Hippo Pathway Effector Tead1 Induces Cardiac Fibroblast to Cardiomyocyte Reprogramming

Background The conversion of fibroblasts into induced cardiomyocytes may regenerate myocardial tissue from cardiac scar through in situ cell transdifferentiation. The efficiency transdifferentiation is low, especially for human cells. We explored the leveraging of Hippo pathway intermediates to enhance induced cardiomyocyte generation. Methods and Results We screened Hippo effectors Yap (yes‐associated protein), Taz (transcriptional activator binding domain), and Tead1 (TEA domain transcription factor 1; Td) for their reprogramming efficacy with cardio‐differentiating factors Gata4, Mef2C, and Tbx5 (GMT). Td induced nearly 3‐fold increased expression of cardiomyocyte marker cTnT (cardiac troponin T) by mouse embryonic and adult rat fibroblasts versus GMT administration alone ( P <0.0001), while Yap and Taz failed to enhance cTnT expression. Serial substitution demonstrated that Td replacement of TBX5 induced the greatest cTnT expression enhancement and sarcomere organization in rat fibroblasts treated with all GMT substitutions (GMTd versus GMT: 17±1.2% versus 5.4±0.3%, P <0.0001). Cell contractility (beating) was seen in 6% of GMTd‐treated cells by 4 weeks after treatment, whereas no beating GMT‐treated cells were observed. Human cardiac fibroblasts likewise demonstrated increased cTnT expression with GMTd versus GMT treatment (7.5±0.3% versus 3.0±0.3%, P <0.01). Mechanistically, GMTd administration increased expression of the trimethylated lysine 4 of histone 3 (H3K4me3) mark at the promoter regions of cardio‐differentiation genes and mitochondrial biogenesis regulator genes in rat and human fibroblast, compared with GMT. Conclusions These data suggest that the Hippo pathway intermediate Tead1 is an important regulator of cardiac reprogramming that increases the efficiency of maturate induced cardiomyocytes generation and may be a vital component of human cardiodifferentiation strategies.

Polyphenols’ Cardioprotective Potential: Review of Rat Fibroblasts as Well as Rat and Human Cardiomyocyte Cell Lines Research

According to the World Health Organization, cardiovascular diseases are responsible for 31% of global deaths. A reduction in mortality can be achieved by promoting a healthy lifestyle, developing prevention strategies, and developing new therapies. Polyphenols are present in food and drinks such as tea, cocoa, fruits, berries, and vegetables. These compounds have strong antioxidative properties, which might have a cardioprotective effect. The aim of this paper is to examine the potential of polyphenols in cardioprotective use based on in vitro human and rat cardiomyocytes as well as fibroblast research. Based on the papers discussed in this review, polyphenols have the potential for cardioprotective use due to their multilevel points of action which include, among others, anti-inflammatory, antioxidant, antithrombotic, and vasodilatory. Polyphenols may have potential use in new and effective preventions or therapies for cardiovascular diseases, yet more clinical studies are needed.

Synchronization of Fibroblasts Ex Vivo in Psychopharmacology

The central oscillator for the inner clock is the suprachiasmatic nuclei of the hypothalamus. Furthermore, many peripheral oscillators are present in tissues such as skin. Human derived fibroblasts provide an advantageous model to study circadian rhythmicity as well as the influence of pharmacological drugs on circadian gene expression. Importantly, the synchronization of the circadian system of fibroblasts can be done by different methods. The review presents an overview of the current knowledge of different synchronization methods mostly used in mice or rat fibroblasts. Furthermore, the review sums up and discusses the role of norepinephrine as a possible synchronizer agent.

In Vitro and In Vivo Comparison Study of Electrospun PLA and PLA/PVA/SA Fiber Membranes for Wound Healing

Wound dressings can accelerate wound healing. The degradable polymer poly(lactic acid) (PLA) shows good mechanical properties and biocompatibility. Sodium alginate (SA) holds good biocompatibility, hemostasis, and high hygroscopicity. Poly(vinyl alcohol) (PVA) has good spinnability as a pharmaceutical excipient. Herein, we carried out a comparison study of electrospun PLA and PLA/PVA/SA fiber membranes for wound healing in vitro and in vivo. In this study, PLA and PLA/PVA/SA nanofiber membranes were fabricated through electrospinning to produce a highly porous and large specific surface area that could promote wound healing. In vitro experiments showed that PLA and PLA/PVA/SA nanofiber membranes could all provide good support for the growth of rat fibroblasts (L929). Moreover, rat fibroblasts displayed slightly better adhesion and proliferation on PLA/PVA/SA than on the PLA fiber membranes. The in vivo potentiality of the PLA and PLA/PVA/SA fiber membranes was assessed in rat models of skin defects in which the PLA and PLA/PVA/SA fiber membranes significantly improved wound healing compared to commercially available gauzes. No significant differences in wound healing were observed between PLA and PLA/PVA/SA fiber membranes in our study. Furthermore, Masson staining and PCR displayed the PLA fiber membrane promoted protein deposition compared to the PLA/PVA/SA fiber membrane. In addition, IHC suggested that PLA/PVA/SA dressing reduced the inflammatory response during early wound healing compared to the PLA fiber membrane. These findings highlight the utility of fiber membranes as novel wound-healing dressings.

A New MicroRNA Cluster Involved in the Reprogramming to a Pluripotent State

Reprogramming of somatic cells to a pluripotent state is a complex, multistage process that is regulated by many factors. Among these factors, non-coding RNAs and microRNAs (miRNAs) have been intensively studied in recent years. MiRNAs play an important role in many processes, particularly in cell reprogramming. In this study, we investigated the reprogramming of rat fibroblasts with a deleted locus encoding a cluster comprising 14 miRNAs (from miR-743a to miR-465). The deletion of this locus was demonstrated to decrease significantly the efficiency of the cell reprogramming. In addition, the cells produced by the reprogramming differed from rat embryonic and induced pluripotent stem cells, which was an indication that reprogramming in these cells had not been completed. We suggest that this miRNA cluster or some of its members are involved in regulating the reprogramming of rat cells to a pluripotent state.