Stem cell study holds out promise for kidney disease

Kidney failure

Image via youtube.com

Kidney failure is the Rodney Dangerfield of diseases, it really doesn’t get the respect it deserves. An estimated 660,000 Americans suffer from kidney failure and around 47,000 people die from it every year. That’s more than die from breast or prostate cancer. But now a new study has identified a promising stem cell candidate that could help in finding a way to help repair damaged kidneys.

Kidneys are the body’s waste disposal system, filtering our blood and cleaning out all the waste products. Our kidneys have a limited ability to help repair themselves but if someone suffers from chronic kidney disease then their kidneys are slowly overwhelmed and that leads to end stage renal disease. At that point the patient’s options are limited to dialysis or an organ transplant.

Survivors hold out hope

Italian researchers had identified some cells in the kidneys that showed a regenerative ability. These cells, which were characterized by the expression of a molecule called CD133, were able to survive injury and create different types of kidney cells.

Researchers at the University of Torino in Italy decided to take these findings further and explore precisely how CD133 worked and if they could take advantage of that and use it to help repair damaged kidneys.

In their findings, published in the journal Stem Cells Translational Medicine, the researchers began by working with a chemotherapy drug called cisplatin, which is used against a broad range of cancers but is also known to cause damage to kidneys in around one third of all patients. The team found that CD133 was an important factor in helping those damaged kidneys recover. They also found that CD133 prevents aging of kidney progenitor cells, the kind of cell needed to help create new cells to repair the kidneys in future.

Hope for further research

The finding opens up a number of possible lines of research, including exploring whether infusions of CD133 could help patients whose kidneys are no longer able to produce enough of the molecule to help repair damage.

In an interview in DD News, Dr. Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine – praised the research:

“This is an interesting and novel finding. Because the work identifies mechanisms potentially involved in the repair of tissue after injury, it suggests the possibility of new therapies for tissue repair and regeneration.”

CIRM is funding several projects targeting kidney disease including four clinical trials for kidney failure. These are all late-stage kidney failure problems so if the CD133 research lives up to its promise it might be able to help people at an earlier stage of disease.

Alpha clinics and a new framework for accelerating stem cell treatments

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Last week, at the World Stem Cell Summit in Miami, CIRM took part in a panel discussion about the role and importance of Alpha Clinics in not just delivering stem cell therapies, but in helping create a new, more collaborative approach to medicine. The Alpha Clinic concept is to create  a network of top medical centers that specialize in delivering stem cell clinical trials to patients.

The panel was moderated by Dr. Tony Atala, Director of the Wake Forest Institute for Regenerative Medicine. He said the term Alpha Clinic came from CIRM and the Alpha Stem Cell Clinic Network that we helped create. That network now has five specialist health care centers that deliver stem cell therapies to patients: UC San Diego, UCLA/UC Irvine, City of Hope, UC Davis, and  UCSF/Children’s Hospital Oakland.

This is a snapshot of that conversation.

Alpha Clinics Advancing Stem Cell Trials

Dr. Maria Millan, CIRM’s President & CEO:

“The idea behind the Alpha Stem Cell Clinic Network is that CIRM is in the business of accelerating treatments to patients with unmet medical needs. We fund research from the earliest discovery stage to clinical trials. What was anticipated is that, if the goal is to get these discoveries into the clinics then we’ll need a specific set of expertise and talents to deliver those treatments safely and effectively, to gather data from those trials and move the field forward. So, we set out to create a learning network, a sharing network and a network that is more than the sum of its parts.”

Dr. Joshua Hare,  Interdisciplinary Stem Cell Institute, University of Miami, said that idea of collaboration is critical to advancing the field:

 

“What we learned is that having the Alpha Stem Cell Clinic concept helps investigators in other areas learn from what earlier researchers have done, helping accelerate their work.

For example, we have had a lot of experience in working with rare diseases and we can use the experience we have in treating one disease area in working in others. This shared experience can help us develop deeper understanding in terms of delivering therapies and dosing.”

Susan Solomon, CEO New York Stem Cell Foundation Research Institute. NYSCF has several clinical trials underway. She says in the beginning it was hard finding reputable clinics that could deliver these potentially ground breaking but still experimental therapies:

 

“My motivation was born out of my own frustration at the poor choices we had in dealing with some devastating diseases, so in order to move things ahead we had to have an alpha clinic that is not just doing clinical trials but is working to overcome obstacles in the field.”

Greg Simon represented the, Biden Cancer Initiative, whose  mission is to develop and drive implementation of solutions to accelerate progress in cancer prevention, detection, diagnosis, research, and care, and to reduce disparities in cancer outcomes. He says part of the problem is that people think there are systems already in place that promote collaboration and cooperation, but that’s not really the case.  

 

“In the Cancer Moonshot and the Biden Cancer Initiative we are trying to create the cancer research initiative that people think we already have. People think doctors share knowledge. They don’t. People think they can just sign up for clinical trials. They can’t. People think there are standards for describing a cancer. There aren’t. So, all the things you think you know about the science behind cancer are wrong. We don’t have the system people think is in place. But we want to create that.

If we are going to have a unified system we need common standards through cancer research, shared knowledge, and clinical trial reforms. All my professional career it was considered unethical to refer to a clinical trial as a treatment, it was research. That’s no longer the case. Many people are now told this is your last best hope for treatment and it’s changed the way people think about clinical trials.”

The Process

Maria Millan says we are seeing these kinds of change – more collaboration, more transparency –  taking place across the board:

“We see the research in academic institutions that then moved into small companies that are now being approved by the FDA. Academic centers, in conjunction with industry partners, are helping create networks and connections that advance therapies.

This gives us the opportunity to have clinical programs and dialogues about how we can get better, how we can create a more uniform, standard approach that helps us learn from each trial and develop common standards that investigators know have to be in place.

Within the CIRM Alpha Stem Cell Clinic Network the teams coming in can access what we have pulled together already – a database of 20 million patients, a single IRB approval, so that if a cliinical trial is approved for one Alpha Clinic it can also be offered at another.”

Greg Simon says to see the changes really take hold we need to ensure this idea of collaboration starts at the very beginning of the chain:

“If we don’t have a system of basic research where people share data, where people are rewarded for sharing data, journals that don’t lock up the data behind a paywall. If we don’t have that system, we don’t have the ability to move therapies along as quickly as we could.

“Nobody wants to be the last person to die from a cancer that someone figured out a treatment for a year earlier. It’s not that the science is so hard, or the diseases are so hard, it the way we approach them that’s so hard. How do we create the right system?”

More may not necessarily be better

Susan Solomon:

“There are tremendous number of advances moving to the clinic, but I am concerned about the need for more sharing and the sheer number of clinical trials. We have to be smart about how we do our work. There is some low hanging fruit for some clinical trials in the cancer area, but you have to be really careful.”

Greg Simon

“We have too many bad trials, we don’t need more, we need better quality trials.

We have made a lot of progress in cancer. I’m a CLL survivor and had zero problems with the treatment and everything went well.

We have pediatric cancer therapies that turned survival from 10 % to 80%. But the question is why doesn’t more progress happen. We tend to get stuck in a way of thinking and don’t question why it has to be that way. We think of funding because that’s the way funding cycles work, the NIH issues grants every year, so we think about research on a yearly basis. We need to change the cycle.”

Maria Millan says CIRM takes a two pronged approach to improving things, renovating and creating:

“We renovate when we know there are things already in place that can be improved and made better; and we create if there’s nothing there and it needs to be created. We want to be as efficient as we can and not waste time and resources.”

She ended by saying one of the most exciting things today is that the discussion now has moved to how we are going to cover this for patients. Greg Simon couldn’t agree more.

“The biggest predictor of survivability of cancer is health insurance. We need to do more than just develop treatments. We need to have a system that enables people to get access to these therapies.”

It’s time to vote for the Stem Cell Person of the Year

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Paul Knoepfler

Oh well, it’s going to be another year of disappointment for me. Not only did I fail to get any Nobel Prize (I figured my blogs might give me a shot at Literature after they gave it to Bob Dylan last year), but I didn’t get a MacArthur Genius Award. Now I find out I haven’t even made the short list for the Stem Cell Person of the Year.

The Stem Cell Person of the Year award is given by UC Davis researcher, avid blogger and CIRM Grantee Paul Knoepfler. (You can vote for the Stem Cell Person of the Year here). In his blog, The Niche, Paul lists the qualities he looks for:

“The Stem Cell Person of the Year Award is an honor I give out to the person in any given year who in my view has had the most positive impact in outside-the-box ways in the stem cell and regenerative medicine field. I’m looking for creative risk-takers.”

“It’s not about who you know, but what you do to help science, medicine, and other people.”

Paul invites people to nominate worthy individuals – this year there are 20 nominees – people vote on which one of the nominees they think should win, and then Paul makes the final decision. Well, it is his blog and he is putting up the $2,000 prize money himself.

This year’s nominees are nothing if not diverse, including

  • Anthony Atala, a pioneering researcher at Wake Forest Institute for Regenerative Medicine in North Carolina
  • Bao-Ngoc Nguyen, who helped create California’s groundbreaking new law targeting clinics which offer unproven stem cell therapies
  • Judy Roberson, a tireless patient advocate, and supporter of stem cell research for Huntington’s disease

Whoever wins will be following in some big footsteps including patient advocates Ted Harada and Roman Reed, as well as scientists like Jeanne Loring, Masayo Takahashi,  and Elena Cattaneo.

So vote early, vote often.

LINK: Vote for the 2017 Stem Cell Person of the Year

Finally a possible use for your excess fat; using it to fix your arthritic knee

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One of the most common questions we get asked at CIRM, almost every other day to be honest, is “are there any stem cell treatments for people with arthritis in their knees?” It’s not surprising. This is a problem that plagues millions of Americans and is one of the leading causes of disability in the US.

Sadly, we have to tell people that there are no stem cell treatments for osteoarthritis (OA) in the knee that have been approved by the Food and Drug Administration (FDA). There’s also a lack of solid evidence from clinical trials that the various approaches are effective.

But that could be changing. There’s a growing number of clinical trials underway looking at different approaches to treating OA in the knee using various forms of stem cells. Sixteen of those are listed at clinicaltrials.gov. And one new study suggests that just one injection of stem cells may be able to help reduce pain and inflammation in arthritic knees, at least for six months. The operative word here being may.

The study, published in the journal Stem Cells Translational Medicine,  used adipose-derived stromal cells, a kind of stem cell taken from the patient’s own fat. Previous studies have shown that these cells can have immune boosting and anti-scarring properties.

The cells were removed by liposuction, so not only did the patient’s get a boost for their knees they also got a little fat reduction. A nice bonus if desired.

The study was quite small. It involved 18 patients, between the ages of 50 and 75, all of whom had suffered from osteoarthritis (OA) in the knee for at least a year before the treatment. This condition is caused by the cartilage in the knee breaking down, allowing bones to rub against each other, leading to pain, stiffness and swelling.

One group of patients were given a low dose of the cells (23,000) injected directly into the knee, one a medium dose (103,000) and one a high dose (503,000).

Over the next six months, the patients were closely followed to see if there were any side effects and, of course, any improvement in their condition. In a news release, Christian Jorgensen, of University Hospital of Montpellier, the director of the study, said the results were encouraging:

“Although this phase I study included a limited number of patients without a placebo arm we were able to show that this innovative treatment was well tolerated in patients with knee OA and it provided encouraging preliminary evidence of efficacy. Interestingly, patients treated with low-dose ASCs significantly improved in pain and function compared with the baseline.”

The researchers caution that the treatment doesn’t halt the progression of OA and does not restore the damaged cartilage, instead it seems to help patients by reducing inflammation.

In a news article about the study Tony Atala, director of the Wake Forest Institute for Regenerative Medicine, in Winston-Salem, N.C. and the editor of Stem Cells Translational Medicine said the study offered the patients involved another benefit:

“In fact, most of the patients (in the study group) who had previously scheduled total knee replacement surgery decided to cancel the surgery. It will be interesting to see if these improvements are seen in larger groups of study participants.”

Interesting is an understatement.

But while this is encouraging it’s important to remember it was done in a small group of patients and needs to be replicated in a much larger group before we can draw any solid conclusions. It will also be important to see if the benefits last longer than six months.

We might not have to wait too long for some answers. The researchers are already running a 2-year trial involving 150 people in Europe.

We’ll let you know what they find.

 

Meet ITOP: A One Stop Shop for 3D Printing Body Parts

“They have managed to create what appears to be the goose that really does lay golden eggs!”

That was how UK surgeon Martin Birchall described it to BBC News. The goose in this case is a 3D bioprinter, and the golden eggs are the human sized tissues that the bioprinter successfully constructed. This breakthrough for the field of tissue engineering was reported on Monday in Nature Biotechnology by a research team led by Anthony Atala, director of Wake Forest Institute for Regenerative Medicine.

Bioprinting: yes, it’s actually a thing

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The 3D bioprinting process. Image: Wake Forest, Nature Biotechnology

To some, printing human body parts may sound like a far-fetched story torn from a science fiction novel but, in reality, development of bioprinters has been underway for a number of years. The bioprinting process isn’t all that different from an inkjet printer except a mixture of gelatin, or hydrogel, and living cells is used as the “ink” to incrementally build a defined  biological structure.

As amazing as this technology is, it has met some limitations. Printing cells into 2D shapes and small 3D structures is doable but a lack of structural stability limits building more complex, human-scale tissues. Also, because oxygen and nutrients can only diffuse about 0.004 inches through living tissue, the cells located inside a large bioprinted structure have trouble with long-term survival (check out yesterday’s blog for a mind-blowning story about one lab’s use of cotton candy to deal with this diffusion issue). These challenges have to be overcome before 3D bioprinting can be used for the repair and replacement of human-sized tissues and organs.

Enter ITOP
That’s where the Atala team’s Integrated Tissue-Organ Printer (ITOP), developed over ten years, comes into the picture. For better structural stability, the printer is configured to deliver the cell/hydrogel “bio-ink” within a stronger type of gel, with the fancy name Pluronic F127, that helps the printed cells maintain their shape during the printing process. Afterward, the Pluronic F127 scaffolding mold is simply washed away from the bioprinted tissue.

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Close-up view of ITOP: a 3D bioprinter. Image: Wake Forest, Nature Biotechnology.

To ensure adequate oxygen diffusion into the bioprinted tissue, a biodegradable polymer, PCL, is dispensed from the printer at regular intervals; this creates microchannels as stand-ins for blood vessels to help oxygen and nutrients readily reach the interior areas of the tissues.  As a bonus, PCL takes about 2 years to biodegrade, providing long term stability.

To prove these innovations of the ITOP actually work, the team built three different tissues: a jawbone fragment, an ear, and muscle.

The making of a jawbone
For reconstruction of the jawbone, a 3D computer model was generated from actual CT scan data of a human jaw with a missing piece of bone – something that might be seen in a traumatic injury to a combat soldier (the work is funded in part by the Armed Forces Institute for Regenerative Medicine). That data was fed into the ITOP with coordinates of the precise printing pattern necessary to rebuild the shape of the jaw fragment. In this case, printing was carried out using human amniotic fluid stem cells (AFSC). With the right cues, these stem cells readily specialize into osteogenic, or bone-forming, cells.

Sure enough, 28 days after being cultured in liquid nutrients containing bone-promoting factors, the surface of the bioprinted human jaw showed calcium deposits, the tell-tale signs of bone formation. How would bioprinted bone fare in a living mammal? To find out, the researchers transplanted small discs of AFSC fabricated bone into a bone defect in mice. After 5 months, the transplanted bone was thriving with plenty of blood vessels and no necrosis, or cell death, inside the bone.

The implications of this bone study are pretty cool. In an interview with BBC news, Atala envisions a not so distant future clinical scenario:

“We’d bring the patient in, do the imaging and then we would take the imaging data and transfer it through our software to drive the printer to create a piece of jawbone that would fit precisely in the patient.”

Vincent van Gogh could have used this technology
But the possibilities don’t end with bone. Next, the team tested the ITOP’s talents at building the complex shapes of the outer human ear. In this case, the printer was loaded up with cartilage-producing cells called chondrocytes. The authors posted a fascinating video of the ear bioprinting process in their online publication.

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A human-sized bioprinted ear. Image: Wake Forest, Nature Biotechnology

Image: Wake Forest, Nature Biotechnology.

After five weeks in liquid nutrients, a matrix of cartilage had grown throughout the ear. And to look at tissue growth in an animal, the ear was implanted under the skin of the mice. A couple of months after implantation, even more cartilage had formed and the shape of the ear was intact.

But wait there’s more: printing skeletal muscle
Since both the jaw bone and ear cartilage represent hard tissues, the team sought to reconstruct muscle, a soft tissue, with the ITOP. Muscle-forming cells, or myoblasts, were printed to mimic the muscle fiber bundles seen in native skeletal muscle. After growing a week in the lab under conditions that stimulate muscle cell formation, the muscle-like fibers were implanted into rats. Two week after implantation, the bioprinted muscle had not only grown into well-organized muscle fibers, they also were functional in that they were responsive to electrical stimulation.

3D bioprinting: getting closer to reality
Atala is the first to admit that a lot more testing is needed to safely bring this technology into a clinical setting for human use. But as he states in a Wake Forest press release, the ITOP brings 3D bioprinting a step closer to reality:

“This novel tissue and organ printer is an important advance in our quest to make replacement tissue for patients. It can fabricate stable, human-scale tissue of any shape. With further development, this technology could potentially be used to print living tissue and organ structures for surgical implantation.”

 

 

Body’s own Healing Powers Could be Harnessed to Regrow Muscle, Wake Forest Study Finds

Imagine being able to repair muscle that had been damaged in an injury, not by transplanting new muscle or even by transplanting cells, but rather simply by laying the necessary groundwork—and letting the body do the rest.

The ability for the human body to regenerate tissues lost to injury or disease may still be closer to science fiction than reality, but scientists at the Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, have gotten us one big step closer.

Reporting in the latest issue of the journal Acta Biomaterialia, Dr. Sang Jin Lee and his research team describe their ingenious new method for regrowing damaged muscle tissue in laboratory rodents—by supercharging the body’s own natural restorative abilities. As Lee explained in a news release:

“Working to leverage the body’s own regenerative properties, we designed a muscle-specific scaffolding system that can actively participate in functional tissue regeneration. This is a proof-of-concept study that we hope can one day be applied to human patients.”

Normally, the body’s muscles—as well as the majority of organs—sit atop a biological ‘scaffold’ created by a matrix of molecules secreted by surrounding cells. This scaffold gives the organs and muscle their three-dimensional structure.

Scientists have identified a protein that may help spur 'in body' muscle regeneration.

Scientists have identified a protein that may help spur ‘in body’ muscle regeneration.

As of right now, if doctors want to replace damaged muscle they have one of two options: either surgically transfer a muscle segment from one part of the body to the other, or engineer replacement muscle tissue in the lab from a biopsy. Both methods, while doable, are not ideal. In the first, you are reducing the strength of the donor muscle; in the second, you have the added challenge of standardizing the engineered cells so that they will graft successfully.

So, Lee and his team focused on a third way: coaxing the body’s own supply of adult stem cells—which are tissue specific and normally used for general small-scale maintenance—to rebuild the damaged muscle from within. Said Lee:

“Our aim was to bypass the challenges of both of these techniques and to demonstrate the mobilization of muscle cells to a target-specific site for muscle regeneration.”

In this study, the researchers developed a method to do just that in the laboratory animals. First, they implanted a new cellular scaffold into the rodents’ legs. After several weeks, they removed the scaffold to see whether any cells had latched on of their own accord.

Interestingly, the team found that without any additional manipulation, the scaffold had developed a network of blood vessels within just four weeks after implanting. They also observed the presence of some early-stage muscle cells. What the researchers wanted to do next was find a way to boost what they already observed naturally.

To do so, they tested whether proteins—previously known to be involved in muscle development—could boost the speed and amount of recruitment of muscle stem cells to the scaffold.

After a series of experiments, they found a leading candidate: a protein called insulin-like growth factor 1, or IGF-1. And when they injected IGF-1 into the newly-implanted scaffolds the difference was remarkable. These scaffolds had about four times as many cells when compared to the plain scaffolds. As Lee explained:

“The protein effectively promoted cell recruitment and accelerated muscle regeneration.”

The real work now begins, added Lee, whose team will now take their research to larger animal models, such as pigs, to see whether their technique can work on a far grander scale.