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Delayed Intramyocardial Delivery of Stem Cells after Ischemia Reperfusion Injury in a Murine Model
Published on: September 3, 2020
CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury
Jiawan Wang1,2, Heng Du1,2, Wanrun Xie3,4,5,6
1Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (J. Wang, H.D., J.B., H.Z., X.L., Y.W., C.H., H.Y., Jiahe Zhang, Y. Li, P.X., S.L., Y. Zhou, J.S., C.Y., Z.L., Y. Liang, M.S.).
Background:
Given the growing acknowledgment of the detrimental effects of excessive myocardial fibrosis on pathological remodeling after myocardial ischemia-reperfusion injury (I/R), targeting the modulation of myocardial fibrosis may offer protective and therapeutic advantages. However, effective clinical interventions and therapies that target myocardial fibrosis remain limited. As a promising chimeric antigen receptor (CAR) cell therapy, whether CAR macrophages (CAR-Ms) can be used to treat I/R remains unclear.
Methods:
The expression of FAP (fibroblast activation protein) was studied in mouse hearts after I/R. FAP CAR-Ms were generated to target FAP-expressing cardiac fibroblasts in mouse hearts after I/R. The phagocytosis activity of FAP CAR-Ms was tested in vitro. The efficacy and safety of FAP CAR-Ms in treating I/R were evaluated in vivo.
Results:
FAP was significantly upregulated in activated cardiac fibroblasts as early as 3 days after I/R. Upon demonstrating their ability to engulf FAP-overexpressing fibroblasts, we intravenously administered FAP CAR-Ms to mice at 3 days after I/R and found that FAP CAR-Ms significantly improved cardiac function and reduced myocardial fibrosis in mice after I/R. No toxicities associated with FAP CAR-Ms were detected in the heart or other organs at 2 weeks after I/R. Finally, we found that FAP CAR-Ms conferred long-term cardioprotection against I/R.
Conclusions:
Our proof-of-concept study demonstrates the therapeutic potential of FAP CAR-Ms in alleviating myocardial I/R and potentially opens new avenues for the treatment of a range of heart diseases that include a fibrotic phenotype.
Insights
Fibroblast activation protein (FAP) targeted chimeric antigen receptor macrophages (CAR-Ms) show promise in treating myocardial ischemia-reperfusion injury (I/R). This therapy reduced fibrosis and improved cardiac function in mice, offering potential new treatments for heart disease.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Immunotherapy
Background:
- Myocardial fibrosis exacerbates pathological remodeling following ischemia-reperfusion injury (I/R).
- Current clinical interventions for myocardial fibrosis are limited.
- Chimeric antigen receptor (CAR) cell therapy, specifically CAR macrophages (CAR-Ms), is a potential therapeutic strategy for I/R, but its efficacy is unproven.
Purpose of the Study:
- To investigate the therapeutic potential of fibroblast activation protein (FAP)-targeted CAR-Ms in treating myocardial I/R.
- To evaluate the safety and efficacy of FAP CAR-Ms in a mouse model of I/R.
Main Methods:
- Assessed FAP expression in mouse hearts post-I/R.
- Generated FAP CAR-Ms to target FAP-expressing cardiac fibroblasts.
- Evaluated FAP CAR-Ms' phagocytosis activity in vitro and therapeutic efficacy and safety in vivo.
Main Results:
- FAP was significantly upregulated in cardiac fibroblasts 3 days after I/R.
- Intravenous administration of FAP CAR-Ms improved cardiac function and reduced myocardial fibrosis in I/R mice.
- FAP CAR-Ms demonstrated long-term cardioprotection against I/R without observed toxicity.
Conclusions:
- This study provides proof-of-concept for FAP CAR-Ms as a viable therapy for myocardial I/R.
- FAP CAR-Ms hold therapeutic potential for various heart diseases characterized by fibrosis.
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