Cyclic Tensile Strain Can Play a Role in Directing both Intramembranous and Endochondral Ossification of Mesenchymal Stem Cells

Abstract

Successfully regenerating damaged or diseased bone and other joint tissues will require a detailed understanding of how joint specific environmental cues regulate the fate of progenitor cells that are recruited or delivered to the site of injury. The goal of this study was to explore the role of cyclic tensile strain (CTS) in regulating the initiation of mesenchymal stem cell/multipotent stromal cell (MSC) differentiation, and specifically their progression along the endochondral pathway. To this end, we first explored the influence of CTS on the differentiation of MSCs in the absence of any specific growth factor, and secondly, we examined the influence of the long-term application of this mechanical stimulus on markers of endochondral ossification in MSCs maintained in chondrogenic culture conditions. A custom bioreactor was developed to apply uniaxial tensile deformation to bone marrow-derived MSCs encapsulated within physiological relevant 3D fibrin hydrogels. Mechanical loading, applied in the absence of soluble differentiation factors, was found to enhance the expression of both tenogenic (COL1A1) and osteogenic markers (BMP2, RUNX2, and ALPL), while suppressing markers of adipogenesis. No evidence of chondrogenesis was observed, suggesting that CTS can play a role in initiating direct intramembranous ossification. During long-term culture in the presence of a chondrogenic growth factor, CTS was shown to induce MSC re-organization and alignment, increase proteoglycan and collagen production, and to enhance the expression of markers associated with endochondral ossification (BMP2, RUNX2, ALPL, OPN, and COL10A1) in a strain magnitude-dependent manner. Taken together, these findings indicate that tensile loading may play a key role in promoting both intramembranous and endochondral ossification of MSCs in a context-dependent manner. In both cases, this loading-induced promotion of osteogenesis was correlated with an increase in the expression of the osteogenic growth factor BMP2. The results of this study demonstrate the potent role that extrinsic mechanical loading plays in guiding stem cell fate, which must be carefully considered when designing cell and tissue-engineering therapies if they are to realize their clinical potential.

Mesenchymal Stem Cells: Cell Fate Decision to Osteoblast or Adipocyte and Application in Osteoporosis Treatment

“…The above inconsistent findings from vibration studies may be due to different vibration parameters (e.g., frequency, magnitude) and experimental design (e.g., treatment time, culture condition). Moreover, other types of mechanical stimuli, such as stretch/tensile strain [ 100 , 101 , 102 , 103 ], pressure/compressive stress [ 104 , 105 ], and shear stress [ 106 , 107 ], have also been studied in regulating MSCs differentiation and most show proosteoblastic and antiadipocytic differentiation roles. Although there are few contrary results, the above findings demonstrate that the mechanical loading promotes osteoblast differentiation and suppresses adipocyte differentiation of MSCs and may through activating ERK1/2, p38 MAPK signaling [ 92 , 99 , 101 , 103 , 104 ], or others.…”

Enthesis Tissue Engineering: Biological Requirements Meet at the Interface

“…For this purpose, bioreactors have been designed to spatially control biomechanical and physical signals to guide cell proliferation, differentiation and, ultimately, tissue formation [194][195][196][197][198], with the application of uniaxial tensile loads and dynamic compressive loading to emulate tendon and bone mechanophysiology, respectively. Using this concept, MSCs have been differentiated in several scaffolds under the influence of different biomechanical stimuli provided in bioreactors [199][200][201][202]. Several strategies have focused on the use of diffusingbased bioreactors to co-differentiate cells along a unique platform creating an interface [197,203,204], but, no studies are still available with the use of these dynamic plataforms Finer spatial control should also be focused to enhance knowledge on the effect of several chemical stimulus and, therefore, improving local cellular modulation and control.…”

A universal multi-platform 3D printed bioreactor chamber for tendon tissue engineering

“…Scleraxis was quickly upregulated being significantly more highly expressed after 24 h over unloaded controls, while tenascin, collagen I and collagen III were all significantly increased after 48 h, data which are supported by several other studies in response to 5% tensile strain. 22,56 We used conventional histological techniques to determine changes in cell alignment and protein production. H&E staining revealed that the tissue-engineered tendon cultured with dynamic 5% strain had a more visibly pronounced alignment and a greater abundance of cells and matrix at the surface than controls, supporting findings from previous studies.…”