Severe hypophosphatasia generally fatal during infancy, bone marrow transplant along with mensenchymal stem cell transplants offers hope

Putnam Valley, NY. (Feb 9, 2015) - Recent research carried out by a team of researchers in Japan has investigated the use of bone marrow transplants (BMTs) to treat hypophosphatasia (HPP). In this study, the researchers carried out BMT for two infants with HPP in combination with allogenic (other-donated) mesenchymal stem cell transplants (MSCTs). The allogenic MSC donors were a parent of the infant.

The study will be published in a future issue of Cell Transplantation and is currently freely available on-line as an unedited early e-pub at: http://ingentaconnect.com/content/cog/ct/pre-prints/content-CT-1337_Taketani_et_al

"Hypophosphatasia" (HPP) is a rare and most often fatal genetic bone disease affecting infants that has no current treatment. The disease is caused by mutations in the ALPL gene, which encodes alkaline phosphatase (ALP). Patients with severe HPP develop bone impairment and have extremely low levels of ALP activity, an enzyme necessary for bone mineralization.

Although there are mild and more severe forms, severe hypophosphatasia prevents proper bone mineralization during perinatal development. When the disease develops perinatally, many infants are still-born, with little evidence of bone mineralization. HPP can also appear in later infancy, generally before an infant reaches the age of six months, with the result that most afflicted infants do not live past the age of six months. Milder forms of HPP can present in later youth or in adulthood.

"Mesenchymal stem cells (MSCs) reside in bone marrow and other tissues and have a self-renewal capacity so that after transplantation they can differentiate into various cell lineages, including bone and cartilage," said Dr. Takeshi Taketani of the Division of Blood Transfusion at Shimane University Hospital in Shimane, Japan. "We performed multiple infusions of MSCs for two infant patients with severe HPP who had already undergone BMT. The adverse events from the BMT were managed and there were no adverse events from the MSC infusions."

After each infant had undergone BMT, one infant received four MSCTs and a second infant received nine MSCTs. Previous research had revealed that MSCT without a prior BMT was ineffective.

The researchers reported that the two infants receiving both BMT and MSCTs improved not only in terms of bone mineralization, but also saw improvements in muscle mass, respiratory function and mental development. Both children continue to survive at age three.

"Our data suggest that allogenic MSCT combined with BMT might be one of the safer and more effective remedies for patients with severe HPP, although long-term effectiveness remains unknown and warrants further study," concluded the researchers. "We need to establish curative, MSC-based treatment strategies that can maintain the long-term survival and differentiation capabilities of transplanted allo-MSCs."

"This study highlights the promise of stem cells in presenting a new frontier for regenerative medicine, with an improvement of HPP-associated symptoms and survival following BMT and MSCT." said Dr. David Eve, Cell Transplantation associate editor, and Instructor of neurosurgery and brain repair at the University of South Florida School of Medicine. "In order to elucidate the mechanisms behind recovery and further extrapolate the study to all HPP patients, a larger cohort and more long term follow-up are needed."

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Infants with rare bone disease improve bone formation after cell transplantation

Since ancient times, humankind has been aware of how important blood is to life. Naturalists speculated for thousands of years on the source of the body's blood supply. For several centuries, the liver was believed to be the site where blood forms. In 1868, however, the German pathologist Ernst Neumann discovered immature precursor cells in bone marrow, which turned out to be the actual site of blood cell formation, also known as hematopoiesis. Blood formation was the first process for which scientists formulated and proved the theory that stem cells are the common origin that gives rise to various types of mature cells.

"However, a problem with almost all research on hematopoiesis in past decades is that it has been restricted to experiments in culture or using transplantation into mice," says Professor Hans-Reimer Rodewald from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). "We have now developed the first model where we can observe the development of a stem cell into a mature blood cell in a living organism."

Dr. Katrin Busch from Rodewald's team developed genetically modified mice by introducing a protein into their blood stem cells that sends out a yellow fluorescent signal. This fluorescent marker can be turned on at any time by administering a specific reagent to the animal. Correspondingly, all daughter cells that arise from a cell containing the marker also send out a light signal.

When Busch turned on the marker in adult animals, it became visible that at least one third (approximately 5000 cells) of a mouse's hematopoietic stem cells produce differentiated progenitor cells. "This was the first surprise," says Busch. "Until now, scientists had believed that in the normal state, very few stem cells - only about ten - are actively involved in blood formation."

However, it takes a very long time for the fluorescent marker to spread evenly into peripheral blood cells, an amount of time that even exceeds the lifespan of a mouse. Systems biologist Prof. Thomas Hfer and colleagues (also of the DKFZ) performed mathematical analysis of these experimental data to provide additional insight into blood stem cell dynamics. Their analysis showed that, surprisingly, under normal conditions, the replenishment of blood cells is not accomplished by the stem cells themselves. Instead, they are actually supplied by first progenitor cells that develop during the following differentiation step. These cells are able to regenerate themselves for a long time - though not quite as long as stem cells do. To make sure that the population of this cell type never runs out, blood stem cells must occasionally produce a couple of new first progenitors.

During embryonic development of mice, however, the situation is different: To build up the system, all mature blood and immune cells develop much more rapidly and almost completely from stem cells.

The investigators were also able to accelerate this process in adult animals by artificially depleting their white blood cells. Under these conditions, blood stem cells increase the formation of first progenitor cells, which then immediately start supplying new, mature blood cells. In this process, several hundred times more cells of the so-called myeloid lineage (thrombocytes, erythrocytes, granulocytes, monocytes) form than long-lived lymphocytes (T cells, B cells, natural killer cells) do.

"When we transplanted our labeled blood stem cells from the bone marrow into other mice, only a few stem cells were active in the recipients, and many stem cells were lost," Rodewald explains. "Our new data therefore show that the findings obtained up until now using transplanted stem cells can surely not be reflective of normal hematopoiesis. On the contrary, transplantation is an exception [to the rule]. This shows how important it is that we actually follow hematopoiesis under normal conditions in a living organism."

The scientists in Rodewald's department, working together with Thomas Hfer, now also plan to use the new model to investigate the impact of pathogenic challenges to blood formation: for example, in cancer, cachexia or infection. This method would also enable them to follow potential aging processes that occur in blood stem cells in detail as they occur naturally in a living organism.

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Live assessment of blood formation

Black South Africans make up about 47 percent of all cancer patients but only 5 percent of donors in the nations bone marrow registry. The gap between those who may need bone marrow or stem cell transplants, and those able to provide them has deadly consequences for cancer patients.

Black South Africans make up about 47 percent of all cancer patients but only 5 percent of donors in the nations bone marrow registry

Maphoko Nthane, 50, had experienced mysterious and severe backaches for months. Doctors ran test after test, but could find nothing wrong with Nthane.

I had a severe back ache for months, she told Health-e News. Whenever I would have that pain, I couldnt sit down I had to walk or stand up.

Doctors eventually diagnosed Nthane with Acute Lymphoblastic Leukaemia, a severe form of cancer affecting a patients blood and bone marrow.

After I was diagnosed I thought I was going to die I didnt know that people with leukaemia could live, Nthane said. My husband was just as traumatised and as a result he didnt know how to support me.

Nthanes cancer failed to respond to standard chemotherapy and ultimately a stem cell transplant saved her life.

As part of stem cell transplants, stem cells are removed from the tissue of donors or, where possible, patients. These cells are usually from human tissues including bone marrow or fat.

Once removed, the stem cells are given high doses of chemotherapy higher than what could be administered to patients before being transplanted into patients in the hope that they will kill other cancerous cells.

Nthane was lucky to find a stem cell donor.

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Deadly shortage of black stem cell donors

WATERTOWN, Conn. (AP) A year ago, Nancy Demers, 71, was diagnosed with myelodysplastic syndrome, a deficiency in the bone marrow. The disease can eventually become leukemia.

Its treated as if it were cancer but there is no cure for it, said her son, Scott Demers.

Now Nancy Demers has a new chance at life, thanks to advances in bone marrow stem cell transplants.

If I didnt do this, once I went out of remission its not if, its when I would go into acute leukemia and there will be nothing there to help me, Nancy Demers said. This will save my life and give me time.

Demers is one of a rapidly growing number of people looking to depend on strangers to donate marrow since she doesnt have a match within her family.

The rising number of patients seeking bone marrow has created new demands on registries that seek to match patient needs with willing donors.

Each sibling has a 25 percent chance of being a transplant match, according to Dr. Joseph Antin, chief and program director of the adult stem cell transplantation program at Dana Farber Brigham and Womens Hospital in Boston.

In the United States, about 30 percent of patients find a donor within their family, according to Be the Match. Those who dont must turn to international registries to find an unrelated donor.

Around 15 years ago, doctors couldnt do a transplant on anyone over the age of 50, according to Dr. Leslie Lehmann, clinical director of the Stem Cell Transplant Center at Dana Farber.

Its a big stress on the body, Lehmann said.

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Registries seek to match donors with rising marrow demand

DEAR DOCTOR K: I have leukemia. Thankfully, a family member was a bone marrow match. Can you tell me what to expect during my bone marrow transplant procedure?

DEAR READER: A bone marrow transplant can be a life-saving treatment. To understand how it works, you need to understand how blood cells are created. And what leukemia is.

Your blood contains red and white blood cells. There are several types of white blood cells, which are a key part of your immune system. All your blood cells are made by blood stem cells, which live primarily in the spongy center of your big bones.

In the years before you got leukemia, each of your blood cells was programmed to live for a while, and then to die only to be replaced by new, young cells.

When you developed leukemia, genetic changes in some white blood cells suddenly kept them from dying. As a result, the number of that type of white blood cell kept growing. An ideal treatment would kill just the cancerous white blood cells, and allow noncancerous new cells to replace them. The ideal treatment has not been discovered. Bone marrow transplant, while less than ideal, is such an important advance that it was honored with the Nobel Prize.

In a bone marrow transplant, all of your white blood cells healthy and cancerous are killed by drugs, radiation or both. Then healthy blood stem cells are infused into your blood. Those cells find their way to your bone marrow, and start to make healthy new red and white blood cells. The new cells will multiply. Ive put an illustration of the transplant process on my website, AskDoctorK.com.

The healthy blood stem cells may be collected from your blood, before the main radiation or chemotherapy begins. The cells are treated to remove any cancer cells, and then stored until the transplant. In your case, the healthy blood stem cells will come from another person (a donor). The donors cells must be a good match for you this means certain markers on their cells and your cells are as similar as possible. This reduces the risk that the cells will be rejected by your body.

Bone marrow transplants are usually used to treat leukemia, lymphomas, Hodgkins disease and multiple myeloma, because these cancers affect the bone marrow directly. The procedure is also used for some noncancerous conditions, such as sickle cell anemia.

You will stay in the hospital for several weeks after the transplant. Until your bone marrow cells multiply to a certain level, you will be at increased risk of infection. Other serious risks include severe bleeding, liver problems and increased risk of developing another cancer.

Another possible problem is that cells from a donor might not match your cells well enough and the new donor cells will begin attacking the cells of your body. This is called graft-versus-host disease. You will take medications to reduce the risk of this happening. Despite the dangers, bone marrow transplantation is usually successful.

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The ins and outs of bone marrow transplantation

Stem Cell-Enhanced Anterior Collateral Ligament (ACL) Reconstruction
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CHICAGO (CBS) More than four years after she was close to dying from leukemia, an 8-year-old girl from Mount Prospect is healthy again, and will meet the German man who helped save her life by supplying a stem cell donation.

Sabrina Chahir was diagnosed with leukemia in 2009, and 80 percent of her blood was filled with cancer cells. To survive, she needed a stem cell/bone marrow transplant, but finding a donor was going to be very difficult.

At the beginning, it was we didnt know if we were able to find one, because Sabrina is half Arabic and half Hispanic, and that is not a usual combination, Sabrinas mother, Natalia Wehr said.

Sabrinas DNA match turned out to be 30-year-old Maximilian Eule, a German supermarket manager living in Austria. He quickly agreed to donate

For me, I was close to crying, because it was like a little girl who was almost close to dying, and has no chance without my blood, he said. You give the girl another chance to stay alive.

Sabrinas mother said, thanks to Eules bone marrow donation, her daughter is healthy again, and like any other 2nd grade girl.

This whole thing is like a dream, she said.

Eule said its awesome Sabrina is now happy, healthy, and taking ballet classes and piano lessons. The two will meet for the first time Thursday night.

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Girl With Leukemia To Meet Stem Cell Donor Who Helped Save Her Life

Since the first experimental bone marrow transplant over 50 years ago, more than one million hematopoietic stem cell transplantations (HSCT) have been performed in 75 countries, according to new research charting the remarkable growth in the worldwide use of HSCT, published in The Lancet Haematology journal.

However, the findings reveal striking variations between countries and regions in the use of this lifesaving procedure and high unmet need due to a chronic shortage of resources and donors that is putting lives at risk.

HSCT (also known as blood and marrow transplant) is most often used to treat diseases of the blood and several types of cancer such as multiple myeloma or leukaemia. For many people with these diseases the only possibility of a cure is to have a HSCT. The procedure provides healthy cells from either the patient (autologous transplantation) or from a healthy donor (allogeneic transplantation) to replace those lost to disease or chemotherapy.

Using data collected by the Worldwide Network for Blood and Marrow Transplantation (WBMT), Professor Dietger Niederwieser from the University Hospital Leipzig in Germany and international colleagues, systematically analysed the growth of HSCT and changes in its use in 194 WHO member countries since the first transplant in 1957. They also examined the link between macroeconomic factors (eg, gross national income and health care expenditure) and transplant frequencies per 10 million inhabitants in each country.

Although only a small number of centres had performed about 10000 transplants by 1985, this had risen to around 500000 ten years later, and doubled to more than 1 million transplants (42% allogeneic and 58% autologous) done at 1516 transplant centres across 75 countries by the end of December 2012 (see table 1 page 2).

Perhaps unsurprisingly, the study found that transplants are more common in countries with greater financial resources and more institutions with the resources and expertise to perform HSCT. Most of the HSCTs have been performed in Europe (53%), followed by the Americas (31%), South East Asia and Western Pacific (15%), and the Eastern Mediterranean and Africa (2%). The findings also reveal significant differences between HSCT use by donor type (autologous or allogeneic), indications for HSCT, and world region (See tables 2, 3, and 4 pages 4-6). For example, donor transplants in 2010 ranged in active countries from 0.4 per 10 million inhabitants in the Philippines and Vietnam to 506 in Israel (see figure 2B page 7).

Numbers of donor transplants have rapidly expanded in all regions without any signs of saturation (see table 1 page 2). This is likely to reflect substantial underuse of this therapy, say the authors, suggesting that more patients would have been treated with allogeneic transplantation had it been accessible, or had suitable donors been available.

In about 30% of cases, a genetically matched donor can be found from within a patient's family. The other 70% have to search for a matched volunteer from national and international registries. The report shows that numbers of countries with registries increased from 2 in 1987 to 57 in 2012, whilst volunteer donors rose from 3072 in 1987 to over 22 million in 2012. The international exchange of stem-cell products also increased to more than 10000 a year between 2006 and 2012, with substantial differences between countries in the amount of stem cells they import or export (see figure 2C page 7).

Despite these increases there are still too many patients who are unable to find a suitable donor. At any time around 1800 people in the UK are waiting for a blood stem cell donation, and over 37000 people are waiting worldwide. Moreover, less than half of the people in the UK diagnosed with a blood cancer ever find a suitable donor [1].

According to Professor Niederwieser, "Patients, many of them children, are facing a life and death situation. Ultimately they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources."[2]

Link:
The Lancet Haematology: Experts warn of stem cell underuse

MIAMI (PRWEB) February 24, 2015

In answer to industry-wide requests for more accessible solutions to stem cell procedures, Global Stem Cells Group, Inc. and Regenestem have announced the launch of two new stem cell harvesting and isolation kits.

The Regenestem BMAC 60 mL concentrating system is a high performing concentrating system for bone marrow aspirate. This kit come complete with a bone marrow filter, a bone marrow aspirating needle and a locking syringe to help maintain suction during the aspirating process. The BMAC 60 kit includes bone marrow concentrate up to 11 times the baseline values, to produce 6-8 mL BMC from a 60 mL sample of bone marrow aspirate.

The Regenestem 60 mL Adipose Derived Stem Cell (ADSC) Kit System includes all the tools and consumables for the extraction of adipose-derived stem cells from 60 mL of lipoaspirated fat. The ADSC kit is currently being used in clinical procedures for lung disease, intra-articular injections for osteoarthritis of the knee and hip, cosmetic surgery and acne scarring, dermal injections, stem cell enriched fat transfer, wounds, chronic ulcers and other chronic conditions. The enzymatic component used to obtain the stromal vascular fraction (SVF) is provided by Adistem.

The Regenestem ADSC Kit System is available in three versions:

Gold, to conduct in-office stem cell procedures with certified GMP components for reliable performance.

Platinum, with all the benefits of the basic (gold) kit plus a sterilized PRP close system with vortex engineering method to minimize platelet loss. One set of individually packed Tulip Gems instruments are added for safe and precise adipose tissue extraction.

Titanium, the perfect state-of-the-art deluxe kit system used by a growing number of regenerative medicine physicians and recognized as the perfect preparation for virtually all clinical applications. Built with Emcyte technology, the Regenestem Titanium kit has been independently reviewed and proven in various critical performance points that make a difference in patient outcomes.

The Titanium kit is currently being used in topical procedures such as intra-articular injection for osteoarthritis of the knee and hip, cosmetic surgery and acne scarring, dermal injection, stem cell enriched fat transfer, wounds chronic ulcers among other chronic conditions.

According to Global Stem Cells Group CEO Benito Novas, the entire Global Stem Cells Group faculty and scientific advisory board worked together to develop the kits.

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Global Stem Cells Group, Inc. Announces Launch of New Stem Cell Harvesting Products

A devoted mum whose sick twins desperately need a double bone marrow transplant has begged the nation: Please save my boys.

Luis and Kian King, seven, have Juvenile Krabbe Disease, which quickly ravages the nervous system and the youngsters are getting worse by the week.

Parents Laura, 36, and Dean, 38, know the odds are stacked against the boys, as doctors battle to find donors for the UKs first twin transplant, before they become too weak to survive treatment.

The average life expectancy of a child with the rare disease is just 12.

Laura pleaded: If you are not on the donor register you could be the match who can give my boys back their lives and their futures and you dont even realise it.

All of us are giant medicine bottles walking around with the ability to help others in their hour of need. It only takes 10 minutes to join the register and you can change a familys life forever.

Juvenile Krabbe Disease which affects fewer than one in a million children has left the boys, who also have cerebral palsy, unable to walk unaided.

Experts have warned that without a stem cell transplant they only have three years left with any real quality of life.

The disease will rob them of their sight and ability to feed themselves, causing them to suffer more and more pain until they can no longer breathe unaided.

With the boys just five years off the average life expectancy of 12, Laura admits their illness haunts her.

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Luis and Kian King: Juvenile Krabbe Disease victims' mum in plea to help save her twin boys

Fayetteville, Arkansas (PRWEB) February 19, 2015

CardioWise, Inc. has completed development of the first fully integrated version of its Multiparametric Strain Analysis Software (MPSA) and has installed it at the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). MPSA software is being used in clinical research protocol number 12-H-0078, sponsored by the NHLBI entitled, Preliminary Assessment of Direct Intra-Myocardial Injection of Autologous Bone Marrow-derived Stromal Cells on Patients Undergoing Revascularization for Coronary Artery Disease (CAD) with Depressed Left Ventricular Function. The Principle Investigator is Dr. Keith A. Horvath, the Director of Cardiothoracic Surgery at the NHLBI and Chief of Cardiothoracic Surgery at Suburban Hospital, where he leads the NIH Heart Center. Details of the study are available here: http://clinicalstudies.info.nih.gov/cgi/wais/bold032001.pl?A_12-H-0078.html@mesenchymal@@@@.

The recently completed integrated version of CardioWise analysis software has been installed at the NIH; and, Dr. Justin Miller, and Dr. Ming Li, both research fellows in the Cardiothoracic Surgery Research Program of the NHLBI, have been trained on its operation and use. They were assigned to the project by Dr. Horvath and Dr. Andrew Arai, Chief of the Advanced Cardiovascular Imaging Research Group in the NHLBIs Division of Intramural Research. CardioWise has completed validation testing of its software and the analyses of the first two patient cardiac MRI (CMR) data sets are in process. The patients who enrolled in the protocol received one baseline CMR scan and three additional follow-up CMR scans. Those CMR scans are being analyzed by CardioWise analysis software and the analyses will be compared to determine whether stem cell injections can improve the contractile function of the heart muscle by repairing damaged tissue.

The installation at the NIH under a Beta site agreement signed in 2014 marks the first clinical test of CardioWise MPSA software outside of Washington University School of Medicine in St. Louis, where it was developed. CardioWise has obtained the exclusive worldwide license for the patent-pending software and accompanying normal hearts database from Washington University in St. Louis. The companys MPSA software is uniquely capable of analyzing the three-dimensional motion of the heart that is acquired from cardiac MRI images and then comparing the analysis at 15,300 points to the motion of a normal heart model. The analysis detects portions of the heart that are moving abnormally and demonstrates to what degree the heart muscle has been affected. Since MRI uses no ionizing radiation or contrast, it is completely non-invasive and poses minimal risk to the patient. This allows the patient to be followed through the course of treatment and to measure outcomes of interventions such as the stem cell therapy currently being evaluated. In the near future, CardioWise MPSA may aid doctors to determine what intervention, such as surgery, stent insertion, or drug is most appropriate for the patient who presents with cardiovascular disease symptoms.

CardioWise is commercializing patent-pending, non-invasive Cardiac Magnetic Resonance Imaging (CMR) analysis software that produces a quantified 4D image model of the human heart, called Multiparametric Strain Analysis (MPSA). CardioWise heart analysis software combined with cardiac MRI is a single diagnostic test that is able to provide quantitative analysis of the myocardium, arteries and valves with an unprecedented level of detail. It has the opportunity to become the new gold standard of care for heart health analysis. CardioWise is a VIC Technology Venture Development portfolio company.

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CardioWise Completes Installation of the First Totally Integrated CardioWise Analysis Software at National Institutes ...

(L-R) Taylor Shorten, Sam Kimura and Alex Kimura (photo courtesy of SAM)

With the support of Delete Blood Cancer DKMS, the two sisters and their best friend Taylor Shorten began their road trip in January to visit all 50 states at churches, colleges, concerts and everything in between to promote increased awareness of blood cancer and blood diseases, in addition to finding donors for Sam and thousands of others.

Despite a busy, sometimes exhausting tour driving across America in a van named Maggie, Sam was able to spend a few moments to talk more about their cause and how people can potentially save someones life.

Alex and I came up with the concept of Sharing Americas Marrow about a year ago. We had been doing bone marrow donor drives ever since my diagnosis of severe aplastic anemia in 2010, but we wanted to do something really big. We enjoyed registering donors and knowing that each person has the potential to be a life-saving match, we decided to create a campaign around that idea. SAM evolved into a 50-state tour around the country with our best friend, Taylor Shorten, to register 50,000 potential donors.

We are working with Delete Blood Cancer DKMS to register potential donors. Delete Blood Cancer provides us with registration supplies in addition to testing each donor kit in the lab for potential donors to be listed on the registry.

Related: Five Healthy Foods For Your Brain

A Donor Jam is what we call a bone marrow donor drive. Its an event where people fill out a registration form and complete a cheek swab to get listed as a potential donor on the national registry. Bone marrow donor drive can sound intense, so we wanted to lighten it up a little and make it sound more fun, because saving lives is just thatfun!

Other groups can absolutely host a Donor Jam with us. With the help of Delete Blood Cancer, we can supply people with registration materials, training on how to register donors, flyers/promotional items to get the word out, etc. so that people can host their very own SAM Donor Jam.

In most cases, the success of allogeneic transplantation depends in part on how well the HLA antigens of the donors stem cells match those of the recipients stem cells. The higher the number of matching HLA antigens, the greater the chance that the patients body will accept the donors stem cells. In general, patients are less likely to develop a complication known as graft-versus-host disease (GVHD) if the stem cells of the donor and patient are closely matched. Thus, finding a perfect match (also known as a 10/10 match) for a patient drastically minimizes the risk that the patient will reject the transplant or develop post-transplant complications.

We just felt that the van had the essence of a Maggie. We didnt necessarily choose the name, the name chose us.

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The Story Of Sharing Americas Marrow

Under normal conditions, many of the different types of tissue-specific adult stem cells, including hematopoietic stem cells, exist in a state or dormancy where they rarely divide and have very low energy demands. "Our theory was that this state of dormancy protected hematopoietic stem cells from DNA damage and therefore protects them from premature aging," says Dr. Michael Milsom, leader of the study.

However, under conditions of stress, such as during chronic blood loss or infection, hematopoietic stem cells are driven into a state of rapid cell division in order to produce new blood cells and repair the damaged tissue. "It's like forcing you out of your bed in the middle of the night and then putting you into a sports car and asking you to drive as fast as you can around a race circuit while you are still half asleep," explains Milsom. "The stem cells go from a state of rest to very high activity within a short space of time, requiring them to rapidly increase their metabolic rate, synthesize new DNA and coordinate cell division. Suddenly having to simultaneously execute these complicated functions dramatically increases the likelihood that something will go wrong."

Indeed, experiments described in the study show that the increased energy demands of the stem cells during stress result in elevated production of reactive metabolites that can directly damage DNA. If this happens at the same time that the cell is trying to replicate its DNA, then this can cause either the death of the stem cell, or potentially the acquisition of mutations that may cause cancer.

Normal stem cells can repair the majority of this stress-induced DNA damage, but the more times you are exposed to stress, the more likely it is that a given stem cell will inefficiently repair the damage and then die or become mutated and act as a seed in the development of leukemia. "We believe that this model perfectly explains the gradual accumulation of DNA damage in stem cells with age and the associated reduction in the ability of a tissue to maintain and repair itself as you get older," Milsom adds.

In addition, the study goes on to examine how this stress response impacts on a mouse model of a rare inherited premature aging disorder that is caused by a defect in DNA repair. Patients with Fanconi anemia suffer a collapse of their blood system and have an extremely high risk of developing cancer. Mouse models of Fanconi anemia have exactly the same DNA repair defect as found in human patients but the mice never spontaneously develop the bone marrow failure observed in nearly all patients.

"We felt that stress induced DNA damage was the missing ingredient that was required to cause hematopoietic stem cell depletion in these mice," says Milsom. When Fanconi anemia mice were exposed to stimulation mimicking a prolonged viral infection, they were unable to efficiently repair the resulting DNA damage and their stem cells failed. In the same space of time that normal mice showed a gradual decline in hematopoietic stem cell numbers, the stem cells in Fanconi anemia mice were almost completely depleted, resulting in bone marrow failure and an inadequate production of blood cells to sustain life.

"This perfectly recapitulates what happens to Fanconi anemia patients and now gives us an opportunity to understand how this disease works and how we might better treat it," commented Milsom.

Prof. Dr. Andreas Trumpp, director of HI-STEM and head of the Division of Stem Cells and Cancer at the DKFZ believes that this work is a big step towards understanding a range of age-related diseases. "The novel link between physiologic stress, mutations in stem cells and aging is very exciting," says Trumpp, a co-author of the study. "By understanding the mechanism via which stem cells age, we can start to think about strategies to prevent or at least reduce the risk of damaged stem cells which are the cause of aging and the seed of cancer."

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The above story is based on materials provided by German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). Note: Materials may be edited for content and length.

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A good night's sleep keeps your stem cells young

Scientists have found that reducing the size of tiny hair like structures on stem cells stops them turning into fat. The discovery could be used to develop a way of preventing obesity.

The research, conducted at Queen Mary University of London (QMUL), found that a slight regulation in the length of primary cilia, small hair-like projections found on most cells, prevented the production of fat cells from human stem cells taken from adult bone marrow.

Part of the process by which calories are turned into fat involves adipogenesis, the differentiation of stem cells into fat cells. The researchers showed that during this process of adipogenesis, the length of primary cilia increases associated with movement of specific proteins onto the cilia. Furthermore, by genetically restricting this cilia elongation in stem cells the researchers were able to stop the formation of new fat cells.

Recent research has found that many conditions including kidney disease, blindness, problems with bones and obesity can be caused by defects in primary cilia.

Melis Dalbay, co-author of the research from the School of Engineering and Materials Science at QMUL, said: This is the first time that it has been shown that subtle changes in primary cilia structure can influence the differentiation of stem cell into fat. Since primary cilia length can be influenced by various factors including pharmaceuticals, inflammation and even mechanical forces, this study provides new insight into the regulation of fat cell formation and obesity.

Professor Martin Knight, a bioengineer and lead author of the research, said: This research points towards a new type of treatment known as cilia-therapy where manipulation of primary cilia may be used in future to treat a growing range of conditions including obesity, cancer, inflammation and arthritis.

Story Source:

The above story is based on materials provided by University of Queen Mary London. Note: Materials may be edited for content and length.

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Changing stem cell structure may help fight obesity

Gut. 2007 May; 56(5): 716724.

Y N Kallis, Department of Medicine, St Mary's Hospital Campus, Imperial College, London, UK

M R Alison, Institute of Cell and Molecular Science, Queen Mary School of Medicine and Dentistry, London, UK

S J Forbes, Tissue Fibrosis and Remodelling Laboratory, MRC/University of Edinburgh Centre for Inflammation Research, Edinburgh, UK

Correspondence to: Professor S J Forbes MRC/University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; stuart.forbes@ed.ac.uk

Stem cells are present in a variety of organs including the bone marrow (BM). Their role is to replenish multiple mature differentiated cell types and thereby achieve longterm tissue reconstitution. Stem cells retain the capacity to generate progeny and renew themselves throughout life. Haematopoietic stem cells (HSCs) are the main stem cell population within the BM and give rise to all mature blood lineages via erythroid, myelomonocytic and lymphoid precursors. A second type of bone marrow stem cell (BMSC), the mesenchymal stem cell (MSC), forms stromal tissue and can give rise to cells of mesodermal origin.

A longstanding principle of cell biology has been that cell loss is reconstituted via stem cells resident within and specific to an organ. However, recent work suggests that this paradigm may not hold for all organs or all types of injury, and tissue damage may attract migratory stem cell populations, particularly those from the BM. This observation has caused considerable interest in the field of liver disease, where new strategies to restore hepatocyte number, augment liver function and counteract progressive organ fibrosis are required. This article will focus on the various relationships between BMSCs and liver disease. It will concentrate on the evidence from animal models and human studies that BMSCs may aid in the regeneration of liver cell populations and may also contribute to the pathogenesis of liver damage. It will discuss the potential to use BMSCs for therapeutic application and review the current status of clinical trials in patients with liver disorders.

The hepatic parenchyma is made up of hepatocytes and cholangiocytes. Unlike other organs such as the gut, liver cell mass is restored primarily through division of the majority of mature hepatocytes and not via a dedicated stem cell population. After a regenerative stimulus, such as a twothirds partial hepatectomy, most hepatocytes rapidly enter the cell cycle and undergo symmetrical mitosis. Liver cell mass can be restored via an average of less than two cell division cycles, albeit individual hepatocytes seem to have an intrinsic capacity for up to 70 doublings in serial transplantation experiments.1 At times of overwhelming cell loss, with longstanding iterative injury (eg, chronic viral hepatitis), or when hepatocyte replication is impeded (eg, replicative senescence of steatohepatitis), regeneration seems to occur via a second cell compartment.2,3 This compartment remains poorly defined and seems to arise from a less differentiated cell population within the terminal branches of the intralobular biliary tree the canals of Hering.4 In rodents these cells are called oval cells, but in humans they are more aptly named hepatic progenitor cells.5 Attempts to identify the originating stem cell are hampered by a paucity of specific cell surface markers.

Initial studies in humans suggested that some hepatocytes have a BM origin. Using Y chromosome tracking, a sparse number of hepatocytes seemed to be originating from the BM in male recipients of female orthotopic liver transplants, and in females who had received bone marrow transplantation (BMT) from male donors and thereafter developed liver disease.6,7 Similarly, other epithelial tissues, such as gut and skin, seemed to harbour cells of BM origin.8 Investigators then turned to an animal model of hereditary type I tryosinaemia, the fumarylacetoacetate hydrolase knockout mouse (FAH(/)), in which it seemed that this potentially fatal enzyme deficiency could be rescued through repopulation of the abnormal liver by BM cells derived from wildtype donors. The implication was that stem cells could cross conventionally demarcated lineage boundaries through a process termed transdifferentiation or stem cell plasticity, leading researchers to question the longheld tenets of cell biology. With time, it became apparent that these initial observations were difficult to reproduce, and later elegant studies in the same FAH(/) mouse model conclusively showed that monocytehepatocyte fusion was the explanation for the restored normal phenotype to the FAHdeficient liver, in which hepatocytes formed by fusion expanded rapidly owing to a considerable survival advantage.9,10

Unfortunately, in the absence of a strong selective pressure, it seems that stable longterm engraftment of BMderived parenchymal cells is unusual. In rats given inhibitors of hepatocyte replication (eg, dgalactosamine, retrorsine or 2acetylaminofluorene), if subjected to a regenerative stimulus such as a partial hepatectomy, BMderived oval cell engraftment can rapidly decrease with time to <1%.11 In the hepatitis B surface antigen transgenic mouse, the BM contributed to hepatocyte repopulation through cell fusion, but only at a very modest rate. In this model, constitutive HBsAg expression induces chronic lowgrade hepatocyte turnover with nodule formation, and inhibition of hepatocyte replication with retrorsine provokes an oval cell response. Here, the contribution from BMderived cells to hepatocyte repopulation waned to just 1.6% by 6months, presumably owing to lack of a sustained selection advantage.12 Likewise, when human HSCs were transplanted into carbon tetrachloride (CCl4)damaged nonobese diabetes/severe combined immune deficiency (NOD/SCID) mice, donorderived hepatocytes expressing mRNA for human albumin and 1 antitrypsin were found in the liver. These hepatocytes occurred through cell fusion, but the phenotype of the chimaeric cells was variable and donorderived genetic material was lost over time.13 When human cord blood, a rich source of progenitor cells, was transplanted into sublethally irradiated NOD/SCID mice, a contribution to the hepatocyte population of only 0.01% was found in the undamaged liver, reportedly through transdifferentiation.14 However, a subsequent study using human cord blood cells again demonstrated only low levels of hepatocyte repopulation even after CCl4induced or hepatocyte growth factor (HGF)induced regeneration. Here the cells were chimaeric for both human and mouse antigens, suggesting that cell fusion rather than transdifferentiation had occurred.15

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In the bone marrow, blood stem cells give rise to a large variety of mature blood cells via progenitor cells at various stages of maturation. Scientists from the German Cancer Research Center (DKFZ) have developed a way to equip mouse blood stem cells with a fluorescent marker that can be switched on from the outside. Using this tool, they were able to observe, for the first time, how stem cells mature into blood cells under normal conditions in a living organism. With these data, they developed a mathematical model of the dynamics of hematopoiesis. The researchers have now reported in the journal Nature that the normal process of blood formation differs from what scientists had previously assumed when using data from stem cell transplantations.

Since ancient times, humankind has been aware of how important blood is to life. Naturalists speculated for thousands of years on the source of the body's blood supply. For several centuries, the liver was believed to be the site where blood forms. In 1868, however, the German pathologist Ernst Neumann discovered immature precursor cells in bone marrow, which turned out to be the actual site of blood cell formation, also known as hematopoiesis. Blood formation was the first process for which scientists formulated and proved the theory that stem cells are the common origin that gives rise to various types of mature cells.

"However, a problem with almost all research on hematopoiesis in past decades is that it has been restricted to experiments in culture or using transplantation into mice," says Professor Hans-Reimer Rodewald from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). "We have now developed the first model where we can observe the development of a stem cell into a mature blood cell in a living organism."

Dr. Katrin Busch from Rodewald's team developed genetically modified mice by introducing a protein into their blood stem cells that sends out a yellow fluorescent signal. This fluorescent marker can be turned on at any time by administering a specific reagent to the animal. Correspondingly, all daughter cells that arise from a cell containing the marker also send out a light signal.

When Busch turned on the marker in adult animals, it became visible that at least one third (approximately 5000 cells) of a mouse's hematopoietic stem cells produce differentiated progenitor cells. "This was the first surprise," says Busch. "Until now, scientists had believed that in the normal state, very few stem cells -- only about ten -- are actively involved in blood formation."

However, it takes a very long time for the fluorescent marker to spread evenly into peripheral blood cells, an amount of time that even exceeds the lifespan of a mouse. Systems biologist Prof. Thomas Hfer and colleagues (also of the DKFZ) performed mathematical analysis of these experimental data to provide additional insight into blood stem cell dynamics. Their analysis showed that, surprisingly, under normal conditions, the replenishment of blood cells is not accomplished by the stem cells themselves. Instead, they are actually supplied by first progenitor cells that develop during the following differentiation step. These cells are able to regenerate themselves for a long time -- though not quite as long as stem cells do. To make sure that the population of this cell type never runs out, blood stem cells must occasionally produce a couple of new first progenitors.

During embryonic development of mice, however, the situation is different: To build up the system, all mature blood and immune cells develop much more rapidly and almost completely from stem cells.

The investigators were also able to accelerate this process in adult animals by artificially depleting their white blood cells. Under these conditions, blood stem cells increase the formation of first progenitor cells, which then immediately start supplying new, mature blood cells. In this process, several hundred times more cells of the so-called myeloid lineage (thrombocytes, erythrocytes, granulocytes, monocytes) form than long-lived lymphocytes (T cells, B cells, natural killer cells) do.

"When we transplanted our labeled blood stem cells from the bone marrow into other mice, only a few stem cells were active in the recipients, and many stem cells were lost," Rodewald explains. "Our new data therefore show that the findings obtained up until now using transplanted stem cells can surely not be reflective of normal hematopoiesis. On the contrary, transplantation is an exception [to the rule]. This shows how important it is that we actually follow hematopoiesis under normal conditions in a living organism."

The scientists in Rodewald's department, working together with Thomas Hfer, now also plan to use the new model to investigate the impact of pathogenic challenges to blood formation: for example, in cancer, cachexia or infection. This method would also enable them to follow potential aging processes that occur in blood stem cells in detail as they occur naturally in a living organism.

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Observing stem cells maturing into blood cells in living mouse

Autologous Stem Cell Transplant | Animation Video
What is a Autologous Stem Cell Transplant? Most stem cells are in your bone marrow. You also have some in your blood that circulate from your bone marrow. Bo...

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Newswise MINNEAPOLIS Stem cell transplants may be more effective than the drug mitoxantrone for people with severe cases of multiple sclerosis (MS), according to a new study published in the February 11, 2015, online issue of Neurology, the medical journal of the American Academy of Neurology.

The study involved 21 people whose disability due to MS had increased during the previous year even though they were taking conventional medications (also known as first-line treatments). The participants, who were an average age of 36, were at an average disability level where a cane or crutch was needed to walk.

In MS, the bodys immune system attacks its own central nervous system. In this phase II study, all of the participants received medications to suppress immune system activity. Then 12 of the participants received the MS drug mitoxantrone, which reduces immune system activity. For the other nine participants, stem cells were harvested from their bone marrow. After the immune system was suppressed, the stem cells were reintroduced through a vein. Over time, the cells migrate to the bone marrow and produce new cells that become immune cells. The participants were followed for up to four years.

This process appears to reset the immune system, said study author Giovanni Mancardi, MD, of the University of Genova in Italy. With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.

Intense immunosupression followed by stem cell treatment reduced disease activity significantly more than the mitoxantrone treatment. Those who received the stem cell transplants had 80 percent fewer new areas of brain damage called T2 lesions than those who received mitoxantrone, with an average of 2.5 new T2 lesions for those receiving stem cells compared to eight new T2 lesions for those receiving mitoxantrone.

For another type of lesion associated with MS, called gadolinium-enhancing lesions, none of the people who received the stem cell treatment had a new lesion during the study, while 56 percent of those taking mitoxantrone had at least one new lesion.

Mancardi noted that the serious side effects that occurred with the stem cell treatment were expected and resolved without permanent consequences.

More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but its very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments, Mancardi said.

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Stem Cell Transplants May Work Better than Existing Drug for Severe Multiple Sclerosis