Research Overview
Effects of treadmill running on aging tendon stem cells (TSCs)

Stem cells play a vital role in maintaining tissue integrity. In this study, we aimed to define the effects of aging and moderate exercise on tendon stem/progenitor cells (TSCs) using in vitro and in vivo models.There was an inverse relationship between age and cell proliferation as well gene expression of the stem cell markers It was found that moderate mechanical streatching in vitro increased the proliferation, stemness, and tenocyte-related gene expression in TSCs and mouse treadmill running in vivo decreased tendon degeneration by reducing lipid deposition, proteoglycan accumulation, and calcification. Based on this study, exercise such as moderate treadmill running could be used to slow down or prevent tendon degeneration due to aging.
KGN effects on tendon-bone healing

Tendon-bone junctions (TBJs) are frequently injured, especially in athletic settings. This study explored the feasibility of using kartogenin (KGN), a biocompound, to enhance the healing of injured TBJs. KGN enhanced cell proliferation in a concentration-dependent manner and induced chondrogenic differentiation in vitro. When injected into intact rat patellar tendons in vivo, KGN induced cartilage-like tissue formation in the injected area. As shown in the figure, when a tendon was injected with KGN, it caused the original patellar tendon tissue to become almost indistinguishable from the newly formed tissues. KGN could be a promising approach to augment and accelerate the formation of cartilage-like tissue in the tendon/bone interface.
Characterization of tendon structure, vascularity, and stem/progenitor cells

Tendon has a unique three compartment structure to function properly. The three parts, paratenon, intrafascicular matrix (IFM), and fascicles may be distinct with respect to their structure and cellular properties, and the way they contribute to tendon injury healing and repair. We performed a detailed characterization and comparison of three well-defined components of porcine Achilles tendon (PAT) in terms of their structural and cellular properties. We show that paratenon and IFM of PAT have loose structure with blood vessels, and they harbor similar stem/progenitor cells and collagen type IV, but fascicles composed mainly of collagen type I without apparent vascularity and stem cells.
The differentiation of TSCs in response to mechanical loading
Mechanical loading is an inherent part of tendon environment. This study focuses on determining the effect of mechanical loading on TSC differentiation. We found that the application of 4% stretching (or "clamp-to-clamp" engineering strain) to TSCs significantly increases cellular expression of collagen type I gene, but not PPAR-gamma (a marker for adipocytes), collagen type II, SOX-9 (two markers for chondrocytes), and Runx2 (marker for osteocytes). However, the application of 8% stretching to TSCs significantly increases expression of all tenocyte and non-tenocyte related genes. We postulate that excessive mechanical loading placed on tendons in vivo may cause the development of tendinopathy through loading-induced aberrant differentiation of TSCs into non-tenocytes.
The preventive effects of metformin on development of tendinopathy
Our group is interested in developing safe and effective therapeutic options for the treatment as well as the rehabilitation of the debilitating chronic tendinopathy. HIgh mobility group box (HMGB1), a potent inflammatory mediator, has been identified as a damage signaling protein for the development and progression of tendinopathy. By repurposing metformin (Met), the well-known diabetes drug and an inhibitor of HMGB1, as novel therapy via IP injection, our group was able to prevent the development of tendinopathy in a mouse model. The results of this study will help us develop a novel and effective local injection of Met (LIM) therapy to treat tendinopathy in clinics.
The role of HMGB1 in tendinopathy development
Tendons are highly prone to overuse injury or tendinopathy in military, athletic, and occupational settings. One of the main focuses of our research is the identification of inflammatory molecules that dive tendon inflammation and degeneration, hallmarks of tendinopathy. We have identified the ubiquitous protein high mobility group box1 (HMGB1), as a potent mediator of tendon inflammation and degeneration in a mouse model of tendon overuse injury induced by intensive treadmill running (ITR). Due to overuse or ITR, HMGB1 is released to the extracellular matrix initiating inflammatory and catabolic responses in tendon initiating the development of tendinopathy. Using IP injections of a natural food sweetener, glycyrrhizin (GL), an inhitor of HMGB1, we were able to block the development of tendinopathy in mice.