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J Biol Chem. 2019 Jun 7;294(23):9134-9146. doi: 10.1074/jbc.RA118.006000. Epub 2019 Apr 25.

Chemical suppression of specific C-C chemokine signaling pathways enhances cardiac reprogramming.

Guo Y1,2, Lei I1,3, Tian S1, Gao W1,4, Hacer K5,6,7, Li Y5,6,7, Wang S5,6,7, Liu L8, Wang Z9.

Author information

1
From the Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109.
2
Department of Spine Surgery, Xiangya Spinal Surgery Center, Xiangya Hospital, Central South University, Changsha 410008, China.
3
Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China.
4
First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
5
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan 48109.
6
Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, and.
7
Department of Medicinal Chemistry, University of Michigan College of Pharmacy, Ann Arbor, Michigan 48109.
8
From the Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, luvul@med.umich.edu.
9
From the Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, zhongw@med.umich.edu.

Abstract

Reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for regenerating a damaged heart. However, low fibroblast-cardiomyocyte conversion rates remain a major challenge in this reprogramming. To this end, here we conducted a chemical screen and identified four agents, insulin-like growth factor-1, Mll1 inhibitor MM589, transforming growth factor-β inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed IMAP, which coordinately enhanced reprogramming efficiency. Using α-muscle heavy chain-GFP-tagged mouse embryo fibroblasts as a starting cell type, we observed that the IMAP treatment increases iCM formation 6-fold. IMAP stimulated higher cardiac troponin T and α-actinin expression and increased sarcomere formation, coinciding with up-regulated expression of many cardiac genes and down-regulated fibroblast gene expression. Furthermore, IMAP promoted higher spontaneous beating and calcium transient activities of iCMs derived from neonatal cardiac fibroblasts. Intriguingly, we also observed that the IMAP treatment repressed many genes involved in immune responses, particularly those in specific C-C chemokine signaling pathways. We therefore investigated the roles of C-C motif chemokine ligand 3 (CCL3), CCL6, and CCL17 in cardiac reprogramming and observed that they inhibited iCM formation, whereas inhibitors of C-C motif chemokine receptor 1 (CCR1), CCR4, and CCR5 had the opposite effect. These results indicated that the IMAP treatment directly suppresses specific C-C chemokine signaling pathways and thereby enhances cardiac reprogramming. In conclusion, a combination of four chemicals, named here IMAP, suppresses specific C-C chemokine signaling pathways and facilitates Mef2c/Gata4/Tbx5 (MGT)-induced cardiac reprogramming, providing a potential means for iCM formation in clinical applications.

KEYWORDS:

C-C chemokine; cardiac reprogramming; cardiomyocyte; cardiomyopathy; cardiovascular disease; cell signaling; cellular immune response; fibrosis; heart regeneration; immune response; myocardial infarction; regeneration; reprogramming; small molecule

PMID:
31023824
PMCID:
PMC6556576
[Available on 2020-06-07]
DOI:
10.1074/jbc.RA118.006000

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