Alayna E. Loiselle, PhD, was awarded the 2022 Kappa Delta Young Investigator Award for her research on the cell biology of tendons and how different cells contribute to the tendon healing process.
The award recognizes outstanding clinical research related to musculoskeletal disease or injury by investigators younger than 40 years.
In 2015, Dr. Loiselle established the Loiselle Lab for Tendon Therapeutics in the Center for Musculoskeletal Research at the University of Rochester Medical Center in Rochester, N.Y., to study tendon function and healing to identify promising therapies. Since then, Dr. Loiselle’s research in the lab has focused on identifying potential therapeutics through the development of mouse models that advance the understanding of how tendon heals.
Acute tendon injuries are very common, with approximately 300,000 surgical tendon repairs per year in the United States. However, tendons are prone to heal with scar tissue, restricting tendon movement and restoration of mechanical properties. Once injured, a tendon never fully recovers, leaving it at an increased risk of reinjury. Currently, there are no consensus biological or pharmacological approaches to improve tendon healing and function.
“Tendons are incredibly strong structures and are pretty resistant to damage until injured, when they respond with scar tissue, disrupting the healing process,” said Dr. Loiselle, associate professor in the Departments of Orthopaedics and Rehabilitation, Biomedical Engineering, and Pathology and Laboratory Medicine at the University of Rochester. “One area of focus in my lab has been to study the fundamentals, such as the cell composition of tendon at baseline, as well as how it changes under different conditions, such as injury. Once we understand the composition and structure of the cell environment, as well as how it changes in different contexts, then we can begin to make more informed, thoughtful decisions to test different therapies to improve the healing process.”
The importance of the cellular environment
When Dr. Loiselle started her independent laboratory, she discovered that testing different therapies to enhance tendon healing was hindered by a lack of understanding of the cellular environment throughout the healing process. As the team began to manipulate signaling pathways in tendon in vivo, it became clear that they needed to understand how different cell populations within tendon interacted. Their efforts then shifted to defining the cellular environments of tendon homeostasis, healing, and pathology to advise which translational therapies would be strong candidates.
After a tendon injury, the inflammatory phase begins and immune cells (e.g., neutrophils, macrophages) are recruited to the repair site. Immune cells are the prevalent cell population during acute inflammation, which is critical to the healing process. The process then moves into the proliferative/granulation tissue phase, characterized by disorganized outer scar tissue consisting of extracellular matrix (ECM; structural support cells that regulate cellular growth) and a highly organized inner bridge made up of tenocytes (a type of tendon cell) and collagen. Although inflammation and ECM synthesis are critical for proper healing, persistent inflammation and excess ECM synthesis lead to scarring, resulting in mechanical and functional deficits in tendon.
“One of the inherent challenges with tendons is that they’re primarily a matrix tissue,” said Dr. Loiselle. “In response to the injury, they make new extracellular matrix, but that matrix is not of a good enough quality, the composition isn’t quite right, or it’s not organized. Because the tendon is an elegant structure, it’s difficult for the cells to make that again from scratch, mainly because we’re not giving them the right cues.”
Cell roles in tendon healing
Scleraxis (Scx) is a transcription factor required for normal tendon development, and Scx-lineage cells are the predominant cell population in tendon. However, the relationship and potential overlap between Scx-lineage cells and other tendon cell populations were unclear. Dr. Loiselle and her team were able to identify four distinct cell populations within adult tendon during homeostasis: Scx+/ S100a4+ (51 percent of the total tendon cell population), Scx+/ S100a4- (17 percent), Scx-/ S100a4+ (20 percent), and Scx-/S100a4- (12 percent). This insight provided the first characterization of the cellular heterogeneity of adult tendon.
The presence of the S100a4 cell population in tendon was especially intriguing to Dr. Loiselle and her team, and they wanted to research its role in tendon healing further. Using mice studies, the team used S100a4+/- mice, finding that the tendons from the mice healed with improved range of motion and increased mechanical properties. The results were surprising, as other approaches that decrease scar formation are typically associated with diminished mechanical properties. The findings, along with other studies, established S100a4+/- as a novel model of mechanically superior regenerative healing that can be leveraged as a potential therapeutic target.
Impact of type II diabetes on tendon healing
Type II diabetes is a prevalent risk factor for the development of tendon pathology, which can lead to pain, reduced flexibility, and diminished range of motion. It can also alter tendon structure, with more pronounced changes associated with poorly controlled diabetes and the duration of the disease. The structural changes can lead to functional deficits, increased risk of tendon rupture, and disruption to the healing process. How diabetes drives this disruption to tendons and tendon healing has been unknown.
Dr. Loiselle and her team utilized mice studies to determine whether treating diabetic status could prevent progression of tendon pathology related to the disease. Mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity/type II diabetes and then were switched to a low-fat diet (LFD). The mice quickly became metabolically normal, with their body weight, fasting blood glucose, glucose tolerance, and body fat percentage mirroring nondiabetic controls. However, this did not prevent tendon pathology progression, as deficits in range of motion and mechanical properties were seen. Treating the systemic symptoms or resolving the status of type II diabetes was not enough to prevent tendon pathology from developing. Dr. Loiselle is exploring tendon-specific treatment approaches to treat tendon pathology.
“Type II diabetes causes issues with the tendon, both in the context of injury as well as day-to-day tendon homeostasis,” said Dr. Loiselle. “Diabetic patients have tendons that aren’t able to move as well, are stiffer, more prone to injury, and have a healing response that is worse; however, we don’t have a great idea of why this happens. Understanding how comorbidities, like type II diabetes, disrupt the homeostatic state of the tendon and influence the overall healing capacity is really important in managing these injuries and potentially preventing them in patients.”
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