mRNA-Based Therapy for Vascular Regeneration
The insufficient perfusion of tissues or organs with blood usually leads to ischemia. During ischemia, the tissues are damaged due to hypoxia, the lack of nutrient supply as well as impeded waste removal, consequently, resulting in a variety of diseases, such as myocardial infarction and stroke. Therefore, the regeneration of new blood vessels is required. In addition to angiogenesis, vasculogenesis is another strategy to form new blood vessels. Vasculogenesis is a method that utilizes bone marrow-derived endothelial progenitor cells (EPCs) to achieve de novo blood vessel generation. The formation of new blood vessels by angiogenesis and vasculogenesis promotes the restoration of blood supply to ischemic tissues and reduces the damage to affected tissues, thus improving the function of affected tissues or organs. Creative Biogene is offering a wide series of mRNA research services, which can accelerate the progress of mRNA-based tissue repair and regeneration research for customers from all over the world. Here, we give a brief introduction to the applications of mRNA-based therapy in vascular regeneration.
Growth factors for the induction of vascularization and angiogenesis
To improve the revascularization of tissues, various growth factors have been investigated, including vascular endothelial growth factor (VEGF), angiopoietin-1 (ANG-1), and fibroblast growth factor (FGF). Among them, vascular endothelial growth factor-A (VEGF-A) is the most intensively studied for the induction of vascularization and angiogenesis. As a naturally occurring protein, VEGF-A can be secreted from many different types of cells, including vascular endothelium cells, stem cells, and cardiomyocytes. VEGF-A binds and activates VEGF receptors, such as VEGFR-1 and VEGFR-2 on vascular endothelial cells (ECs) and EPCs, and the major proangiogenic signal is generated from the ligand-activated VEGFR-2. The promotion of new blood vessels happens from the early stages of embryo development and throughout life to replace diseased or damaged blood vessels. Angiopoietin-1 (ANG-1) produced by peri-endothelial cells (peri-ECs) and platelets, can bind to Tie2 receptors on ECs and maintains endothelial integrity and reduces the effects of inflammation. Therefore, it prevents vascular leakage and stabilizes vessels. Moreover, ANG-1 further takes part in the migration and reorganization of ECs. Stromal cell-derived factor-1α (SDF-1α), also known as CXCL12, can attenuate EC apoptosis and stimulate new vessel capillary tube formation. As a chemokine, it also mediates the mobilization and recruitment of EPCs via identifying CXCR4 receptors on the cell surface.
mRNA-based therapy for vascular regeneration
In recent years, the expression of exogenous proteins by the delivery of in vitro-transcribed (IVT) mRNAs has attracted great attention as an alternative strategy to the viral vector or plasmid DNA (pDNA)- based gene delivery methods. Since the mRNA does not enter the nucleus, the synthetic mRNA can be efficiently delivered to cells, including dividing and non-dividing cells. The transfection of synthetic mRNA leads to the transient and no-footprint generation of exogenous proteins in the cells. At present, an important focus of vascular regeneration is VEGF-A. VEGF-A has shown potency as an angiogenic factor, involved in the migration and differentiation of progenitor cells, the survival and proliferation of ECs, and the sprouting and permeability of vessels. mRNA-induced transient expression of VEGF-A may lead to the creation of blood vessels and restoration of blood supply, and can avoid the negative effects of prolonged VEGF-A expression. IVT mRNA encoding VEGF-A provides a regenerative treatment option for ischemic vascular diseases.
Murine EPCs were engineered by the exogenous delivery of synthetic mRNAs to increasingly express the proangiogenic proteins (VEGF-A, SDF-1α, and ANG-1). (Steinle, H., et al., 2018)
The applications of IVT mRNA encoding VEGF-A
- Limb ischemia.
- Diabetic wound healing.
- Ischemic cardiovascular disease, such as myocardial infarction.
- Tissue engineering, such as improving the vascularization of scaffolds and promoting vessel anastomosis with the host vasculature.
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- Steinle, H., et al. (2018). "Improving the angiogenic potential of EPCs via engineering with synthetic modified mRNAs." Molecular Therapy-Nucleic Acids, 13, 387-398.