Pathophysiology and therapeutic potential of cardiac fibrosis

Abstract

Inflammatory and fibrotic responses to myocardial damage are essential for cardiac repair; however, these responses often result in extensive fibrotic remodeling with impaired systolic function. Recent reports have suggested that such acute phase responses provide a favorable environment for endogenous cardiac regeneration, which is mainly driven by the division of pre-existing cardiomyocytes (CMs). Existing CMs in mammals can re-acquire proliferative activity after substantial cardiac damage, and elements other than CMs in the physiological and/or pathological environment, such as hypoxia, angiogenesis, and the polarity of infiltrating macrophages, have been reported to regulate replication. Cardiac fibroblasts comprise the largest cell population in terms of cell number in the myocardium, and they play crucial roles in the proliferation and protection of CMs. The in vivo direct reprogramming of functional CMs has been investigated in cardiac regeneration. Currently, growth factors, transcription factors, microRNAs, and small molecules promoting the regeneration and protection of these CMs have also been actively researched. Here, we summarize and discuss current studies on the relationship between cardiac inflammation and fibrosis, and cardiac regeneration and protection, which would be useful for the development of therapeutic strategies to treat and prevent advanced heart failure.

Keywords: Angiogenesis; Cardiac fibroblasts; Cardiac regeneration; Cardiomyocytes; Direct reprogramming.

Fig. 1

Interactions among cardiac cells. Most types of cardiac cells, including CMs, cardiac fibroblasts, macrophages, and endothelial cells, regulate cardiac fibrosis and regeneration in a coordinated manner. Some paracrine factors from fibroblasts, including TGF-β and IGF-1, are known to promote the hypertrophic responses of CMs. The regulation of hypoxic environment and macrophage polarization is a key factor for enhancing crucial angiogenic responses involved in cardiac repair and regeneration

Fig. 2

Current strategies for cardiomyocyte regeneration. a Endogenous cardiac regeneration is primarily driven by the division of pre-existing CMs; currently, paracrine factors, the microenvironment, and small molecules that regulate this process are under investigation. b The direct reprogramming of cardiac fibroblasts into CMs is induced by a combination of cardiac-specific transcription factors and compounds. Investigations to improve the efficiency and maturity of generated CMs are currently in progress

Fig. 3

Angiogenic and fibrogenic responses during cardiac tissue injury and repair. Both MEndT and EndMT actively contribute to cardiac angiogenesis and fibrosis after cardiac injury. Embryonic macrophages can promote angiogenesis and subsequent cardiac regeneration in neonatal mice after cardiac injury, but infiltrate macrophages during adult cardiac injury do not