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Tissue development 'roadmap' created to guide stem cell medicine

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In a boon to stem cell research and regenerative medicine, scientists at Boston Children's Hospital, the Wyss Institute for Biologically Inspired Engineering at Harvard University and Boston University have created a computer algorithm called CellNet as a "roadmap" for cell and tissue engineering, to ensure that cells engineered in the lab have the same favorable properties as cells in our own bodies. CellNet and its application to stem cell engineering are described in two back-to-back papers in the August 14 issue of the journal Cell.

Scientists around the world are engaged in culturing pluripotent stem cells (capable of forming all the body's tissues) and transforming them into specialized cell types for use in research and regenerative medicine. Available as an Internet resource for any scientist to use, CellNet provides a much needed "quality assurance" measure for this work.

The two papers also clarify uncertainty around which methods are best for stem cell engineering, and should advance the use of cells derived from patient tissues to model disease, test potential drugs and use as treatments. For example, using CellNet, one of the studies unexpectedly found that skin cells can be converted into intestinal cells that were able to reverse colitis in a mouse model.

"To date, there has been no systematic means of assessing the fidelity of cellular engineeringto determine how closely cells made in a petri dish approximate natural tissues in the body," says George Q. Daley, MD, PhD, Director of the Stem Cell Transplantation Program at Boston Children's and senior investigator on both studies. "CellNet was developed to assess the quality of engineered cells and to identify ways to improve their performance."

Gene Signatures

CellNet applies network biology to discover the complex network of genes that are turned on or off in an engineered cell, known as the cell's Gene Regulatory Network or GRN. It then compares that network to the cell's real-life counterpart in the body, as determined from public genome databases. Through this comparison, researchers can rigorously and reliably assess:

"CellNet will also be a powerful tool to advance synthetic biologyto engineer cells for specific medical applications," says James Collins, PhD, Core Faculty member at the Wyss Institute and the William F. Warren Distinguished Professor at Boston University, co-senior investigator on one of the studies.

Putting CellNet to the Test

The researchersincluding co-first authors Patrick Cahan, PhD and Samantha Morris, PhD, of Boston Children's, and Hu Li, PhD, of the Mayo Clinic, first used CellNet to assess the quality of eight kinds of cells created in 56 published studies.

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Tissue development 'roadmap' created to guide stem cell medicine

Trying out a stem cell facial

TO SOME people, the term stem cell may seem kind of taboo. I personally would not want something from animals injected into my system. But Im okay with non-invasive treatments, so I was interested to try out a plant-based stem cell facial.

After cleansing and toning, cotton pads moistened with a clear solution were laid on my eyelids to protect them from a three-minute steaming session. This was followed by a special tool called a scrubber that kind of looks like a computer mouse, but helps to remove dead skin cells and unblock pores without using the rather painful pricking tool.

Next, a rejuvenating gel was applied, followed by the plant-derived stem cell formula. A unique cooling machine was used to massage it into the skin for 10 minutes. Using this machine for cold electrophoresis helps the skin absorb serums and vitamins, without having to use injections. This was great for someone like me, who is wary of invasive treatments. The cooling machine feels like having an ice-cold metal ball massaged on the face; very invigorating, indeed.

Just when I thought my skin already got a lot of pampering, the stem cell was followed by a face mask full of natural vitamins. While it penetrated into my skin, I was given an arm and foot massage, which was nice for further relaxation.

With my combination skin, I looked pretty greasy right afterwards. When I woke up the next day, I didnt see a visible difference in my skin, but it was very smooth and supple to the touch. You may not see instant results with a treatment like this, but its a good treatment to maintain radiance, softness and hydration from beneath the surface of the skin.

This type of facial is not recommended for those with oily or acne-prone skin because the added oiliness may exacerbate problems, but it is ideal for those with dry or mature skin, as it is deeply nourishing and moisturizing. After the first treatment or over time, depending on the condition of your skin, stem cell diminishes fine lines, prevents wrinkles, and promotes cell renewal (a process that slows with age) to give that glowing look that signifies healthy, youthful skin.

I tried out the stem cell facial at Lohas skin and slimming center on Paseo Saturnino, Banilad. Its a more upscale experience here with your own room, as opposed to being in one large room with dividers, in case privacy is an issue for you. All of their machines and products are brought in from Korea and their staff, like my therapist Jennylyn, are highly knowledgeable and know just how much pressure to apply during the treatment. The service, facilities and products used add up to a luxurious treatment session that makes one feel very pampered.

Published in the Sun.Star Cebu newspaper on August 15, 2014.

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Trying out a stem cell facial

New Blood: Tracing the Beginnings of Hematopoietic Stem Cells

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Newswise Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells.

Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. Notch signaling between emitting and receiving cells is key to establishing HSC fate during development, said Traver. What has not been known is where, when and how Notch signal transduction is mediated.

Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues much earlier in the process than previously anticipated.

More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.

To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells, said Traver. This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.

Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.

The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells pluripotent cells artificially derived from non-pluripotent cells, such as skin cells that are being used in other therapeutic research efforts.

Co-authors include Isao Kobayashi, Jingjing Kobayashi-Sun, Albert D. Kim and Claire Pouget, UC San Diego Department of Cellular and Molecular Medicine; Naonobu Fujita, UC San Diego Section of Cell and Developmental Biology; and Toshio Suda, Keio University, Japan.

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New Blood: Tracing the Beginnings of Hematopoietic Stem Cells

Animal-free reprogramming of adult cells improves safety

20 hours ago Growing stem cells in conditions free of animal material makes them safe for use in humans. Credit: Eraxion/iStock/Thinkstock

Human stem cells produced through genetic reprogramming are beset by safety concerns because current techniques alter the DNA of the stem cells and use material from animals to grow them. Now, A*STAR researchers have developed an efficient approach that produces safe, patient-specific human stem cells.

Human induced pluripotent stem cells have the potential to treat a number of diseases without the ethical issues associated with embryonic stem cells. Pluripotent stem cells can be produced from adult cells by introducing genes that reprogram them. Typically, the stem cells are grown on a layer of mouse cells in solutions (known as media) that contain animal proteinsand therefore, potentially may also carry disease. For such stem cells to be safe for use in humans, they need to be grown in 'xeno-free' conditions, which are devoid of material from other animals.

Andrew Wan and Hong Fang Lu at the A*STAR Institute of Bioengineering and Nanotechnology in Singapore and colleagues set out to develop a new xeno-free system. The researchers carried out the genetic reprogramming of cells on an artificially produced protein substrate rather than mouse cells. They also used media that contained no animal components. The result was more efficient reprogramming than seen with conventional approaches.

"A xeno-free system will eliminate the risk of disease transmission from other species, which is important for regulatory approval," explains Wan. "Yet there have been few studies on cell reprogramming under totally xeno-free conditions."

The researchers went one step further by addressing the problem of cells acquiring alterations to their DNA during reprogramming.

"Incorporation of transgenes into the genome of the cell poses another safety issue, risking unwanted genetic alterations," explains Lu. "In our work, the transgenes were introduced to initiate the reprogramming, but after this they were removed from the cell, leading to transgene-free stem cells."

The researchers demonstrated that after genetic reprogramming and the removal of the added genes, the stem cells could still develop into different cells types. They were even able to induce them to form dopaminergic neurons, the type that degenerates in Parkinson's disease. The conditions in which the stem cells were grown mean that they are suitable for clinical use and can be derived from a patient's own cells, ensuring complete compatibility.

"Regulatory approval for clinical application of stem cells largely depends on the conditions in which the stem cells are derived," says Wan. "We present a workable protocol for the reprogramming of fibroblasts to stem cells that minimizes any potential safety risks."

Explore further: Discovery may make it easier to develop life-saving stem cells

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Animal-free reprogramming of adult cells improves safety

Cell discovery brings blood disorder cure closer

PUBLIC RELEASE DATE:

13-Aug-2014

Contact: Lucy Handford media@monash.edu Monash University

A cure for a range of blood disorders and immune diseases is in sight, according to scientists who have unravelled the mystery of stem cell generation.

The Australian study, led by researchers at the Australian Regenerative Medicine Institute (ARMI) at Monash University and the Garvan Institute of Medical Research, is published today in Nature. It identifies for the first time mechanisms in the body that trigger hematopoietic stem cell (HSC) production.

Found in the bone marrow and in umbilical cord blood, HSCs are critically important because they can replenish the body's supply of blood cells. Leukemia patients have been successfully treated using HSC transplants, but medical experts believe blood stem cells have the potential to be used more widely.

Lead researcher Professor Peter Currie, from ARMI explained that understanding how HSCs self-renew to replenish blood cells is a "Holy Grail" of stem cell biology.

"HSCs are one of the best therapeutic tools at our disposal because they can make any blood cell in the body. Potentially we could use these cells in many more ways than current transplantation strategies to treat serious blood disorders and diseases, but only if we can figure out how they are generated in the first place. Our study brings this possibility a step closer," he said.

A key stumbling block to using HSCs more widely has been an inability to produce them in the laboratory setting. The reason for this, suggested from previous research, is that a molecular 'switch' may also be necessary for HSC formation, though the mechanism responsible has remained a mystery, until now.

In this latest study, ARMI researchers observed cells in the developing zebra fish - a tropical freshwater fish known for its regenerative abilities and optically clear embryos - to gather new information on the signalling process responsible for HSC generation.

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Stem cell discovery: Australian scientists make significant find while studying zebrafish

Australian scientists studying zebrafish have stumbled upon what they say is one of the most significant discoveries in stem cell research.

In research published on Thursday in the journal Nature, the Monash University scientists revealed that they uncovered how one of the most important stem cells in blood and bone marrow, the haematopoietic stem cell (HSC), is formed.

Professor Peter Currie, from Monash University's Australian Regenerative Medicine Institute, said the discovery brought researchers closer to growing HSCs in a lab.

"HSCs are the basis of bone marrow transplantations as a therapy, so when a leukaemia patient receives bone marrow, it's really these HSCs that do the heavy lifting," Professor Currie said.

"So when clinicians do bone marrow transplants, they need to find a matching donor recipients and we know that's a hit or miss procedure.

"So for many years people have been trying to make HSCs in the dish, and they've had very little success in doing this."

Professor Currie, who led the study, said the discovery brought scientists much closer to achieving that aim.

"It's the discovery of a completely new cell type that basically is required to give instructions to the HSC to make it become what it needs to become," he said.

"It means we now understand how HSC form in the body better, we can use that information to try to grow these cells in the dish and we hope that will lead to better treatment for people with leukaemia and blood disorders."

Professor Currie said he specialises in muscle stem cell biology and accidentally came across the discovery while studying muscle stem cells in zebrafish.

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Stem cell discovery: Australian scientists make significant find while studying zebrafish

Cellular Dynamics reports higher quarterly revenues and bigger losses

Cellular Dynamics International said revenues for the quarter that ended June 30 rose nearly 30 percent over the same quarter last year but expenses jumped even more quickly.

The Madison stem cell company reported a net loss of $8.6 million, or 54 cents a share, on $3.6 million in revenues for the most recent quarter compared with a $5.1 million net loss, or $2.92 a share, on revenues of $2.8 million for the same period last year.

Costs rose because of higher research and development expenses related to CDI's contract to set up a stem cell bank with the California Institute for Regenerative Medicine, San Francisco, and to higher expenses resulting from CDI's initial public stock offering in July 2013, the company said.

At the same time, CDI said, it has manufactured stem cells for 179 customers in the past 12 months, up from 136 customers in the previous year, and the largest customers increased their purchases by 45 percent.

"We intend to achieve profitability in the long term," said the company, which was founded in 2004 by UW-Madison stem cell pioneer James Thomson.

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Cellular Dynamics reports higher quarterly revenues and bigger losses

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WASHINGTON A U.S. researcher who co-authored controversial papers on stem cell development will quit his post at Brigham and Womens Hospital in Boston on Sept. 1, the institution said Tuesday.

Charles Vacanti, chairman of the hospitals Department of Anesthesiology, Preoperative and Pain Medicine, was involved in the publication by a Japanese institution of two theses on so-called STAP cells whose credibility came into question earlier this year.

Vacanti, known as a mentor of Haruko Obokata at the Japanese government-affiliate Riken institute who is a key author of the papers, will remain on faculty, the Boston hospital said.

Following a one-year sabbatical Vacanti intends to focus his energies on regenerative medicine and mentoring the next generation of anesthesiologists, the hospital said.

It remains unknown if his latest step is linked with the STAP cell controversy.

According to a U.S.-based expert on regenerative medicine, Vacanti of Harvard Medical School is believed to have written an email informing his colleagues and others of his intention to resign from the post.

Paul Knoepfler, associate professor at the University of Californias Davis School of Medicine, released Vacantis email on his blog on Monday.

It is with somewhat mixed emotions that I share with you my decision to step down, it reads.

Vacanti did not mention whether his decision has to do with his involvement in the papers on STAP cells that were published in the British science journal Nature in January and retracted in July after critical errors were found.

I plan to take a one-year sabbatical to contemplate my future goals, redirect my efforts and spend time doing some of the things that I enjoy most, the email says.

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Cedars-Sinai Heart Institute Opens First-of-its-Kind Research Stem Cell Clinic for Cardiac Patients

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Newswise LOS ANGELES (Aug. 12, 2014) Regenerative medicine experts at the Cedars-Sinai Heart Institute have opened a new clinic to evaluate heart and vascular disease patients for participation in stem cell medical studies.

Led by Eduardo Marbn, MD, PhD, director of the Cedars-Sinai Heart Institute, and Timothy Henry, MD, director of the Heart Institutes Cardiology Division, the doctors and researchers at the Cedars-Sinai Heart Institute Regenerative Medicine Clinic use a scientific approach to assess the possible benefits of stem cells to repair damaged or diseased cardiovascular tissues. The clinic is believed to be the first at a major U.S. academic medical center dedicated to matching patients with appropriate stem cell clinical trials, whether those research interventions are available at the medical center or at other institutions.

The Heart Institute Regenerative Medicine Clinic offers consultative services for patients with heart and vascular disease who may qualify for investigative stem cell therapy. The goal is to provide research options to patients who remain symptomatic on their current management regimen, or for patients with stable heart disease who are concerned about disease progression.

Over the past decade, medical experts have predicted that in the future, stem cell therapies would transform heart disease treatment and save lives, said Shlomo Melmed, MD, dean of the Cedars-Sinai faculty and the Helene A. and Philip E. Hixon Distinguished Chair in Investigative Medicine. At Cedars-Sinai, we have a track record of successfully directing cardiac stem cell studies as well as transferring innovations from the laboratory to the patient bedside.

In 2009, Marbn and his team completed the worlds first procedure in which a patients own heart tissue was used to grow specialized heart stem cells. The specialized cells were then injected back into the patients heart in an effort to repair and re-grow healthy muscle in a heart that had been injured by a heart attack. Results, published in The Lancet in 2012, showed that one year after receiving the stem cell treatment, heart attack patients demonstrated a significant reduction in the size of the scar left on the heart muscle after a heart attack.

Henry has served as principal investigator of multiple large, multicenter trials in acute coronary syndromes, myocardial infarction and angiogenesis, including several ongoing cardiovascular stem cell trials. He also is principal investigator for one of seven NIH Clinical Cardiovascular Stem Cell Centers.

Our goal is to help make stem cells a regular treatment option for heart disease, Henry said. Right now, many patients with advanced heart disease have limited treatment options. Stem cells offer not only hope but a real chance of a game-changing treatment.

As part of each patients assessment in the Heart Regenerative Medicine Clinic, physicians will evaluate patients interested in participating in stem cell clinical trials at Cedars-Sinai and, for patients willing to travel at other medical institutions across the nation. For patients willing to travel to participate in research, Cedars-Sinai physicians will work closely with investigators at other centers to expedite referrals and seamlessly transfer all relevant medical records.

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Cedars-Sinai Heart Institute Opens First-of-its-Kind Research Stem Cell Clinic for Cardiac Patients

UCSD Looking For Spinal Cord Injury Patients To Test Stem Cell Treatment

The UC San Diego Health System put out a call Monday for eight spinal cord injury patients to take part in a five-year test of the safety of a new treatment involving neural stem cells.

The researchers are looking for people who suffered an injury to the middle or lower levels of the spine's thoracic vertebrae between one and two years ago. According to UCSD, the injury must be between the seventh and 12th thoracic vertebrae.

"The goal of this study is to evaluate the safety of transplanting neural stem cells into the spine for what one day could be a treatment for spinal cord injuries," said Dr. Joseph Ciacci, the study's principal investigator and a neurosurgeon at UC San Diego Health System. "The study's immediate goal, however, is to determine whether injecting these neural stem cells into the spine of patients with spinal cord injury is safe."

The doctors also want to know how long the transplanted stem cells will last, and whether drugs designed to prevent rejection by the immune system are effective, according to UCSD Health.

The researchers will also look for possible changes in motor and sensory function, bowel and bladder function, and pain levels.

The stem cells were tested in laboratory rats by Ciacci and Dr. Martin Marsala, of the UC San Diego School of Medicine. They detected signs of improved motor function with minimal side effects. The cells have also been tested for safety in human patients with amyotrophic lateral sclerosis commonly known as ALS or Lou Gehrig's Disease.

UCSD cautioned prospective test subjects that since human tests are just beginning, unforeseen risks, complications or unpredictable outcomes are possible.

The clinical trial at UC San Diego Health System is funded by Neuralstem Inc. and was launched and supported by the UC San Diego Sanford Stem Cell Clinical Center. The center was recently created to "advance leading-edge stem cell medicine and science, protect and counsel patients, and accelerate innovative stem cell research into patient diagnostics and therapy," according to UCSD.

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UCSD Looking For Spinal Cord Injury Patients To Test Stem Cell Treatment