Relationship of matrix stiffness and cell morphology in regulation of osteogenesis and adipogenesis of BMSCs.

BACKGROUNDS: Matrix stiffness has been found to regulate cell morphology, while both cell morphology and matrix stiffness are verified as important factors directing BMSCs (bone marrow mesenchymal stem cells) differentiation. This study aimed to investigate whether matrix stiffness depended on cell morphology to regulate osteogenesis and adipogenesis of BMSCs on 2D substrates. METHODS AND RESULTS: First, we seeded BMSCs on tissue culture plates (TCPs) with different fibronectin (FN) concentrations and cytoskeleton inhibitor cytochalasin D, and FN was found to promote cell spreading and osteogenesis while inhibiting adipogenesis of BMSCs through F-actin reorganization. Based on these, we modulated BMSCs morphology on 0.5 kPa and 32 kPa CytoSoft® substrates through FN. High concentration of FN (300 µg/ml) coated on 0.5 kPa substrates promoted cell spreading to similar levels with 32 kPa substrates coated with 100 µg/ml of FN, and cells in both groups dominantly commit osteogenesis. On the other hand, low FN concentration (30 µg/ml) on 32 kPa substrates induced restricted cell morphology similar with 0.5 kPa substrates coated with 100 µg/ml of FN, and cells in both groups mainly commit adipogenesis. Immunofluorescence indicated nuclear translocation and higher intensity of YAP/TAZ when cells spread to larger areas, regardless of matrix stiffness. However, when cell spreading areas were fixed as similar levels, matrix stiffness didn't significantly affect YAP/TAZ intensity or location. CONCLUSIONS: Matrix stiffness failed to regulate BMSCs differentiation and YAP/TAZ activity without corresponding cell morphology. Cell spreading area could mediate effects of matrix stiffness on osteogenesis and adipogenesis of BMSCs.

The role of nervous system in adaptive response of bone to mechanical loading.

Bone tissue is remodeled through the catabolic function of the osteoclasts and the anabolic function of the osteoblasts. The process of bone homeostasis and metabolism has been identified to be co-ordinated with several local and systemic factors, of which mechanical stimulation acts as an important regulator. Very recent studies have shown a mutual effect between bone and other organs, which means bone influences the activity of other organs and is also influenced by other organs and systems of the body, especially the nervous system. With the discovery of neuropeptide (calcitonin gene-related peptide, vasoactive intestinal peptide, substance P, and neuropeptide Y) and neurotransmitter in bone and the adrenergic receptor observed in osteoclasts and osteoblasts, the function of peripheral nervous system including sympathetic and sensor nerves in bone resorption and its reaction to on osteoclasts and osteoblasts under mechanical stimulus cannot be ignored. Taken together, bone tissue is not only the mechanical transmitter, but as well the receptor of neural system under mechanical loading. This review aims to summarize the relationship among bone, nervous system, and mechanotransduction.

Perspective into the regulation of cell-generated forces toward stem cell migration and differentiation.

Stem cells are promising candidates for cell-based therapies in diverse conditions including regenerating damaged tissues, treating inflammation in virtue of sepsis, acute renal failure, and cardiovascular disease. Advancement of these therapies relies on the ability to guide stem cells to migrate directly and differentiate towards specific cell phenotypes. During the past decade, many researchers have demonstrated that exogenous applied forces could significantly affect the migration and lineage differentiation of stem cells. Besides, recent advances have highlighted the critical role of internal forces due to cell-matrix interaction in the function of stem cells. Stem cells can generate contractile forces to sense the mechanical properties of cell-generated force microenvironment, and thereby perceive mechanical information that directs broad aspects of stem cell functions, including migration and lineage commitment. In the review, we recount the cell-generated force microenvironment of stem cells and discuss the interactions between cell-generated forces with migration and differentiation of stem cells. We also summarize key experimental evidence of a tight linkage between migration and lineage differentiation of stem cells and pose important unanswered questions in this field.

Nucleoskeletal stiffness regulates stem cell migration and differentiation through lamin A/C.

Stem cell-based tissue engineering provides a prospective strategy to bone tissue repair. Bone tissue repair begins at the recruitment and directional movement of stem cells, and ultimately achieved on the directional differentiation of stem cells. The migration and differentiation of stem cells are regulated by nucleoskeletal stiffness. Mechanical properties of lamin A/C contribute to the nucleoskeletal stiffness and consequently to the regulation of cell migration and differentiation. Nuclear lamin A/C determines cell migration through the regulation of nucleoskeletal stiffness and rigidity and involve in nuclear-cytoskeletal coupling. Moreover, lamin A/C is the essential core module regulating stem cell differentiation. The cells with higher migration ability tend to have enhanced differentiation potential, while the optimum amount of lamin A/C in migration and differentiation of MSCs is in conflict. This contrary phenomenon may be the result of mechanical microenvironment modulation.