficial effects when injected into the damaged heart. Also, scientists at the Children’s Hospital Boston have found adult bone marrow stem cells to protect against chronic lung disease [2] in mice models.

Induced pluripotent stem cells have also been tested for their ability to differentiate, and lab results showed that iPSCs made from skin samples may be useful in treating neurological disorders like Parkinson’s disease or Down’s syndrome [8].

Researchers in Japan managed to generate human liver buds from induced pluripotent stem cells, the scientists using three different types of stem cells for this purpose: part of them were hepatocytes coaxed from iPSCs, others were endothelial stem cells and others were mesenchymal stem cells. The liver buds were grown in vitro for a few days then transplanted to mice, where they quickly connected with the blood vessels and continued to grow.

Other studies have shown that iPSCs grown from embryonic cord-blood cells can be used for repairing the damaged retina of mice and regrowing the vascular vessels. Scientists from the Japan Ministry Health are currently conducting a clinical trial using autologous iPSCs in six patients affected by age-related macular degeneration. IPSCs used for this trial are derived from skin cells, and reprogrammed to differentiate into retinal pigment epithelial cells.

Adult stem cells have been used in treating leukemia and blood or bone related cancers utilizing bone marrow transplants [1]; mesenchymal stem cells have been shown to help in repairing the damaged cartilage in patients with articular cartilage defects [3] and to improve the outcome in spinal cord injuries [4]. Peripheral vascular disease [6] and liver cirrhosis [7] may also be treatable with adult stem cells.

Although adult stem cells and iPSCs can be differentiated in a wider variety of cells, not all of them have been tested in human subjects, one of the biggest barriers being the potential immunological rejection.

References

[1] http://en.wikipedia.org/wiki/Adult_stem_cell
[2] http://www.childrenshospital.org/news-and-events/2009/december-2009/bone-marrow-stem-cells-may-prevent-chronic-lung-disease
[3] http://www.ncbi.nlm.nih.gov/pubmed/18038395
[4] http://www.pubstemcell.com/monthly/006030700113.htm
[5] http://stemcells.nih.gov/info/scireport/pages/chapter9.aspx
[6] http://www.ncbi.nlm.nih.gov/pubmed/21671823
[7] http://www.ncbi.nlm.nih.gov/pubmed/16778155
[8] http://www.eurostemcell.org/factsheet/stem-cell-research-therapy-types-stem-cells-and-their-current-uses#iPS