Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Inhibition of cAMP/PKA/CREB Signaling Axis Improves Fibroblast Plasticity for Direct Cardiac Reprogramming

Version 1 : Received: 20 April 2021 / Approved: 21 April 2021 / Online: 21 April 2021 (09:39:05 CEST)

A peer-reviewed article of this Preprint also exists.

Bektik, E.; Sun, Y.; Dennis, A.T.; Sakon, P.; Yang, D.; Deschênes, I.; Fu, J.-D. Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming. Cells 2021, 10, 1572. Bektik, E.; Sun, Y.; Dennis, A.T.; Sakon, P.; Yang, D.; Deschênes, I.; Fu, J.-D. Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming. Cells 2021, 10, 1572.

Journal reference: Cells 2021, 10, 1572
DOI: 10.3390/cells10071572

Abstract

Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenging technology of regenerative medicine for damaged myocardium. Efforts have been focused on improving the efficiency by understanding fundamental mechanisms. One of the major challenges is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed that a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in the primary cell culture of tissues. Both forskolin, which activates adenylyl cyclase and increases cAMP concentration, and TGFbeta inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of iCM reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblast could improve their plasticity for reprogramming, and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold amount of reprogrammed iCMs compared to that of untreated control cells. In conclusion, suppression of cAMP/PKA/CREB signaling axis improves fibroblast plasticity for direct cardiac reprogramming.

Keywords

induced cardiomyocyte; epigenetic reprogramming; heart regeneration; cell plasticity; transdifferentiation; CREB-CBP

Subject

LIFE SCIENCES, Biochemistry

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