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

## TL;DR

This review explores how M1 and M2 macrophages influence the development and function of stem cell-derived heart cells, offering insights into improving their use in cardiac regeneration.

## Contribution

The review provides an integrated perspective on how macrophage polarization affects stem cell-derived cardiomyocyte maturation and proposes new therapeutic strategies.

## Key findings

- M1 macrophages hinder SC-CM maturation by inhibiting the Wnt/β-catenin pathway and promoting an immature glycolytic state.
- M2 macrophages support SC-CM maturation through trophic factors and metabolic reprogramming toward oxidative phosphorylation.
- Strategies like co-transplantation and engineered exosomes are suggested to leverage macrophage polarization for better cardiac regeneration.

## 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.