Fibroblast to Cardiomyocyte Reprogramming via TGF-β Inhibition

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Solution Overview

Problem

Current methods for converting fibroblasts into cardiomyocytes are inefficient and slow, with pro-fibrotic signaling pathways acting as a major barrier to cardiac reprogramming.

Innovation Solution

Inhibition of pro-fibrotic signaling using small molecules that target the transforming growth factor-β/SMAD or Rho kinase pathways, combined with the delivery of reprogramming factors such as miR-1, miR-133, GATA4, Hand2, and MEF2C, to convert fibroblasts into beating cardiomyocytes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If GMT or GHMT transcription factors are used to reprogram fibroblasts into cardiomyocytes, then cardiomyogenic reprogramming is achieved, but the process is slow and inefficient

Engineering Contradiction:

Improvereprogramming efficiencyVSAvoidreprogramming duration

Core Design Contradiction:

ProductivityVSLoss of time

Solution Approach 1:

The patent changes the molecular parameters of the reprogramming system by introducing small molecule inhibitors (A83-01 for TGF-β/SMAD pathway, Y-27632 for Rho kinase pathway) that modify the signaling environment. This parameter change removes molecular barriers that prevent efficient reprogramming, enabling conversion of approximately 60% of fibroblasts into cardiomyocytes in less than two weeks, significantly improving both efficiency and speed compared to GMT or GHMT alone

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces small molecule inhibitors as intermediary substances that mediate between the reprogramming factors and the fibroblasts. These intermediaries (A83-01 and Y-27632) temporarily block pro-fibrotic signaling pathways, creating a permissive state that facilitates rapid and efficient cardiomyogenic conversion without requiring prolonged exposure to reprogramming factors

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If pro-fibrotic signaling pathways are active during reprogramming, then fibroblast characteristics are maintained, but cardiac reprogramming is blocked

Engineering Contradiction:

Improvecardiomyocyte conversion rateVSAvoidpro-fibrotic signaling inhibition

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful pro-fibrotic signaling that normally blocks reprogramming into a beneficial condition by using small molecule inhibitors to temporarily suppress it. The inhibitors A83-01 and Y-27632 transform the obstructive fibrotic signaling environment into a permissive state that actively promotes cardiomyogenic conversion, achieving approximately 60% conversion efficiency in less than two weeks

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent applies preliminary anti-action by pre-treating fibroblasts with small molecule inhibitors that block pro-fibrotic signaling pathways before and during the reprogramming process. This preliminary suppression of TGF-β/SMAD and Rho kinase pathways removes molecular barriers in advance, allowing reprogramming factors to efficiently convert fibroblasts into cardiomyocytes without resistance from fibrotic signaling

Inventive Principle:

Principle #9Preliminary anti-action

Data Source

PatentUS10519423B1High efficiency reprogramming of fibroblasts into cardiomyocytes

Publication Date: 2019.12.31 THE REGENTS OF THE UNIVERSITY OF COLORADO

AI summary

Pro-fibrotic signaling potently antagonizes cardiac reprogramming. Inhibition of pro-fibrotic signaling using small molecules that target the transforming growth factor-β/SMAD, or Rho kinase leads to conversion of approximately 60% of fibroblasts into beating cardiomyocytes. Conversely, over-activation of these pro-fibrotic signaling networks inhibits cardiac reprogramming. Using the disclosed methods, fibroblasts are converted to spontaneously contracting cardiomyocytes in less than two weeks.