Fibrin‐targeting delivery: a novel platform for cardiac regenerative medicine

Myocardial infarction (MI) and subsequent heart failure secondary to the massive lost of cardiomyocyte is a major cause of morbidity and mortality world-wide. Given the limited endogenous potential for renewal of cardiomyocytes in adults, cardiac cell-based therapies generating new cardiomyocytes and vessels have emerged as a promising treatment to reverse functional deterioration and prevent the progression to CHF. Although different type of stem cells, including mesenchymal stem cells (MSCs), CD34 cells and cardiac-derived stem cells, have been clinically tried, poor cell homing, retention and engraftment remain major obstacles to achieve a significant functional benefit [1–3]. It has long been a hot issue to find an effective homing target in cardiac cellular therapy. To direct transplanted stem cells to the injured heart, we and other groups sought to cellular magnetic targeting, which did enhance the therapeutic effects of stem cells through increasing cell retention in ischaemia/reperfusion rat models [4–7]. However, the external magnetic force can only promote a transient and imprecise stay in the heart, with a hidden risk of unfavourable vascular embolization and an inhomogeneous distribution of the donor cells [8, 9]. Therefore, the precise cell homing to the injured myocardium depends on the biological homing mechanisms. The first prerequisite for biologically targeting therapy is to find a good target element, which should exclusively express in the injured region or at least distribute in a concentration-gradient pattern. A rapid and dynamic change occurs in the local myocardial microenvironment following MI. Cytokine network system, myocardial parenchymal cell components and extracellular matrix may all serve as a possible candidate target after the injury of myocardium. Much efforts have been made in identifying chemokine and its receptors (CXCR4/SDF-1 axis, etc.) in the last decades [10]. However, the cytokine-based method has been far away from being able to effectively regulate stem cells migrating to target tissue due to the extremely complicity of the cytokine interaction and the homing molecular mechanisms [11, 12]. Recently, components released from injured cardiomyocyte (such as myosin light chain, actin and myosin associated proteins) have been explored as novel homing targets [13–16]. However, cardiomyocyte components may also release into the bloodstream, weakening the specificity of tissue distribution. Then, how about the performance of the extracellular matrix proteins? Actually, extracellular matrix proteins, as a possible cell homing target, has long been neglected in the field of cardiovascular disease. Fibrin is a fibrous protein involved in the tissue healing, blood clotting and tumour invasion. Tissue injury and healing (such as MI) witness the dynamic changes in the composition of the extracellular matrix. Increased vascular permeability results in extensive extravasation of plasma proteins that form a fibrin-based provisional matrix, providing the scaffold for the infiltration of granulation tissue cells [17]. With the organization of the injury, the fibrin network is lysed and replaced by fibronectin, hyaluronan, matricellular proteins and collagen. In tumour tissues, tumour cells continue to secrete vascular permeability factor (i.e. VEGF-A and VEGF), the fibrinogen was secreted into the stroma of malignant lesions to form a large number of fibrin [18]. Taking advantage of the fibrin deposition that is characteristic of tumours, Chung et al. constructed special chemotherapeutic agents with the fibrin-binding peptide, which facilitate efficient delivery of chemotherapeutic agents to malignant gliomas while minimizing systemic toxicity and side effects [19]. These findings suggest that the fibrin-targeting therapy may be a generalizable platform technology for tissue injury, because the fibrin-based provisional matrix is a basic pathologic process in tissue healing. Based on the spatiotemporal pattern of the expression of fibrin after myocardial ischaemia/reperfusion injury, fibrin satisfies the basic requirement as a homing target molecule in regenerative medicine. From the space angles, fibrin only deposits in the infarcted area, while rarely fibrin exists in the healthy myocardium [20, 21]. So the fibrin deposition region is exactly in accordant with the target region of regenerative therapy. From the perspective of timing, fibrin forms immediately after cardiac myocyte necrosis in the setting of myocardial injury, and fibrin deposition was transient and followed by formation of a mature collagen-based scar after 7–14 days of reperfusion in a mouse model of reperfused infarction [20]. The duration of the fibrin is coincident with the optimal timing of cell transplantation, which was recently suggested as the first week after MI [22, 23]. In addition, fibrin has pleiotropic effects on issue repair, including mediating the migration of inflammatory cells and the proliferation of stem cells [24, 25]. What is more, fibrin-based bioscaffolds have been extensively applied in stem cell therapeutics and the cardiac muscle tissue engineering [26, 27]. Therefore, the spatiotemporal characteristics of fibrin expression after MI, including specifically appearance in the infarcted area spatially and in early repair phase temporarily, along with its pleiotropic effects, render fibrin a perfect target for the delivery of stem cells. Another prerequisite for biologically targeting therapy is to endow the therapeutic cells with the specific and efficient binding capacity with the target component. It can be fulfilled by ligand modification of cell membrane. Although antibody has been traditionally used as the fibrin-targeting ligand in detecting fibrin component These authors contributed equally to this work. *Correspondence to: Junbo GE E-mail: [email protected]