A ‘living bandage’ made from stem cells, which could revolutionise the treatment and prognosis of a common sporting knee injury, has been trialled in humans for the first time by scientists at the Universities of Liverpool and Bristol.
Meniscal tears are suffered by over one million people a year in the US and Europe alone and are particularly common in contact sports like football and rugby. 90% or more of tears occur in the white zone of meniscus which lacks a blood supply, making them difficult to repair. Many professional sports players opt to have the torn tissue removed altogether, risking osteoarthritis in later life.
The Cell Bandage has been developed by spin-out company Azellon, and is designed to enable the meniscal tear to repair itself by encouraging cell growth in the affected tissue.
A prototype version of the Cell Bandage was trialled in five patients, aged between 18 and 45, with white-zone meniscal tears. The trial received funding support from Innovate UK and the promising results have been published today in the journal Stem Cells Translational Medicine.
The procedure involved taking stem cells, harvested from the patient’s own bone marrow, which were then grown for two weeks before being seeded onto a membrane scaffold that helps to deliver the cells into the injured site. The manufactured Cell Bandage was then surgically implanted into the middle of the tear and the cartilage was sewn up around the bandage to keep it in place.
All five patients had an intact meniscus 12 months post implantation. By 24 months, three of the five patients retained an intact meniscus and had returned to normal knee functionality whilst the other two patients required surgical removal of the damaged meniscus due to a new tear or return of symptoms.
Professor Anthony Hollander, Chair of Stem Cell Biology at the University of Liverpool and Founder and Chief Scientific Officer of Azellon, said: “The Cell Bandage trial results are very encouraging and offer a potential alternative to surgical removal that will repair the damaged tissue and restore full knee function.
“We are currently developing an enhanced version of the Cell Bandage using donor stem cells, which will reduce the cost of the procedure and remove the need for two operations.”
The Cell Bandage was produced by the Advanced Therapies Unit at the NHS Blood & Transplant facility in Speke, Liverpool and implanted into patients at Southmead Hospital in Bristol, under the supervision of Professor Ashley Blom, Head of Orthopaedic Surgery at the University of Bristol.
Professor Blom commented: “The Cell Bandage offers an exciting potential new treatment option for surgeons that could particularly benefit younger patients and athletes by reducing the likelihood of early onset osteoarthritis after meniscectomy.”
A spokesperson for Innovate UK said: “Turning stem cell research into clinical and commercial reality requires close collaboration between businesses, universities, and Hospitals. It’s great to see this inter-disciplinary approach has led to such an exciting outcome from this first-in-human trial.”
The paper ‘Repair of torn avascular meniscal cartilage using undifferentiated autologous mesenchymal stem cells: from in vitro optimisation to a first-in-human study is published in Stem Cells Translational Medicine.
Scientists from the McEwen Centre for Regenerative Medicine, University Health Network, have developed the first functional pacemaker cells from human stem cells, paving the way for alternate, biological pacemaker therapy.
Their findings, “Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker,” published online in Nature Biotechnology on Dec. 12, detail how human pluripotent stem cells can be coaxed in 21 days to develop into pacemaker cells, which regulate heart beats with electrical impulses. These human pacemaker cells were tested in rat hearts and were shown to function as a biological pacemaker, by activating the electrical impulses that trigger the contraction of the heart.
Pluripotent stem cells have the potential to differentiate into more than 200 different cell types that make up every tissue and organ in the body.
Sinoatrial node pacemaker cells are the heart’s primary pacemaker, controlling the heartbeat throughout life. Defects in the pacemaker can lead to heart rhythm disorders that are commonly treated by implantation of electronic pacemaker devices. Learning how to generate pacemaker cells could help in understanding disorders in pacemaker cells, and provide a cell source for developing a biological pacemaker. Biological pacemakers represent a promising alternative to electronic pacemakers, overcoming such drawbacks as a lack of hormonal responsiveness and the inability to adapt to changes in heart size in pediatric patients.
The researchers used a developmental-biology approach to establish a specific protocol for generating the pacemaker cells.
“What we are doing is human biology in a petri dish,” says Dr. Gordon Keller, Director of the McEwen Centre, the senior author, and a trailblazer in generating a wide variety of specialized cells from human stem cells. “We are replicating nature’s way of making the pacemaker cell.”
Based on previous findings in animal models, the researchers at the McEwen Centre tested and mapped out the specific developmental pathway of how human pluripotent stem cells become pacemaker cells. This was achieved by testing different signaling molecules at different times throughout the 21 days to guide the cells towards their goal.
“It’s tricky,” says Dr. Stephanie Protze, a post-doctoral fellow in the laboratory of Dr. Keller and the first author in the Nature paper. “You have to determine the right signaling molecules, at the right concentration, at the right time to stimulate the stem cells.”
Adds Dr. Keller, who is also a Professor in the Department of Medical Biophysics at the University of Toronto: “We understand the importance of precision in developmental biology in setting out the process by which organisms grow and develop. We use that same precision in the petri dish because we are replicating these same processes.”
Once the team established which signaling pathways are activated at different stages to generate the pacemaker cells, they demonstrated that the new pacemaker cells could initiate and regulate the heartbeat in rats.
The researchers noted that human clinical trials to test such biological pacemakers are from five to 10 years away, and that the next step is to launch safety and reliability pre-clinical trials on the pacemaker cells.
Meanwhile, researchers can use their new technology to make pacemaker cells from patients suffering from pacemaker dysfunction. They can then use these patient-specific cells to study the “disease in a (petri) dish” and to identify new drugs that will improve their pacemaker function.
Long term, the team hopes to develop a biological pacemaker to transplant into patients who need an electronic one. More than 10,000 electric pacemakers are implanted annually in Canada, with more than 120,000 patients living with them. They can last anywhere from five to 10 years or more – on the average about seven years. If successful, the biological pacemaker holds the promise of a lifelong cure.
Mechanisms underlying direct programming of stem cells could eventually lead to cell-replacement therapies
A team of scientists has uncovered details of the cellular mechanisms that control the direct programming of stem cells into motor neurons. The scientists analyzed changes that occur in the cells over the course of the reprogramming process. They discovered a dynamic, multi-step process in which multiple independent changes eventually converge to change the stem cells into motor neurons.
“There is a lot of interest in generating motor neurons to study basic developmental processes as well as human diseases like ALS and spinal muscular atrophy,” said Shaun Mahony, assistant professor of biochemistry and molecular biology at Penn State and one of the lead authors of the paper. “By detailing the mechanisms underlying the direct programing of motor neurons from stem cells, our study not only informs the study of motor neuron development and its associated diseases, but also informs our understanding of the direct programming process and may help with the development of techniques to generate other cell types.”
The direct programming technique could eventually be used to regenerate missing or damaged cells by converting other cell types into the missing one. The research findings, which appear online in the journal Cell Stem Cell on December 8, 2016, show the challenges facing current cell-replacement technology, but they also outline a potential pathway to the creation of more viable methods.
“Despite having a great therapeutic potential, direct programming is generally inefficient and doesn’t fully take into account molecular complexity,” said Esteban Mazzoni, an assistant professor in New York University’s Department of Biology and one of the lead authors of the study. “However, our findings point to possible new avenues for enhanced gene-therapy methods.”
The researchers had shown previously that they can transform mouse embryonic stem cells into motor neurons by expressing three transcription factors — genes that control the expression of other genes — in the stem cells. The transformation takes about two days. In order to better understand the cellular and genetic mechanisms responsible for the transformation, the researchers analyzed how the transcription factors bound to the genome, changes in gene expression, and modifications to chromatin at 6-hour intervals during the transformation.
“We have a very efficient system in which we can transform stem cells into motor neurons with something like a 90 to 95 percent success rate by adding the cocktail of transcription factors,” said Mahony. “Because of that efficiency, we were able to use our system to tease out the details of what actually happens in the cell during this transformation.”
“A cell in an embryo develops by passing through several intermediate stages,” noted Uwe Ohler, senior researcher at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin and one of the lead authors of the work. “But in direct programming we don’t have that: we replace the gene transcription network of the cell with a completely new one at once, without the progression through intermediate stages. We asked, what are the timing and kinetics of chromatin changes and transcription events that directly lead to the final cell fate?”
The research team found surprising complexity — programming of these stem cells into neurons is the result of two independent transcriptional processes that eventually converge. Early on in the process, two of the transcription factors — Isl1 and Lhx3 — work in tandem, binding to the genome and beginning a cascade of events including changes to chromatin structure and gene expression in the cells. The third transcription factor, Ngn2, acts independently making additional changes to gene expression. Later in the transformation process, Isl1 and Lhx3 rely on changes in the cell initiated by Ngn2 to help complete the transformation. In order for direct programming to successfully achieve cellular conversion, it must coordinate the activity of the two processes.
“Many have found direct programming to be a potentially attractive method as it can be performed either in vitro — outside of a living organism — or in vivo — inside the body and, importantly, at the site of cellular damage,” said Mazzoni. “However, questions remain about its viability to repair cells — especially given the complex nature of the biological process. Looking ahead, we think it’s reasonable to use this newly gained knowledge to, for instance, manipulate cells in the spinal cord to replace the neurons required for voluntary movement that are destroyed by afflictions such as ALS.”
Learn more: How to Make a Motor Neuron
By coating tiny gel beads with lung-derived stem cells and then allowing them to self-assemble into the shapes of the air sacs found in human lungs, researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have succeeded in creating three-dimensional lung “organoids.” The laboratory-grown lung-like tissue can be used to study diseases including idiopathic pulmonary fibrosis, which has traditionally been difficult to study using conventional methods.
“While we haven’t built a fully functional lung, we’ve been able to take lung cells and place them in the correct geometrical spacing and pattern to mimic a human lung,” said Dr. Brigitte Gomperts, an associate professor of pediatric hematology/oncology and the study’s lead author.
Idiopathic pulmonary fibrosis is a chronic lung disease characterized by scarring of the lungs. The scarring makes the lungs thick and stiff, which over time results in progressively worsening shortness of breath and lack of oxygen to the brain and vital organs. After diagnosis, most people with the disease live about three to five years. Though researchers do not know what causes idiopathic pulmonary fibrosis in all cases, for a small percentage of people it runs in their families. Additionally, cigarette smoking and exposure to certain types of dust can increase the risk of developing the disease.
To study the effect of genetic mutations or drugs on lung cells, researchers have previously relied on two-dimensional cultures of the cells. But when they take cells from people with idiopathic pulmonary fibrosis and grow them on these flat cultures, the cells appear healthy. “Scientists have really not been able to model lung scarring in a dish,” said Gomperts, who is a member of the UCLA Broad Stem Cell Research Center. The inability to model idiopathic pulmonary fibrosis in the laboratory makes it difficult to study the biology of the disease and design possible treatments.
Gomperts and her colleagues started with stem cells created using cells from adult lungs. They used those cells to coat sticky hydrogel beads, and then they partitioned these beads into small wells, each only 7 millimeters across. Inside each well, the lung cells grew around the beads, which linked them and formed an evenly distributed three-dimensional pattern. To show that these tiny organoids mimicked the structure of actual lungs, the researchers compared the lab-grown tissues with real sections of human lung.
“The technique is very simple,” said Dan Wilkinson, a graduate student in the department of materials science and engineering and the paper’s first author. “We can make thousands of reproducible pieces of tissue that resemble lung and contain patient-specific cells.”
Moreover, when Wilkinson and Gomperts added certain molecular factors to the 3-D cultures, the lungs developed scars similar to those seen in the lungs of people who have idiopathic pulmonary fibrosis, something that could not be accomplished using two-dimensional cultures of these cells.
Using the new lung organoids, researchers will be able to study the biological underpinnings of lung diseases including idiopathic pulmonary fibrosis, and also test possible treatments for the diseases. To study an individual’s disease, or what drugs might work best in their case, clinicians could collect cells from the person, turn them into stem cells, coax those stem cells to differentiate into lung cells, then use those cells in 3-D cultures. Because it’s so easy to create many tiny organoids at once, researchers could screen the effect of many drugs. “This is the basis for precision medicine and personalized treatments,” Gomperts said.
Technique uses 3-D weaving to grow a living hip replacement
With a goal of treating worn, arthritic hips without extensive surgery to replace them, scientists have programmed stem cells to grow new cartilage on a 3-D template shaped like the ball of a hip joint. What’s more, using gene therapy, they have activated the new cartilage to release anti-inflammatory molecules to fend off a return of arthritis.
The technique, demonstrated in a collaborative effort between Washington University School of Medicine in St. Louis and Cytex Therapeutics Inc. in Durham, N.C., is described July 18 in Proceedings of the National Academy of Sciences.
The discovery one day may provide an alternative to hip-replacement surgery, particularly in younger patients. Doctors are reluctant to perform such operations in patients under age 50 because prosthetic joints typically last for less than 20 years. A second joint-replacement surgery to remove a worn prosthetic can destroy bone and put patients at risk for infection.
“Replacing a failed prosthetic joint is a difficult surgery,” said Farshid Guilak, PhD, a professor of orthopedic surgery at Washington University. “We’ve developed a way to resurface an arthritic joint using a patient’s own stem cells to grow new cartilage, combined with gene therapy to release anti-inflammatory molecules to keep arthritis at bay. Our hope is to prevent, or at least delay, a standard metal and plastic prosthetic joint replacement.”
Scientists at the Gladstone Institutes have invented a new way to create three-dimensional human heart tissue from stem cells. The tissue can be used to model disease and test drugs, and it opens the door for a precision medicine approach to treating heart disease. Although there are existing techniques to make three-dimensional tissues from heart cells, the new method dramatically reduces the number of cells needed, making it an easier, cheaper, and more efficient system.
“We have bioengineered micro-scale heart tissues with a method that can easily be reproduced, which will enable scientists in stem cell biology and the drug industry to study heart cells in their proper context,” said first author Nathaniel Huebsch, PhD, a postdoctoral fellow in the Conklin lab at Gladstone. “In turn, this will enhance our ability to discover treatments for heart disease.”
Creating heart cells from induced pluripotent stem cells (iPSCs) that are derived from a patient’s skin cells enables scientists to study and test drugs on that patient’s specific disease. However, cells made from iPSCs are relatively immature, resembling heart cells in an embryo more than cells in an adult. As such, these cells are inadequate for drug testing because they do not properly predict how a drug will affect adult heart cells. Additionally, heart cells created from iPSCs are challenging to make and work with, so creating large quantities can be difficult. Therefore, the fewer cells needed, the better.
The micro heart muscle addresses both of these concerns.
Effectiveness of Gene Editing in Human Stem Cells Improves Tenfold Using New Technique
For the first time, researchers have employed a gene-editing technique involving low-dose irradiation to edit the genome of patient stem cells, according to a study published in the journal Stem Cells Translational Medicine. This method, developed by researchers in the Cedars-Sinai Board of Governors Regenerative Medicine Institute, is 10 times more effective than techniques currently in use.
“This novel technique allows for far more efficient gene editing of stem cells and will increase the speed of new discoveries in the field,” said co-senior author Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute.
The irradiation method could prove effective in learning more about diseases such as spinal muscular atrophy, muscular dystrophy and Huntington’s disease. Gene editing allows scientists to correct disease causing mutations and, theoretically, cure the disease in the petri dish. Additionally, gene-editing technology allows scientists to create disease mutations in normal cells, thus modeling human disease.