**1. Introduction**

Tendinopathy is a common cause of recurring pain and long-term impairment in leisure and professional athletes, increased age being an additional risk factor. The prevalence of clinically manifest conditions in risk groups is high: in a cohort of football players, 21% suffered from Achilles tendon problems [1]. Moreover, even in clinically healthy volunteers, ultrasonographic evidence of Achilles tendon alterations was found in 16% [2]. This indicates that clinical manifestation is only the tip of the iceberg, the basis of which is a long-term interplay of inflammatory and degenerative changes.

Tendons have to withstand high mechanical loads and serve as an energy storage with elastic properties. The required biomechanical properties are provided by the extracellular matrix (ECM) [3], which is largely composed of hierarchically structured, cross-linked, and crimped collagen type I fibrils. The tenocytes, while representing only 5% of the tissue volume, maintain the ECM structure by constant remodeling. This normally enables biochemical and biomechanical adaptations to exercise [4]. Recurrent overuse impairs this physiological adaptation.

The onset of tendinopathy is currently understood as the result of a failed healing response to repeated tissue trauma. Microruptures, oxidative, mechanical, and heat stress activate resident cells and trigger a cascade of inflammation and degeneration, culminating in ECM deterioration. Key molecules involved include vascular endothelial growth factor (VEGF), interleukin (IL)-1, tumor necrosis factor (TNF)-α, prostaglandin (PG)E2, glutamate, and substance P [5, 6]. These mediators foster the ingrowth of blood vessels and nerves and the activation of nociceptive pathways. They are also implicated in the upregulation and activation of matrix metalloproteinases (MMP) and downregulation of their endogenous inhibitors (tissue inhibitors of matrix metalloproteinases; TIMP) [7]. This entails ECM degradation which successively alters and weakens the ECM structure [6]. When the accumulated damage and sensitization reach a threshold, clinical manifestation of tendinopathy comprises classical signs of inflammation including pain. Furthermore, provoked by new overload events, massive tissue trauma can occur. The resolution of inflammation is crucial to limit tissue damage, yet this mechanism often fails. Promoting fibrosis, a lack of pro-resolving signals, and persistence of macrophages entails the continuing activation of fibroblasts [8, 9]. Furthermore, macrophages could further contribute to ECM degradation via MMP secretion. Once at a diseased state, the intrinsic regenerative capacity of tendons is poor. Although endogenous mesenchymal stem-like cells with high tenogenic potential reside within tendons [10–12], these are susceptible to damage and suffer age-related changes [13, 14]. In pathological states, they could even contribute to fatty degeneration, fibrosis, and heterotopic ossifications [15, 16].

Treatment of tendinopathy still represents an unsolved challenge. Mainly, the use of strict rehabilitation exercise regimens is sufficiently evidence based [17, 18]. Anti-inflammatory drugs are frequently used, but they do not only counteract the active inflammation but also its resolution [19]. Biologicals such as platelet rich plasma have also received much attention, but clinical evidence is not convincing [17, 20, 21]. Research also focuses on the potential of endogenous tendon progenitor cells [22], which may be a promising strategy but will not be addressed in this review.

Multipotent mesenchymal stromal cells (MSCs) represent a therapeutic tool which might meet the clinical need of an adaptive treatment that simultaneously addresses different aspects of the disease. MSCs reside in virtually any tissue, in close proximity to the vasculature [23, 24]. MSCs derived from bone marrow and adipose tissue (BMSC and ASC, respectively) have been most extensively characterized [25, 26]. The fibroblast-like cells have been defined by a set of inclusion and exclusion antigens, their plastic-adherence, and trilineage differentiation potential in vitro [26]. While their differentiation potential into mesenchymal cell types, including tenocytes [27], has led to their extensive use in tissue engineering, it has become evident that their therapeutic potential by far exceeds cell replacement [24, 28]. While proof of MSC engraftment is often lacking, MSC-based cell therapy has shown beneficial effects in diverse scenarios in animal models, mostly mediated by immunomodulatory and trophic mechanisms [29–33]. Particularly, the immunomodulatory potential is extensively being researched and already exploited clinically, e.g., for treatment of graft-versus-host disease [34–36].

The use of MSC for tendon repair was first suggested in 1998 [37] and, interestingly, has been published as a case report on an equine patient as early as 2003 [38]. Since then, several experimental animal studies—the recent ones being reviewed here—and case series in equine patients [39–41] have raised hope that local implantation of MSC into acute tendon defects improves healing. However, translational progress into human orthopedics is underwhelming, and although equine patients are being treated and few first-in-man clinical trials have been performed or initiated [42–44], convincing evidence from randomized, controlled clinical studies has neither been obtained in equine nor in human patients so far [45]. This

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**Figure 1.** *In vitro models.*

*Mechanisms of Action of Multipotent Mesenchymal Stromal Cells in Tendon Disease*

focusing on MSC-based cell therapy using BMSC or ASC.

**2. Tendon regeneration and defect models**

**2.1 In vitro and ex vivo models**

other musculoskeletal tissues [95].

may in part be due to our still limited understanding of the MSC mechanisms of action in tendon healing, which delays the development of targeted treatment

The aim of this review was to collect the evidence for the different possible MSC mechanisms of action in the treatment of tendon disease. In vitro and in vivo studies published within the last 5 years were screened and their results were compiled,

In vitro and ex vivo models relevant to MSC mechanisms of action in tendon regeneration comprise two major groups, with some overlap (**Figure 1**). The first includes the wide range of models for tenogenic differentiation [10, 46–94]. Among these, approaches in three-dimensional dynamic cultures appear most representative for MSC mechanisms in vivo [57, 58, 64, 70, 74, 77, 79, 83, 84, 86, 87]. Typically assessed parameters following tenogenic differentiation include the expression of tenogenic transcription factors (scleraxis and, in the more recent studies, mohawk), the transmembrane glycoprotein tenomodulin, as well as the expression and deposition of extracellular matrix components (e.g., collagen I, collagen III, decorin, and tenascin-C) and biomechanical parameters in case of tissue engineered constructs. Upregulation of matrix components such as collagen I or tenascin-C and improved construct strength do not only suggest tenogenic differentiation but also indicate ECM-modulating activities of the MSC. However, it should be acknowledged that no truly specific tendon marker has yet been identified, and that only expression patterns of combined marker sets, e.g., collagen I, scleraxis, and tenascin-C, discriminate healthy tendon from diseased tendon or

The second group includes models investigating the interaction of MSC with tenocytes and/or the tendon ECM, using co-cultures of MSC and tenocytes, their respective conditioned media, or tendon explants [48, 69, 74, 75, 88, 91, 92, 94, 96–105].

*DOI: http://dx.doi.org/10.5772/intechopen.83745*

approaches.

may in part be due to our still limited understanding of the MSC mechanisms of action in tendon healing, which delays the development of targeted treatment approaches.

The aim of this review was to collect the evidence for the different possible MSC mechanisms of action in the treatment of tendon disease. In vitro and in vivo studies published within the last 5 years were screened and their results were compiled, focusing on MSC-based cell therapy using BMSC or ASC.
