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Published on: September 15, 2023
Controlled Release of Collagen-Binding SDF-1α Improves Cardiac Function after Myocardial Infarction by Recruiting
Jie Sun1, Yannan Zhao1,2, Qingguo Li3
1Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing 400038, China.
Insights
A novel recombinant chemokine, collagen-binding domain-stromal cell-derived factor-1α (CBD-SDF-1α), enables sustained release in the ischemic heart. This improves cardiac function by recruiting stem cells and increasing capillary density.
Area of Science:
- Biochemistry
- Regenerative Medicine
- Cardiovascular Research
Background:
- Stromal cell-derived factor-1α (SDF-1α) promotes cardiac regeneration by mobilizing stem cells to ischemic areas.
- Native SDF-1α exhibits rapid diffusion, leading to reduced local concentration and potential side effects.
- A controlled release system is crucial for maintaining effective SDF-1α concentrations in the ischemic heart.
Purpose of the Study:
- To develop a recombinant chemokine with sustained release properties for treating myocardial infarction.
- To evaluate the efficacy of the engineered chemokine in vitro and in vivo models of cardiac injury.
Main Methods:
- Engineered a recombinant chemokine, CBD-SDF-1α, by fusing SDF-1α with a collagen-binding domain.
- Assessed in vitro sustained release from a collagen gel.
- Administered CBD-SDF-1α via intramyocardial injection in an acute myocardial infarction mouse model.
- Evaluated stem cell recruitment (c-kit positive cells), capillary density, and cardiac function.
Main Results:
- CBD-SDF-1α demonstrated specific binding to collagen and sustained release in vitro.
- In vivo, CBD-SDF-1α remained localized in the ischemic heart, achieving controlled release.
- CBD-SDF-1α significantly enhanced c-kit(+) stem cell recruitment, increased capillary density, and improved cardiac function post-myocardial infarction.
- Native SDF-1α (NAT-SDF-1α) showed no significant beneficial effects.
Conclusions:
- CBD-SDF-1α effectively binds to collagen, enabling controlled in vitro and in vivo release.
- Local delivery of CBD-SDF-1α mobilizes endogenous stem cells to the ischemic heart.
- This approach improves cardiac function after myocardial infarction, offering a promising therapeutic strategy.
Abstract:
Stromal cell-derived factor-1α (SDF-1α) is a well-characterized chemokine that mobilizes stem cells homing to the ischemic heart, which is beneficial for cardiac regeneration. However, clinically administered native SDF-1α diffuses quickly, thus decreasing its local concentration, and results in side effects. Thus, a controlled release system for SDF-1α is required to produce an effective local concentration in the ischemic heart. In this study, we developed a recombinant chemokine, consisting of SDF-1α and a collagen-binding domain, which retains both the SDF-1α and collagen-binding activity (CBD-SDF-1α). In an in vitro assay, CBD-SDF-1α could specifically bind to a collagen gel and achieve sustained release. An intramyocardial injection of CBD-SDF-1α after acute myocardial infarction demonstrated that the protein was largely tethered in the ischemic area and that controlled release had been achieved. Furthermore, CBD-SDF-1α enhanced the recruitment of c-kit positive (c-kit(+)) stem cells, increased capillary density and improved cardiac function, whereas NAT-SDF-1α had no such beneficial effects. Our findings demonstrate that CBD-SDF-1α can specifically bind to collagen and achieve controlled release both in vitro and in vivo. Local delivery of this protein could mobilize endogenous stem cells homing to the ischemic heart and improve cardiac function after myocardial infarction.
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