**4. Extracellular matrix modulation**

The restoration of the ECM architecture and functionality is a major goal in regenerative tendon therapies. Based on the early hypothesis of MSC engraftment and tenogenic differentiation, it was assumed that the differentiated cells would subsequently synthesize new tendon ECM. Indeed, MSCs are capable to synthesize a considerable amount of extracellular matrix even in an undifferentiated state [160]. Furthermore, the composition of the ECM synthesized by differentiated MSC reflects the respective tissue lineage, which is well-established for their chondrogenic or osteogenic differentiation. Corresponding in vitro data exist for the differentiation into the tenogenic lineage, although not always consistent between studies. There is also in vivo evidence that MSC transplantation improves tendon ECM structure. However, this is not necessarily due to ECM synthesis by the MSC themselves but might also be a consequence of protective and stimulatory effects on

**77**

highly targeted manner.

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

tenocytes, which in turn might be capable to synthesize the new ECM. Moreover, importantly, there is not simply a lack of ECM in tendinopathy but rather a dysfunctional ECM composition and structure, due to the imbalance of remodeling activities. Particularly, in later stages of the disease, chondroid degeneration and fibrosis impair ECM functionality, thus effective ECM regeneration would also comprise its remodeling and the restoration of physiological remodeling activity within the

As most tenogenic differentiation studies investigated the expression and/ or deposition of tendon-specific extracellular matrix molecules as a marker for successful differentiation, there is quite extensive evidence that the ECM synthesis by MSC is altered during tenogenic differentiation. However, there is some discrepancy between different studies as to whether the ECM molecule expression pattern of tenogenic MSC truly corresponds to that of healthy tendon

Collagen I, the most abundant protein in healthy tendons, was shown to be upregulated by ectopic mohawk or scleraxis expression [52], in response to treatment with TGF-β superfamily growth factors [60, 67, 88, 93] or scaffold stiffness and alignment [61–63, 74, 81], as well as in three-dimensional dynamic cultures with uniaxial cyclic loading [58, 64, 77, 87]. Furthermore, co-culture with tenocytes in hypoxic conditions or integration of integrin-binding peptides in the scaffold increased collagen I expression on mRNA as well as protein level [69, 72]. However, in other studies, no collagen I upregulation was observed in response to growth factors such as TGF-β [49] or cyclic loading in two-dimensional ASC or BMSC cultures, respectively [66]. Data are particularly conflicting with regard to whether the presence of tendon ECM components promotes or counteracts collagen I expression [46, 47, 58, 64, 65, 83, 84, 88]. Furthermore, even if collagen I is upregulated, which would enable the MSC to contribute to tendon ECM synthesis, this often occurs in conjunction with the upregulation of other extracellular matrix molecules, such as collagen III, decorin, tenascin-C, or cartilage oligomeric matrix protein [60, 61, 69, 70, 72, 74, 77, 83]. While these molecules are important components of native tendon ECM, contributing to collagen organization and fibrillogenesis, their increased presence is also indicative of tendon degeneration or fibrosis [161–163]. Therefore, in order to achieve a beneficial ECM replacement by MSC, their ECM synthesis would have to be highly balanced. It is not yet sufficiently proven that this can be achieved by

With respect to the hypothesis of active ECM remodeling by MSC, comparatively few data exist so far. Treatment with BMP-12 induced an enhanced secretion of MMP-1 and -8 by ASC [93]. Similarly, ASC culture in collagen scaffolds increased MMP-1, -2, -8, -9, and -13 gene expression and MMP activity compared to two-dimensional culture [46]. For tendon-derived stem cells, it was also found that cyclic mechanical loading did not only upregulate ECM-related genes but also the integrins α1, -α2, and -α11, as well as MMP-9, -13, and -14 [164]. Thus, tenogenic stimuli may increase expression and activation of MMP by MSC. Furthermore, it was found that BMSC inhibits MMP activity in the cell culture medium through secretion of TIMP-1 and TIMP-2, even in an inflammatory environment [165], but that BMSC as well as ASC accumulate active MMP at their cell surface [166]. Although these latter two studies did not focus on tendon therapies, they suggest that MSCs could contribute to matrix remodeling in a

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

tendon.

tissue.

**4.1 In vitro evidence**

inducing tenogenic differentiation.

tenocytes, which in turn might be capable to synthesize the new ECM. Moreover, importantly, there is not simply a lack of ECM in tendinopathy but rather a dysfunctional ECM composition and structure, due to the imbalance of remodeling activities. Particularly, in later stages of the disease, chondroid degeneration and fibrosis impair ECM functionality, thus effective ECM regeneration would also comprise its remodeling and the restoration of physiological remodeling activity within the tendon.
