Abstract
Tendon injuries represent a clinical challenge in regenerative medicine because their natural repair process is complex and inefficient. The high incidence of tendon injuries is frequently associated with sports practice, aging, tendinopathies, hypertension, diabetes mellitus, and the use of corticosteroids. The growing interest of scientists in using adipose-derived mesenchymal stem cells (ADMSC) in repair processes seems to be mostly due to their paracrine and immunomodulatory effects in stimulating specific cellular events. ADMSC activity can be influenced by GDF-5, which has been successfully used to drive tenogenic differentiation of ADMSC in vitro. Thus, we hypothesized that the application of ADMSC in isolation or in association with GDF-5 could improve Achilles tendon repair through the regulation of important remodeling genes expression. Lewis rats had tendons distributed in four groups: Transected (T), transected and treated with ADMSC (ASC) or GDF-5 (GDF5), or with both (ASC+GDF5). In the characterization of cells before application, ADMSC expressed the positive surface markers, CD90 (90%) and CD105 (95%), and the negative marker, CD45 (7%). ADMSC were also differentiated in chondrocytes, osteoblast, and adipocytes. On the 14th day after the tendon injury, GFP-ADMSC were observed in the transected region of tendons in the ASC and ASC+GDF5 groups, and exhibited and/or stimulated a similar genes expression profile when compared to the in vitro assay. ADMSC up-regulated Lox, Dcn, and Tgfb1 genes expression in comparison to T and ASC+GDF5 groups, which contributed to a lower proteoglycans arrangement, and to a higher collagen fiber organization and tendon biomechanics in the ASC group. The application of ADMSC in association with GDF-5 down-regulated Dcn, Gdf5, Lox, Tgfb1, Mmp2, and Timp2 genes expression, which contributed to a lower hydroxyproline concentration, lower collagen fiber organization, and to an improvement of the rats’ gait 24 h after the injury. In conclusion, although the literature describes the benefic effect of GDF-5 for the tendon healing process, our results show that its application, isolated or associated with ADMSC, cannot improve the repair process of partial transected tendons, indicating the higher effectiveness of the application of ADMSC in injured Achilles tendons. Our results show that the application of ADMSC in injured Achilles tendons was more effective in relation to its association with GDF-5.
Highlights
Tendon injuries are very common and their natural repair process is extremely slow, complex, and inefficient due to their intrinsic hypocellularity and hypovascularity, representing a clinical challenge to orthopedists mainly because these injuries often respond poorly to treatment [1].As reviewed by Zabrzyński et al [2], the occurrence of tendon injuries is associated with sports, aging, tendinophaties, hypothyroidism, hypertension, diabetes mellitus, arthropathies, corticosteroids, vitamin C deficiency, and others
adipose-derived mesenchymal stem cells (ADMSC) have been proposed as a new treatment to improve this repair process due to its multipotency, cultivation facility, high yield, and, because they originate from adult donors, lack of ethical issues
ADMSC differentiated in chondrocytes, osteoblasts, and adipocytes, showing multilineage differentiation
Summary
Tendon injuries are very common and their natural repair process is extremely slow, complex, and inefficient due to their intrinsic hypocellularity and hypovascularity, representing a clinical challenge to orthopedists mainly because these injuries often respond poorly to treatment [1].As reviewed by Zabrzyński et al [2], the occurrence of tendon injuries is associated with sports, aging, tendinophaties, hypothyroidism, hypertension, diabetes mellitus, arthropathies, corticosteroids, vitamin C deficiency, and others. Collagen fibers are the main component of the abundant extracellular matrix (ECM) of tendons, and with the proteoglycans (PG), the collagen fibers form a highly organized supramolecular structure, able to attend to the biomechanical demands on the tissue [3,4]. Small leucine-rich proteoglycans (SLRPs), such as decorin, fibromodulim, and biglycan, are the most abundant PG in tendons, with decorin representing 80% of the total proteoglycan content of the tissue [5]. Besides the parallel bundles of predominantly type I collagen fibers and PG, non-collagenous glycoproteins, matrix metalloproteinases (MMP), growth factors, and cells comprise elements of the tendons [5,7,8,9]
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