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*

Psoriasis is a common chronic inflammatory disease in which keratinocytes proliferate abnormally due to excessive immune action. Psoriasis can be associated with various comorbidities and has a significant impact on health-related quality of life. Although many systemic treatments, including biologic agents, have been developed, topical treatment remains the main option for psoriasis management. Consequently, there is an urgent need to develop topical treatments with minimal side effects and high efficacy. Mesenchymal stem cells (MSCs) exhibit excellent immune regulation, anti-inflammatory activities, and therapeutic effects, and MSC-derived extracellular vesicles (EVs) can serve as crucial mediators of functional transfer from MSCs. Therefore, this study aimed to develop a safe and easy-to-use emulsion cream for treating psoriasis using MSC conditioned media (CM) containing EVs. We developed an enhanced Wharton’s jelly MSC (WJ-MSC) culture method through a three-dimensional (3D) culture containing exogenous transforming growth factor-β3. Using the 3D culture system, we obtained CM from WJ-MSCs, which yielded a higher EV production compared to that of conventional WJ-MSC culture methods, and investigated the effect of EV-enriched 3D-WJMSC-CM cream on psoriasis-related inflammation. Administration of the EV-enriched 3D-WJ-MSC-CM cream significantly reduced erythema, thickness, and scaling of skin lesions, alleviated imiquimod-induced psoriasiform lesions in mice, and ameliorated histopathological changes in mouse skin. The upregulated mRNA expression of inflammatory cytokines, including IL-17a, IL-22, IL-23, and IL-36, decreased in the lesions. In conclusion, we present here a new topical treatment for psoriasis using an MSC EV-enriched cream.

Psoriasis is a common chronic inflammatory disease in which keratinocytes proliferate abnormally due to excessive immune action. Psoriasis can be associated with various comorbidities and has a significant impact on health-related quality of life. Although many systemic treatments, including biologic agents, have been developed, topical treatment remains the main option for psoriasis management. Consequently, there is an urgent need to develop topical treatments with minimal side effects and high efficacy. Mesenchymal stem cells (MSCs) exhibit excellent immune regulation, anti-inflammatory activities, and therapeutic effects, and MSC-derived extracellular vesicles (EVs) can serve as crucial mediators of functional transfer from MSCs. Therefore, this study aimed to develop a safe and easy-to-use emulsion cream for treating psoriasis using MSC conditioned media (CM) containing EVs. We developed an enhanced Wharton’s jelly MSC (WJ-MSC) culture method through a three-dimensional (3D) culture containing exogenous transforming growth factor-β3. Using the 3D culture system, we obtained CM from WJ-MSCs, which yielded a higher EV production compared to that of conventional WJ-MSC culture methods, and investigated the effect of EV-enriched 3D-WJMSC-CM cream on psoriasis-related inflammation. Administration of the EV-enriched 3D-WJ-MSC-CM cream significantly reduced erythema, thickness, and scaling of skin lesions, alleviated imiquimod-induced psoriasiform lesions in mice, and ameliorated histopathological changes in mouse skin. The upregulated mRNA expression of inflammatory cytokines, including IL-17a, IL-22, IL-23, and IL-36, decreased in the lesions. In conclusion, we present here a new topical treatment for psoriasis using an MSC EV-enriched cream.

Psoriasis is a common chronic inflammatory disease in which keratinocytes proliferate abnormally due to excessive immune action. Psoriasis can be associated with various comorbidities and has a significant impact on health-related quality of life. Although many systemic treatments, including biologic agents, have been developed, topical treatment remains the main option for psoriasis management. Consequently, there is an urgent need to develop topical treatments with minimal side effects and high efficacy. Mesenchymal stem cells (MSCs) exhibit excellent immune regulation, anti-inflammatory activities, and therapeutic effects, and MSC-derived extracellular vesicles (EVs) can serve as crucial mediators of functional transfer from MSCs. Therefore, this study aimed to develop a safe and easy-to-use emulsion cream for treating psoriasis using MSC conditioned media (CM) containing EVs. We developed an enhanced Wharton’s jelly MSC (WJ-MSC) culture method through a three-dimensional (3D) culture containing exogenous transforming growth factor-β3. Using the 3D culture system, we obtained CM from WJ-MSCs, which yielded a higher EV production compared to that of conventional WJ-MSC culture methods, and investigated the effect of EV-enriched 3D-WJMSC-CM cream on psoriasis-related inflammation. Administration of the EV-enriched 3D-WJ-MSC-CM cream significantly reduced erythema, thickness, and scaling of skin lesions, alleviated imiquimod-induced psoriasiform lesions in mice, and ameliorated histopathological changes in mouse skin. The upregulated mRNA expression of inflammatory cytokines, including IL-17a, IL-22, IL-23, and IL-36, decreased in the lesions. In conclusion, we present here a new topical treatment for psoriasis using an MSC EV-enriched cream.