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Transplantation of Neonatal Mouse Cardiac Macrophages into Adult Mice
Published on: March 20, 2021
CAR Macrophages Engineered In Vivo for Attenuating Myocardial Ischemia-Reperfusion Injury
Heng Du1,2,3, Xintong You1,2,3, Jiahe Zhang1,2,3
1State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (H.D., X.Y., J. Zhang, S.L., Y.Z., Y.W., C.Y., Y.M., X.L., H.Z., Y.L., J.S., H.Y., P.X., C.H., Y.X., Z.G., J. Zang, T.W., M.S.).
Lipid nanoparticles delivering FAP CAR mRNA generate macrophages that reduce heart fibrosis and improve function after injury. This therapy shows lasting benefits and no toxicity, offering a promising treatment for myocardial ischemia-reperfusion injury.
Area of Science:
- Cardiovascular Research
- Biotechnology
- Regenerative Medicine
Background:
- Myocardial ischemia-reperfusion (I/R) injury leads to fibrosis, impairing cardiac function and electrical conduction.
- Current clinical treatments for I/R-induced fibrosis are insufficient.
- There is a critical need for novel therapeutic strategies to address myocardial fibrosis.
Purpose of the Study:
- To investigate macrophage-targeted lipid nanoparticles (LNPs) delivering fibroblast activation protein (FAP)-targeted chimeric antigen receptor (CAR) mRNA.
- To evaluate the in vivo generation of FAP CAR macrophages for treating myocardial fibrosis post-I/R injury.
- To assess the therapeutic potential of FAP CAR macrophages in improving cardiac function and reducing fibrosis.
Main Methods:
- Formulation of LNPs encapsulating FAP CAR mRNA for targeted delivery.
- In vitro validation of FAP CAR macrophage phagocytosis of FAP-overexpressing fibroblasts.
- In vivo studies in mice with I/R injury, administering PBS, control LNPs, or LNP-FAP CAR.
- Assessment of macrophage biodistribution, fibrosis reduction, cardiac function (echocardiography), and safety.
Main Results:
- LNP-FAP CAR successfully generated functional FAP CAR macrophages in vitro and in vivo.
- FAP CAR macrophages selectively targeted and phagocytosed activated cardiac fibroblasts in I/R hearts.
- Significant reduction in cardiac fibroblasts and myocardial fibrosis was observed.
- Marked improvement in cardiac function with no detectable toxicity, even with delayed treatment.
Conclusions:
- In vivo generated FAP CAR macrophages effectively mitigate cardiac fibrosis and improve heart function after I/R injury.
- The LNP-FAP CAR platform demonstrates lasting benefits and a favorable safety profile.
- This approach offers a promising therapeutic strategy for myocardial I/R injury and other fibrotic heart diseases.
