Taking Blood From Fukushima Radiation Workers To Prepare For Future Stem Cell Transplants In Case They Are Exposed To High Doses Of Radiation

In Correspondence published Online First and an upcoming Lancet, Japanese experts suggest that blood products be taken from workers dealing with the ailing Fukushima Nuclear Facility-so that, should they accidently be exposed to high and health-damaging doses of radiation during the clean-up operation, they will be able to receive treatment by undergoing stem cell transplanation using their own cells (autologous transplant). The Correspondence authors are represented by Dr Shuichi Taniguchi, Toranomon Hospital, Tokyo, Japan, and Dr Tetsuya Tanimoto, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.

The authors say: "The danger of a future accidental radiation exposure is not passed, since there has been a series of serious aftershocks even [during] this April."

Generally, rapidly dividing cells, such as intestinal-tract cells, reproductive germ cells essential for fertility, and haemopoietic cells, are most vulnerable to radiation, which can depress bone marrow from a dose of about 2 Gy or higher. Haemopoietic cells are the precursor stem cells that later become a wide range of different blood cells in the body.

In previous nuclear disasters and accidents, allogeneic stem-cell transplantation (ie stem cells from a donor) has been used, But this has major limitations, such as time-consuming donor searching, graft failure, graft-versus-host disease (GVHD), or profound immune suppression after transplantation.

Instead of this, the Japanese call for collection of the peripheral blood stem cells (PBSC) of the workers themselves so that they could have future transplants should the need arise. This technique has several advantages over allogeneic transplantation; it does not cause GVHD, and does not require immunosuppressant drugs that make radiation victims even more vulnerable to infection. Further, the technique can more rapidly restore normal haemopoietic functionality in the body, the safety of the collection method is proven, and the cells are easy to freeze and store. Finally, it could be used to treat future leukaemia (a known possibility of radiation exposure) as well as bone marrow defects. But the authors also acknowledge autologous transplant is not perfect since it can rescue injury of bone marrow only and not other tissues, such as gastrointestinal tract, skin, or lung.

The authors say that 107 transplant teams are standing by in Japan to collect and store haemopoietic stem cells from the workers who are striving to restrain the radiation, and more than 50 hospitals in Europe have agreed to help the workers if required. But the Nuclear Safety Commission of Japan is resisting the plan, due to the "physical and psychological burden for nuclear workers", and there being "no consensus among international authoritative bodies, and no sufficient agreement among the Japanese public."

Tanimoto, Taniguchi and colleagues add: "The most important mission is to save the nuclear workers' lives and to protect the local communities. Such an approach would be the industry's best defence: if a fatal accident happened to the nuclear workers, the nuclear power industry of Japan would collapse."

They conclude: "The process to completely shut down the reactors in Fukushima is expected to take years. The risk of accidental radiation exposure will thus accumulate for the nuclear workers and banking of their autologous PBSCs will become increasingly important. A judgment of right or wrong on this scheme must be determined from the standpoint of the nuclear workers and their families, not from a point of view of cost-benefit balance in ordinary times. Toranomon Hospital in Tokyo is ready to harvest and bank autologous PBSCs for the nuclear workers upon request."

Source
The Lancet

Long-Term Studies Find Enhanced Cord Blood Stem Cell Transplants To Be Safe

Main Category: Stem Cell Research
Also Included In: Transplants / Organ Donations
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An innovative experimental treatment for boosting the effectiveness of stem-cell transplants with umbilical cord blood has a favorable safety profile in long-term animal studies, report scientists from Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center (BIDMC), and Children's Hospital Boston (CHB).

Analysis of long-term safety testing in nonhuman primates, published online by the journal Cell Stem Cell, revealed that, after one year following transplant, umbilical cord blood units treated with a signaling molecule called 16,16-dimethyl PGE2 reconstituted all the normal types of blood cells, and none of the animals receiving treated cord blood units developed cancer. Wolfram Goessling, MD, PhD, of Dana-Farber and Brigham and Women's Hospital, is the first author of the paper, and Trista North, PhD, of BIDMC is the senior author.

The results of long-term safety studies in mice were previously submitted to the Food and Drug Administration to gain permission for a Phase 1 clinical trial under an Investigational New Drug (IND) application. Principal investigator, Corey Cutler, MD, a Dana-Farber transplant specialist, initiated the trial in 2009 at Dana-Farber and the Massachusetts General Hospital. The IND is sponsored by Fate Therapeutics, Inc. of San Diego.

Goessling and North were post-doctoral fellows in the laboratory of co-author Leonard Zon, MD, a stem cell researcher at CHB and a scientific founder of Fate Therapeutics, when they hit upon 16,16-dimethyl PGE2 while looking for compounds that could regulate the production of hematopoietic stem cells. The initial testing made use of zebra fish models. Goessling commented that "this is the first time a compound discovered in zebra fish has received a nod from the FDA for a clinical trial."

One of the limitations of cord blood as a transplant source is the cells engraft, or "take," in the recipient's bone marrow more slowly than matched donor cells form bone marrow. In addition, there is a higher failure rate for cord blood transplants. Thus there is a need for ways to improve the speed and quality of cord blood transplantation.

Notes:

The research was supported by funding from the Harvard Stem Cell Institute, the National Institutes of Health, and the Howard Hughes Medical Institute.

The other authors are Michael Dovey, PhD, and James M. Harris, BIDMC; Xiao Guan, PhD, and Thorsten Schlaeger, PhD, CHB; Joseph Stegner and Myriam Armant, PhD, Center for Human Cell Therapy, Immune Disease Institute, Boston; Ping Jin, PhD, and David Stroncek, MD, National Institutes of Health, Bethesda, Md.; Naoya Uchida, MD, and John F. Tisdale, MD, National Heart, Lung, and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md.; Robyn S. Allen, Robert E. Donahue, VMD, Mark E. Metzger, and Aylin C. Bonifacino, National Heart, Lung, and Blood Institute, Bethesda, Md.

Source:
Bill Schaller
Dana-Farber Cancer Institute

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Fukushima Workers Should Store Own Blood For Future Stem Cell Contingency If Radiation Exposure Was High

In order to prepare for any future stem cell transplants required as a result of accidental exposure to high doses of radiation during clean up, Fukushima workers have been advised to store their own blood now, Japanese experts wrote in the medical journal The Lancet today. Undergoing stem cell transplantation using their own cells - termed autologous transplant - is an option that should be available to them, the authors stress.

The Lancet Correspondence was represented by Dr Tetsuya Tanimoto, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, and Dr Shuichi Taniguchi, Toranomon Hospital, Tokyo.

They wrote:

"The danger of a future accidental radiation exposure is not passed, since there has been a series of serious aftershocks even (during) this April."

Rapidly dividing cells are vulnerable to radiation damage, which can depress bone marrow from a dose of approximately 2 Gy or more. Examples of cells that divide rapidly include reproductive germ cells, hemopoietic cells, and the cells of the intestinal tract. Hemopoietic (hematopoietic) cells are known as precursor cells - they can eventually become any of several types of blood cells.

Using stem cells from a donor for transplantation, known as allogeneic stem-cell transplantation, in previous nuclear accidents has had its problems, such as graft failure, graft-versus-host disease, profound immune suppression after transplantation, and delays in trying to find a donor.

The authors say the workers' own peripheral blood stem cells should be used in case of future transplant needs. Using one's own blood does away with the need for immunosuppressant medications which make the patient very vulnerable to infections, there is no graft-versus-host disease, and no time is wasted hunting around for a donor.

Autologous transplantation can restore normal hemopoietic functionality much more quickly. Collecting the blood has been proven to be safe, and the cells can be frozen and stored.

The stored blood would also be useful for treating future leukemia, a type of cancer linked to radiation exposure. Bone marrow defects could also be treated.

However, the authors add that autologous transplant has its limitations too - it can only address bone injury, and not other tissues, such as skin, lung or GI tract.

The scientists add that there are 107 transplant teams on stand-by in Japan ready to collect and store hemopoietic stem cells from workers who are bravely trying to hold back the radiation. Over 50 European hospitals are also available to help out.

The Nuclear Safety Commission of Japan is concerned about the "physical and psychological burden for nuclear workers". The Commission adds that there is "..no consensus among international authoritative bodies, and no sufficient agreement among the Japanese public."

The authors said:

"The most important mission is to save the nuclear workers' lives and to protect the local communities. Such an approach would be the industry's best defence: if a fatal accident happened to the nuclear workers, the nuclear power industry of Japan would collapse.

(conclusion) The process to completely shut down the reactors in Fukushima is expected to take years. The risk of accidental radiation exposure will thus accumulate for the nuclear workers and banking of their autologous PBSCs will become increasingly important. A judgment of right or wrong on this scheme must be determined from the standpoint of the nuclear workers and their families, not from a point of view of cost-benefit balance in ordinary times. Toranomon Hospital in Tokyo is ready to harvest and bank autologous PBSCs for the nuclear workers upon request. "

"Safety of workers at the Fukushima Daiichi nuclear power plant"
Tetsuya Tanimoto, Naoyuki Uchida, Yuko Kodama, Takanori Teshima, Shuichi Taniguchi
The Lancet DOI:10.1016/S0140-6736(11)60519-9

Written by Christian Nordqvist
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

'Universal' Virus-Free Method Developed By Scientists To Turn Blood Cells Into 'Beating' Heart Cells

Johns Hopkins scientists have developed a simplified, cheaper, all-purpose method they say can be used by scientists around the globe to more safely turn blood cells into heart cells. The method is virus-free and produces heart cells that beat with nearly 100 percent efficiency, they claim.

"We took the recipe for this process from a complex minestrone to a simple miso soup," says Elias Zambidis, M.D., Ph.D., assistant professor of oncology and pediatrics at the Johns Hopkins Institute for Cell Engineering and the Kimmel Cancer Center.

Zambidis says, "many scientists previously thought that a nonviral method of inducing blood cells to turn into highly functioning cardiac cells was not within reach, but "we've found a way to do it very efficiently and we want other scientists to test the method in their own labs." However, he cautions that the cells are not yet ready for human testing.

To get stem cells taken from one source (such as blood) and develop them into a cell of another type (such as heart), scientists generally use viruses to deliver a package of genes into cells to, first, get them to turn into stem cells. However, viruses can mutate genes and initiate cancers in newly transformed cells. To insert the genes without using a virus, Zambidis' team turned to plasmids, rings of DNA that replicate briefly inside cells and eventually degrade.

Adding to the complexity of coaxing stem cells into other cell types is the expensive and varied recipe of growth factors, nutrients and conditions that bathe stem cells during their transformation. The recipe of this "broth" differs from lab to lab and cell line to cell line.

Reporting in the April 8 issue of Public Library of Science ONE (PLoS ONE), Zambidis' team described what he called a "painstaking, two-year process" to simplify the recipe and environmental conditions that house cells undergoing transformation into heart cells. They found that their recipe worked consistently for at least 11 different stem cell lines tested and worked equally well for the more controversial embryonic stem cells, as well as stem cell lines generated from adult blood stem cells, their main focus.

The process began with Johns Hopkins postdoctoral scientist Paul Burridge, Ph.D., who studied some 30 papers on techniques to create cardiac cells. He drew charts of 48 different variables used to create heart cells, including buffers, enzymes, growth factors, timing, and the size of compartments in cell culture plates. After testing hundreds of combinations of these variables, Burridge narrowed the choices down to between four to nine essential ingredients at each of three stages of cardiac development.

Beyond simplification, an added benefit is reduced cost. Burridge used a cheaper growth media that is one-tenth the price of standard media for these cells at $250 per bottle lasting about one week.

Zambidis says that he wants other scientists to test the method on their stem cell lines, but also notes that the growth "soup" is still a work in progress. "We have recently optimized the conditions for complete removal of the fetal bovine serum from one brief step of the procedure - it's made from an animal product and could introduce unwanted viruses," he says.

In their experiments with the new growth medium, the Hopkins team began with cord blood stem cells and a plasmid to transfer seven genes into the stem cells. They delivered an electric pulse to the cells, making tiny holes in the surface through which plasmids can slip inside. Once inside, the plasmids trigger the cells to revert to a more primitive cell state that can be coaxed into various cell types. At this stage, the cells are called induced pluripotent stem cells (iPSC).

Burridge then bathed the newly formed iPSCs in the now simplified recipe of growth media, which they named "universal cardiac differentiation system." The growth media recipe is specific to creating cardiac cells from any iPSC line.

Finally, they incubated the cells in containers that removed oxygen down to a quarter of ordinary atmospheric levels. "The idea is to recreate conditions experienced by an embryo when these primitive cells are developing into different cell types," says Burridge. They also added a chemical called PVA, which works like glue to make cells stick together.

Nine days later, the nonviral iPSCs turned into functional, beating cardiac cells, each the size of a needlepoint.

Burridge manually counted how often iPSCs formed into cardiac cells in petri dishes by peering into a microscope and identifying each beating cluster of cells. In each of 11 cell lines tested, each plate of cells had an average of 94.5 percent beating heart cells. "Most scientists get 10 percent efficiency for IPSC lines if they're lucky," says Zambidis.

Zambidis and Burridge also worked with Johns Hopkins University bioengineering experts to apply a miniversion of an electrocardiograph to the cells, which tests how cardiac cells use calcium and transmit a voltage. The resulting rhythm showed characteristic pulses seen in a normal human heart.

Virus-free, iPSC-derived cardiac cells could be used in laboratories to test drugs that treat arrhythmia and other conditions. Eventually, bioengineers could develop grafts of the cells that are implanted into patients who suffered heart attacks.

Zambidis' team has recently developed similar techniques for turning these blood-derived iPSC lines into retinal, neural and vascular cells.

Notes:

The research was funded by the Maryland Stem Cell Research Fund and the National Institutes of Health.

Research participants include Susan Thompson, Michal Millrod, Seth Weinberg, Xuan Yuan, Ann Peters, Vasiliki Mahairaki, Vassilis E. Koliatsos, and Leslie Tung at Johns Hopkins.

Source:
Vanessa Wasta
Johns Hopkins Medical Institutions

 

Prostate Cancer Spreads To Bones By Overtaking The Home Of Blood Stem Cells

Like bad neighbors who decide to go wreck another community, prostate and breast cancer usually recur in the bone, according to a new University of Michigan study.

Now, U-M researchers believe they know why. Prostate cancer cells specifically target and eventually overrun the bone marrow niche, a specialized area for hematopoietic stem cells, which make red and white blood cells, said Russell Taichman, professor at the U-M School of Dentistry and senior author of the study.

Once in the niche, the cancer cells stay dormant and when they become active again years later, that's when tumors recur in the bone. The implication is that this may give us a window as to how dormancy and recurrence take place.

Taichman and a team of researchers looked in the bone marrow and found cancer cells and hematopoietic stem cells next to one another competing for the same place. The finding is important because it demonstrates that the bone marrow niche plays a central role in bone metastasis---cancers that spread into the bone-- giving researchers a new potential drug target.

Drugs could be developed to keep the types of cancers that likely recur in the bone from returning, Taichman said. For example, these drugs could either halt or disrupt how the cancer cells enter or behave in the niche, or keep the cancer cells from out-competing the stem cells.

Cancer cells act a lot like stem cells in that they must reproduce, so the U-M research group hypothesized that prostate cancer cells might travel to the niche during metastasis. One of the jobs of the niche is to keep hematopoietic stem cells from proliferating---which may be the case for cancer cells, as well, the researchers found.

So why does cancer recur? Say a person has a tumor and surgeons cut it out or do radiation, but it recurs in the bone marrow five years later, Taichman said. Those cancer cells had been circulating in the body well before the tumor was discovered, and one place those cancer cells hid is the niche.

"So what have the cancer cells been doing during those five years? Now we have a partial answer---they've been sitting in this place whose job it is to keep things from proliferating and growing," Taichman said.

"Our work also provides an explanation as to why current chemotherapies often fail in that once cancer cells enter the niche, most likely they stop proliferating," said Yusuke Shiozawa, lead author of the study. "The problem is that most of the drugs we use to try to treat cancer only work on cells that are proliferating."

Metastases are the most common malignant tumors involving the skeleton, and nearly 70 percent of patients with breast and prostate cancer have bone involvements. Roughly 15 percent to 30 percent of patients with lung, colon, stomach, bladder, uterus, rectum, thyroid or kidney cancer have bone lesions.

Researchers aren't quite sure how the cancer cells out-compete the stem cells in the niche. However, they do know the stem cells were displaced because when cancer cells were in the niche scientists also found evidence of immature blood stem cells in the blood stream, instead of in the marrow where they were supposed to be, Taichman said.

"Eventually the entire blood system is going to collapse," he said. "For example, the patient ultimately becomes anemic, gets infections, and has bleeding problems. We really don't know why people with prostate cancer die. They end up dying from different kinds of complications in part because the marrow is taken over by cancer."

The next step is to find out how the tumor cell gets into the niche and becomes dormant, and exactly what they do to the stem cells when they are there. Researchers also want to know if other types of cancer cells, such as breast cancer, also go to the niche.

The study, "Prostate Cancer Metastases Target the Hematopoietic Stem Cell Niche to Establish Footholds in Marrow," appears online in the Journal of Clinical Investigation.

Source: University of Michigan