‘By introducing specific gene proteins to the cells, they become different cells. With this in mind, we can genetically engineer new skeletal tissue – ligaments, cartilage, tendons.’It’s a moment that every athlete fears – when they get the news that they have a career-threatening ligament or tendon tear. And it’s not just the pros. Millions of Americans play tennis, jog, or join pickup softball or basketball games every day without proper stretching, resulting in similar injuries.
Over 200,000 Americans undergo tendon or ligament repair each year, usually consisting of tissue grafting and synthetic prostheses, but rarely offering a full pre-injury recovery or a long-term solution. With tendon and ligament injuries presenting a major clinical challenge to orthopedic medicine, Israeli researchers at the Hebrew University of Jerusalem are using adult stem cells to provide new hope for both patients and doctors.
In studies conducted on rats, the researchers at the Skeletal Biotechnology Laboratory at the university’s Faculty of Dental Medicine have successfully used adult stem cells to form new tendon or ligament tissue. This novel approach for tendon regeneration was reported in the April issue of the Journal of Clinical Investigation.
“What we’re doing is using adult stem cells taken from the bone marrow and genetically engineering them. By introducing specific gene proteins to the cells, they become different cells. With this in mind, we can genetically engineer new skeletal tissue – ligaments, cartilage, tendons,” said Dr. Gadi Pelled, a senior scientist in the lab, who worked together with team leader Prof. Dan Gazit.
“What happens in tendons and ligaments when there is a partial tear, is that they don’t regenerate by themselves – they form scar tissue, which is less elastic and doesn’t provide as much functionality,” Pelled told ISRAEL21c.
“Of course in a complete tear, it doesn’t heal at all. Either the patient becomes disabled, or there are a number of sub-optimal procedures. Orthopedic surgeons are therefore looking for an alternative.”
Pelled and the HU team began their attempts to find that alternative by taking mesenchymal stem cells (MSCs), which reside in the bone marrow and fat tissues, and injecting two proteins called Smad8 and BMP2.
According to Pelled, the fortified cells were then implanted into the torn Achilles tendons of rats. The researchers found that the cells not only survived the implantation process, but also were recruited to the site of the injury and were able to repair the tendon.
“There was complete healing in seven weeks – which is very quick,” said Pelled.
The cells also changed their appearance to look more like tendon cells (tenocytes), and significantly increased production of collagen, a protein critical for creating strong yet flexible tendons and ligaments.
Tendon tissue repair was detected using a special type of imaging known as proton DQF MRI, developed by Prof. Gil Navon at Tel Aviv University, which recognizes differences among collagen-containing tissue such as tendon, bone, skin, and muscle.
“The imaging emits a white symbol which identifies whether the new cells generated are tendons or not,” said Pelled.
The two proteins – BMP and Smad – are involved in other tissues, including nerve and liver tissue, suggesting that this type of delivery technology may be helpful for other degenerative diseases, according to the researchers.
The research could also affect injuries to the invertbrate disc, which, according to Pelled, “consists of in large part a tendon that deteriorates over time, and results in a large segment of the population suffering from lower back pain.”
“Our next step will be to conduct the tests on large animals. For tendons and ligaments, goats are the best subjects,” said Pelled, adding that pigs would be used for tests on the invertebrate disc.
He explained that the research has grown out of clinical trials currently being conducted on humans in collaboration with the Hadassah Medical Center and pharmaceutical giant Teva on the subject of bone regeneration using the same adult stem cells.
“It’s using the same original cells as our ligament study. But the nice thing about this is that depending on the protein that you introduce, it creates different tissue,” said Pelled. “For example, if you’re attempting to generate new tendon tissue, you wouldn’t want bone tissue to be formed, so that determines which protein you introduce.”
The HU tendon and ligament regeneration study has been acclaimed by peers. In an accompanying commentary in the journal, Dwight A. Towler and Richard Gelberman from the Washington University School of Medicine in St. Louis, Missouri, state, “Given our limited understanding of how MSCs become tenocytes, the recent progress demonstrated in these studies is quite remarkable and may be potentially useful in cell-based therapeutic approaches to musculoskeletal injuries.”
The study was supported by GENOSTEM, an integrated project of the European Union for the engineering of mesenchymal stem cells in connective tissue disorders.