Vitamin C Improves Therapeutic Effects of Adipose-derived Stem Cell Transplantation in Mouse Tendonitis Model

Abstract

Abstract. Background Tendons are tough bands of dense and fibrous regular connective tissue that usually connect muscle to bone and are capable of withstanding tension (1). Tendons comprise of collagen bundles similar to those seen in ligaments (1).Tendinopathy is the most frequent tendon disorder (2-4) and is usually described as an over-use of tendons (5). Tendinopathy can develop in any tendon, but is most frequently found in the following tendons: Achilles, patellar, shoulder rotator cuff, and forearm extensor tendons (6). Tendonitis, a type of tendinopathy, is an inflammatory process in the tendon (5). Tendonitis often occurs in daily life and through sports, but tendon repair requires a long period of time because tendons have a low blood supply compared with other organs (7).Many challenging therapies, such as the use of nonsteroidal anti-inflammatory medications, eccentric exercises, topical glyceryl trinitrate, and shock-wave therapy, are performed to treat tendinopathy (8-11). Cell therapy is a new type of therapy for tendinopathy that occurs after tendon injury (12, 13). Recently, mesenchymal stem cell therapy, especially that using adipose-derived stem cells (ASCs), has emerged as a new therapeutic option for tendinopathy (14-16).Vitamin C is known to be a potent antioxidant (17) and can increase the viability of transplanted cells by reducing oxidative and inflammatory stress. Previous studies have revealed that vitamin C promoted tendon healing by stimulating extracellular matrix remodeling as a precursor of collagen synthesis (18,19). In addition, vitamin C increased the therapeutic effects of combination stem cell therapy in a muscle laceration model (20). However, there has been no study as far as we are aware on the therapeutic effects of combination stem cell therapy and vitamin C administration on tendinopathy.We hypothesized that combined therapy using ASCs and vitamin C might improve tendon regeneration in tendinopathy. To determine the combined effects of ASCs transplantation with vitamin C, we used senescence marker protein 30 (Smp30)-knockout mice that cannot biosynthesize vitamin C by themselves (21). 343

Combined ascorbic acid and T3 produce better healing compared to bone marrow mesenchymal stem cells in an Achilles tendon injury rat model: a proof of concept study

“…Our results do not confirm the findings of previous studies regarding the use of AA in combination with MSCs [39, 46]. This is likely because of the different methodology and different model used and the different source of the stem cells.…”

“…Ascorbic acid stimulates a wide range of tissue functions; it contributes not only to increased collagen synthesis and cross-linking, but also plays key roles in stem cell function, such as in the differentiation of mesenchymal stem cells into tenocytes [37, 38]. Supplementation with ascorbic acid also enhances tendon healing in mouse models [39]. Moreover, thyroid hormones are major determinants of tissue function, playing well-defined roles in cell signaling.…”

“…This is likely because of the different methodology and different model used and the different source of the stem cells. Kang et al used AA to stimulate MSCs before transplantation in a mouse tendonitis model, using adipose-derived cells [39]. Durant et al used an in vitro model employing tendon-derived stem cells, which may have had some bearing on the results obtained [46].…”

In Vitro Induction of Tendon-Specific Markers in Tendon Cells, Adipose- and Bone Marrow-Derived Stem Cells is Dependent on TGFβ3, BMP-12 and Ascorbic Acid Stimulation

“…As confirmation of the importance of ascorbic acid, we observed the complete loss of tendon matrix marker expression in all cell types cultured in the absence of ascorbic acid and b-FGF. Moreover, an in vivo study recently demonstrated superior tendon healing when AA was used in combination with ASCs versus ASCs alone [20]. Further studies should investigate the individual contributions of CTGF, AA and b-FGF in the production of tendon-like ECM.…”

“…However, the direct use of BMSCs at the target site in vivo can lead to the formation of ectopic bone or cartilage, and the biomechanical strength of repaired tendons is often unsatisfactory [12,15,16]. Similarly, ASCs have shown promising results in the enhancement of tendon repair and regeneration in different animal models [17,18,19,20], but effective strategies to prevent their commitment towards adipogenic differentiation remain to be fully investigated [21].…”