Research progress on the effects of M1/M2 macrophages on the differentiation and maturation of stem cell-derived cardiomyocytes: a review

Abstract

Stem cell-derived cardiomyocytes (SC-CMs) represent a promising cell source for cardiac regenerative medicine, disease modeling, and drug screening. However, their clinical translation faces significant challenges, including functional immaturity, poor long-term survival, and inadequate integration with host tissue following transplantation. The immune microenvironment, particularly the dynamic polarization of macrophages into pro-inflammatory (M1) or reparative (M2) phenotypes, is increasingly recognized as a critical regulator of cardiac repair, yet a systematic understanding of its specific effects on SC-CM fate remains incomplete. This review aims to comprehensively evaluate the dual regulatory roles of M1 and M2 macrophages on the differentiation efficiency, structural and functional maturation, and in vivo transplantation efficacy of SC-CMs. A systematic literature search was conducted in PubMed, Web of Science, Nature, and CNKI for relevant studies published from database inception to July 2025. After screening, 92 articles were included for analysis. The synthesized evidence demonstrates that M1 macrophages and their secreted factors (e.g., TNF-α, IL-1β) impede cardiac differentiation by inhibiting the Wnt/β-catenin pathway, disrupt sarcomeric organization and calcium handling, and maintain SC-CMs in a glycolytic, immature state. In contrast, M2 macrophages enhance SC-CM maturation by providing trophic support (e.g., IGF-1, HGF), promoting electrophysiological maturation and metabolic reprogramming towards oxidative phosphorylation, and facilitating angiogenesis via VEGF. The novelty of this review lies in its integrated perspective on macrophage-driven immunomodulation as a central axis for SC-CM maturation. Furthermore, it discusses emerging therapeutic strategies—such as optimized transplantation timing, co-transplantation with immunomodulatory cells, engineered exosomes, and smart biomaterials—that leverage macrophage polarization to create a favorable microenvironment for SC-CMs. Ultimately, harnessing macrophage-SC-CM crosstalk is a crucial step toward advancing clinically effective and immunologically informed cardiac regeneration therapies.

1. Introduction

Cardiovascular disease is the leading cause of death worldwide. Myocardial infarction (MI), which leads to massive loss of cardiomyocytes and subsequent fibrotic scar formation, is a major pathological basis for heart failure [1]. The self-regenerative capacity of the adult heart is extremely limited. Therefore, treatment for end-stage heart failure often ultimately relies on heart transplantation, but the severe shortage of donors limits this approach [2]. The rise of regenerative medicine, particularly the development of human pluripotent stem cell (hPSC) technologies, including embryonic stem cells and induced pluripotent stem cells, provides an unlimited cell source for generating functional cardiomyocytes (i.e., stem cell-derived cardiomyocytes [SC-CMs]), offering revolutionary hope for cardiac repair [3].

However, despite technological advancements, the clinical application of SC-CMs still faces two core challenges. First, SC-CMs obtained from in vitro differentiation resemble fetal rather than adult cardiomyocytes in terms of structure, gene expression, metabolism, and electrophysiological properties. This functional immaturity of SC-CMs causes difficulty for them to achieve effective electro-mechanical integration with host mature myocardium and may even trigger fatal arrhythmias [4]. Second, when SC-CMs are transplanted into the injured heart, they encounter an extremely hostile microenvironment, such as ischemia, hypoxia, and a strong host immune inflammatory response, leading to massive death of the transplanted cells. Additionally, tumorigenicity is a major concern in the application of pluripotent stem cells (PSCs) for myocardial regeneration because cardiac regeneration requires large quantities of cardiomyocytes differentiated from PSCs [5].

Previously, the heart was often considered a terminally differentiated organ with few immune cells. Traditional research primarily focused on optimizing biochemical signaling pathways (e.g., BMP, Wnt, and FGF) for inducing cardiac differentiation [6]. However, increasing evidence in recent years has indicated that the heart...