Abstract
Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. However, postnatal and adult fibroblasts are less efficient for reprogramming compared with embryonic fibroblasts, and barriers to cardiac reprogramming associated with aging remain undetermined. In this study, we screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2. Intriguingly, diclofenac promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs). Mechanistically, diclofenac enhanced cardiac reprogramming by inhibiting cyclooxygenase-2, prostaglandin E2/prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1β signaling and by silencing inflammatory and fibroblast programs, which were activated in postnatal and adult TTFs. Thus, anti-inflammation represents a new target for cardiac reprogramming associated with aging.
Highlights
Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients
We found that a traditional non-steroidal antiinflammatory drug (NSAID), diclofenac, greatly promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs), by suppressing COX-2/prostaglandin E2 (PGE2)/E2 (PGE2)/PGE receptor 4 (EP4) pathways and silencing inflammatory and fibroblast gene expression
Diclofenac promoted cardiac reprogramming in TTFs via the suppression of COX-2/PGE2/EP4/cAMP/PKA/interleukin 1β (IL-1β)/IL1R1 signaling, with the inhibition of inflammatory and fibroblast gene expression
Summary
Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. We screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata[4], Mef2c, and Tbx[5] (GMT) or GMT plus Hand[2]. Zhou et al.[6] recently reported that comparative gene expression analyses showed iCMs induced in vitro exhibited more adult cardiomyocyte-like features, such as fatty acid oxidation and cellcycle exit, than exhibited by induced pluripotent stem cell (iPSC)derived CMs. direct cardiac reprogramming has potential for disease modeling, drug screening, and cardiac repair, if the iCMs can be efficiently generated from fibroblasts[7]. Improvements in reprogramming efficiency were shown mainly in mouse embryonic fibroblasts (MEFs), and cardiac reprogramming from more differentiated fibroblasts, such as mouse postnatal and adult tail-tip fibroblasts (TTFs), remained inefficient[13,16]. Diclofenac enhanced cardiac reprogramming via the inhibition of cyclooxygenase-2 (COX-2)/ prostaglandin E2 (PGE2)/PGE receptor 4 (EP4)/interleukin 1β (IL-1β)/interleukin 1 receptor type 1 (IL-1R1) signaling and subsequent suppression of inflammatory and fibroblast gene programs, which were activated in postnatal and adult fibroblasts
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