Mechanisms of Strain-Mediated Mesenchymal Stem Cell Apoptosis

Abstract

Mechanical conditioning of mesenchymal stem cells (MSCs) has been adopted widely as a biophysical signal to aid tissue engineering applications. The replication of in vivo mechanical signaling has been used in in vitro environments to regulate cell differentiation, and extracellular matrix synthesis, so that both the chemical and mechanical properties of the tissue-engineered construct are compatible with the implant site. While research in these areas contributes to tissue engineering, the effects of mechanical strain on MSC apoptosis remain poorly defined. To evaluate the effects of uniaxial cyclic tensile strain on MSC apoptosis and to investigate mechanotransduction associated with strain-mediated cell death, MSCs seeded on a 2D silicone membrane were stimulated by a range of strain magnitudes for 3 days. Mechanotransduction was investigated using the stretch-activated cation channel blocker gadolinium chloride, the L-type voltage-activated calcium channel blocker nicardipine, the c-jun NH(2)-terminal kinase (JNK) blocker D-JNK inhibitor 1, and the calpain inhibitor MDL 28170. Apoptosis was assessed through DNA fragmentation using the terminal deoxynucleotidyl transferase mediated-UTP-end nick labeling method. Results demonstrated that tensile strains of 7.5% or greater induce apoptosis in MSCs. L-type voltage-activated calcium channels coupled mechanical stress to activation of calpain and JNK, which lead to apoptosis through DNA fragmentation. The definition of the in vitro boundary conditions for tensile strain and MSCs along with a proposed mechanism for apoptosis induced by mechanical events positively contributes to the development of MSC biology, bioreactor design for tissue engineering, and development of computational methods for mechanobiology.

Numerical modeling of cell differentiation and proliferation in force-induced substrates via encapsulated magnetic nanoparticles

“…This refers to distinguishing between their original tissue, the magnitude and duration of the mechanical signal received by the cell and the degree of preconditioning. Besides, experiments show that cell apoptosis may occur because of the deformation threshold which is durable for a typical cell [22,31]. Experimental observations by Kearney et al [31] indicate that tensile strain induced on MSCs mediates cell apoptosis.…”

“…Besides, experiments show that cell apoptosis may occur because of the deformation threshold which is durable for a typical cell [22,31]. Experimental observations by Kearney et al [31] indicate that tensile strain induced on MSCs mediates cell apoptosis. For instance, the findings of Gladman et al [22] indicate that, depending on the duration of the imposed strain, injury beyond 20% of the tensile cyclic strain leads to significant neuronal cell death.…”

“…Cells may respond to the mechanical properties of their ECM, such as substrate stiffness, by differentiation, proliferation and/or apoptosis [22,23,31,67]. Experiments demonstrate that a specific deformation range sensed by a cell leads to a specific differentiation [10,34,69].…”

“…To avoid such abnormal conditions, cells have to be particularized in such a way as to differentiate or proliferate in response to appropriate biological stimuli. Experiments have shown that, besides other factors [58,59], the mechanical structure of cellular micro-environments plays an important role in cell differentiation and proliferation [22,23,31,67]. For instance, Mesenchymal Stem Cells (MSCs) differentiate into specific phenotypes with high sensitivity to the tissue rigidity where they reside in.…”

The role of mechanical signals in regulating chondrogenesis and osteogenesis of mesenchymal stem cells

“…Tensile strain can also regulate chondrogenic differentiation and glycosaminoglycan synthesis of MSCs embedded in collagen-GAG scaffolds . It has also been demonstrated that the application of tensile strains of 7.5% or greater induces apoptosis of MSCs seeded onto 2D silicone membranes (Kearney et al, 2008). Huang et al (2004) have demonstrated that mechanical signals induce chondrogenesis of bone-marrow derived MSCs as effectively as growth factor (TGF-β1) stimulation.…”