miRNA Reprogramming Smooth Muscle Cells Endothelial Repair
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Solution Overview
Problem
Current therapies for endothelial repair after vascular damage, such as balloon angioplasty or stent placement, are inefficient due to slow endothelial cell growth and rapid atherosclerotic events, with existing methods relying on progenitor cells or induced pluripotent stem cells that require optimization and are limited by cell source and individual pathologies.
Innovation Solution
A method using miR-143-3p and/or miR-145-5p inhibitors coupled with miR-146a-5p and miR-181b-5p mimics to transdifferentiate vascular smooth muscle cells or fibroblasts into inducible endothelial cells, which are transcriptionally, phenotypically, and functionally similar to native endothelial cells, facilitating endothelial repair.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If progenitor cells or induced pluripotent stem cells are used for endothelial repair, then endothelial regeneration can be facilitated, but the therapy requires optimization and is limited by cell source and individual pathologies
Solution Approach 1:
The patent changes the molecular parameters of the target cells by introducing specific miRNA combinations (inhibiting anti-endothelial miRNAs and overexpressing pro-endothelial miRNAs) to transform the cell phenotype from smooth muscle to endothelial, eliminating the need for complex progenitor cell therapies
Solution Approach 2:
The patent extracts and eliminates the limitations associated with progenitor cell therapy by directly reprogramming existing vascular smooth muscle cells in situ, removing the need for external cell sources and complex therapy optimization
2Reliability
If endothelial cells are used for vascular repair, then endothelial lining can be restored, but endothelial cell growth is relatively slow compared to perivascular cells
Solution Approach 1:
The patent enables vascular smooth muscle cells to self-transform into endothelial cells through miRNA reprogramming, utilizing the cells' own regulatory mechanisms to accelerate regeneration without relying on slow-growing external endothelial cell sources
Solution Approach 2:
Instead of introducing slow-growing endothelial cells to repair damage, the patent inverts the approach by transforming the abundant, fast-growing vascular smooth muscle cells into endothelial cells, reversing the traditional repair strategy
3Productivity
If miRNA reprogramming is used to transdifferentiate smooth muscle cells into endothelial cells, then rapid endothelial regeneration can be achieved, but the process requires specific miRNA combinations and delivery methods
Solution Approach 1:
The patent combines multiple miRNA functions into a single therapeutic approach by simultaneously inhibiting anti-endothelial miRNAs (miR-143-3p, miR-145-5p) and overexpressing pro-endothelial miRNAs (miR-146a-5p, miR-181b-5p) to achieve comprehensive cellular reprogramming
Solution Approach 2:
The patent uses lipid nanoparticles as intermediary carriers to deliver the miRNA combinations to target cells, simplifying the delivery process while maintaining high efficacy through controlled release and targeted uptake
Data Source
AI summary
Described herein is a panel of three or four miRNAs that can be used to transdifferentiate vascular smooth muscle cells or fibroblasts into endothelial cells. As demonstrated herein, miR-143-3p and/or miR-145-5p inhibitors coupled with miR-5 146a-5p and miR-18lb-5p mimics were sufficient for accomplishing this transformation. This transdifferentiation protocol can be used to generate inducible endothelial cells that are transcriptionally, phenotypically, and functionally similar to other endothelial cells. This miRNA-engineered approach is useful in a range of cardiovascular-based therapies. In some embodiments, the methods use a 4-miRNA consisting of miR-143-3p and/or miR-145-Sp inhibitors, and miR-146a-5p and miR-181b-5p mimics, to produce iECs from SMCs or fibroblasts. In some embodiments, the SMC are isolated from aorta, coronary artery, pulmonary artery, umbilical artery, bladder smooth muscle cells, or derived from adipose tissue smooth muscle cells or progenitors, or blood derived circulating smooth muscle cell progenitors.