BACKGROUND: During cardiogenesis, cardiac cells receive various stimuli, such as biomechanical and chemical cues, from the surrounding microenvironment, and these signals induce the maturation of heart cells. Mechanical force, especially tensile force in the heart, is one of the key stimuli that induce cardiomyocyte (CM) maturation through mechanotransduction, a process through which physical cues are transformed into biological responses. However, the effects and mechanisms of tensile force on cell maturation are poorly studied. METHODS: In this study, we developed a cyclic stretch system that mimics the mechanical environment of the heart by loading tensile force to human-induced pluripotent stem cell (hiPSC)-derived CMs. hiPSC-CMs cultured with the cyclic stretch system analyzed morphological change, immunofluorescent staining, expression of maturation markers in mRNA, and beating properties compared to static cultures. RESULTS: hiPSC-CMs cultured with the cyclic stretch system showed increased cell alignment, sarcomere length and expression of maturation markers in mRNA, such as TNNI3, MYL2 and TTN, compared to static cultures. Especially, the expression of genes related to nuclear mechanotransduction, such as Yap1, Lamin A/C, plectin, and desmin, was increased in the cyclically stretched hiPSC-CMs. Furthermore, the volume of the nucleus was increased by as much as 120% in the cyclic stretch group. CONCLUSION These results revealed that nuclear mechanotransduction induced by tensile force is involved in CM maturation. Together, these findings provide novel evidence suggesting that nuclear mechanotransduction induced by tensile force is involved in the regulation of cardiac maturation.

BACKGROUND: The interplay between neurogenesis and angiogenesis is crucial during the development mediated by neuro-angiogenic morphogens. In particular, the angiogenic activity of neuropeptides and their role in tissue regeneration have long been investigated for better understanding of their biological mechanisms and further applications. However, there have been few studies for direct comparison of angiogenic activities of neuropeptides for in vitro and in vivo models. In this study, we report that direct comparison of the angiogenic activities of neuropeptide Y, secretoneurin, and substance P (SP) immobilized on hydrogels in in vitro and in vivo experiments. METHODS: A hyaluronic acid-based hydrogel is prepared by utilizing acrylated hyaluronic acid and thiolated peptides as a crosslinker and angiogenic factors, respectively. Angiogenic activities of three neuropeptides are evaluated not only by in vitro angiogenic and gene expression assays, but also by an in vivo chronic myocardial infarction model. RESULTS: The comparison of in vitro angiogenic activities of three peptides demonstrates that the SP-immobilized hydrogel shows a higher degree of cell network formation and angiogenic-specific genes than those of the other peptides and the control case. In addition, a three-dimensional angiogenic assay illustrates that more sprouting is observable in the SP group. Evaluation of regenerative activity in the chronic myocardial infarction model reveals that all three peptideimmobilized hydrogels induce increased cardiac function as well as structural regeneration. Among all the cases, the SP group provided the highest regenerative activity both in vitro and in vivo. CONCLUSION: In our comparison study, the SP-immobilized hydrogel shows the highest angiogenic activity and tissue regeneration among the test groups. This result suggests that nerve regeneration factors help angiogenesis in damaged tissues, which also highlights the importance of the neuro-angiogenic peptides as an element of tissue regeneration.
Angiogenesis Inducing Agents ; Gene Expression ; Hyaluronic Acid ; Hydrogel ; Hydrogels ; In Vitro Techniques ; Myocardial Infarction* ; Nerve Regeneration ; Neurogenesis ; Neuropeptide Y* ; Neuropeptides* ; Peptides ; Regeneration ; Substance P*