Mitochondria-Boosted Macrophages Accelerate Heart Repair After Heart Attack

Myocardial infarction (MI) triggers a hostile ischemic microenvironment—marked by hypoxia, oxidative stress, metabolic crisis, and inflammatory mediator accumulation—that severely damages mitochondria in infiltrating macrophages. This mitochondrial dysfunction prevents macrophages from transitioning from an inflammatory M1 phenotype to the reparative M2 phenotype required for effective cardiac healing, creating a self-perpetuating cycle of impaired recovery. Existing mitochondria-targeted therapies address only single aspects of this damage and are insufficient when mitochondria or mitochondrial DNA are already severely compromised.

To overcome this limitation, investigators at Zhongshan Hospital, Fudan University engineered a novel cell therapy: mitochondria-transplanted macrophages (MTMs, or Mito-T-Macros). Healthy mitochondria were isolated from the hearts of C57BL/6J mice, quality-verified by membrane potential assessment (TMRE staining and flow cytometry), and introduced into bone marrow-derived macrophages (BMDMs) at an optimized concentration (8×10⁴ mitochondria per 10⁵ cells) for 2 hours. Live-cell imaging confirmed rapid internalization, with peak uptake between 0–8 hours. Transplanted mitochondria co-localized with endogenous mitochondria, and MTMs adopted a spindle-shaped M2-like morphology versus the oval shape of untreated controls.

In vitro, MT robustly induced M2 polarization, significantly upregulating M2 markers (CD206, CD163, Arg-1) and the anti-inflammatory cytokine IL-10 at the mRNA level. MTMs also showed enhanced functional capacities critical to tissue repair: superior migration, invasion, and phagocytic activity compared to untreated macrophages. Mechanistically, MT accelerated the phenotypic transition toward the reparative state and prolonged macrophage activity during the healing phase, partly through improved oxidative phosphorylation metabolism.

In a mouse MI model, intravenous or intramyocardial delivery of MTMs led to significantly improved cardiac function, reduced left ventricular remodeling, decreased fibrosis, limited cardiomyocyte apoptosis, and enhanced angiogenesis. Histological and flow cytometric analyses revealed that MTM therapy promoted early and sustained infiltration of reparative CD206⁺ macrophages into the injured myocardium. A particularly notable finding was that a fraction of transplanted mitochondria were released from MTMs and subsequently internalized by neighboring cardiomyocytes, suggesting an additional, cell-extrinsic mechanism of myocardial support beyond macrophage polarization alone.

These findings establish MTM therapy as a multi-mechanistic strategy for post-MI repair: simultaneously reprogramming macrophage immunophenotype, enhancing repair-relevant effector functions, and donating healthy mitochondria to injured cardiomyocytes. While results are currently limited to murine models, the approach leverages autologous or allogeneic macrophage platforms already under clinical investigation, and builds on prior clinical experience with direct mitochondrial transplantation in ischemic heart disease.