Reprogramming by the heart: diclofenac on the limelight

Once damaged, the human heart does a poor job of repairing itself, so this is a key priority for treating heart failure. One way of restoring cardiac function is to reprogram non-cardiac body cells such as fibroblasts into heart muscle cells (cardiomyocytes) using a collection of cardiac transcription factors. This bypasses the need to use stem cells as an intermediate and avoids stimulating the proliferation of existing cardiomyocytes. However, the reprogramming of postnatal and adult fibroblasts is inefficient compared with that of embryonic fibroblasts, and the challenges associated with reprogramming aged cells are unclear. A new study in Nature Communications has advanced this field by using a high-throughput screening approach to identify diclofenac, an FDA-approved drug commonly used to treat inflammation and rheumatic diseases, as a factor promoting cardiac reprogramming in postnatal and adult fibroblasts but not embryonic ones. The finding by researchers at the University of Tsukuba and their research colleagues in a Japan-wide university collaboration also helps define the barriers unique to cellular aging.

Taketaro Sadahiro, co-author of this research, esplained: “Previous methods of identifying cardiac reprogramming factors have been labor intensive and unsuitable for large-scale screening. As an alternative approach, we developed a high-content technique to screen a chemical library of 8400 compounds. The first round of screening identified 37 potential compounds, which were narrowed down to four in the second round. The most powerful of these four molecules was diclofenac”. Based on these findings, diclofenac was shown to improve cardiac reprogramming in a dose-dependent manner largely by inhibiting the enzyme COX-2, which is highly expressed in postnatal and adult fibroblasts. The team found that diclofenac functioned during the early stages of cardiac reprogramming, and increased the generation of cardiomyocytes more quickly and efficiently than TGF-beta and Wnt inhibitors, which are factors known to promote reprogramming. The drug greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c and Tbx5 or Hand2 transcription factors.

Diclofenac also suppressed a battery of signaling molecules involved in inflammation. Basically, since diclofenac blocked prostaglandin E2 (PGE2) production, scientists realized that its effect was linked to the suppression of the PGE2-EP4R-PKA-IL1beta axis. Consistent with the importance of inflammation in preventing cardiac reprogramming, microarray data showed that diclofenac downregulated fibroblast and inflammatory genes, and upregulated cardiac genes. Thus, diclofenac was responsible for silencing fibroblast signatures, which occurred prior to cellular reprogramming into cardiomyocytes. After fibroblast treatment, a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed that a panel of cardiac genes related to different functions, including sarcomeric structures (Actc1, Myh6, Tnnc1) and ion channels (Kcnd2, Pln, Scn5a, Slc8a1), were strongly up-regulated in the reprogrammed fibroblasts with diclofenac. As well as COX-2, genes associated with inflammation and fibroblasts were also shown to be more highly expressed in postnatal and adult cells, compared with embryonic fibroblasts.

This indicated that inflammation and fibrogenesis are age-related barriers to cardiac reprogramming. These findings have important implications for the development of new therapies for cardiac regeneration in pediatric and adult patients.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Muraoka N, Nara K et al. Nat Commun. 2019 Feb 20; 10(1):674. 

Al-Kofahi M et al. Biomed Pharmacother. 2018; 107:1591-1600. 

Dong YH et al. Br J Clin Pharmacol. 2018 May; 84(5):1045-1056.

Informazioni su Dott. Gianfrancesco Cormaci 1423 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it