Efficiently Reprogramming Fibroblasts into Cardiomyocytes for Heart Regeneration

The heart regenerates only very poorly, and responds to injury by producing scar tissue, a process that involves fibroblast cells. Additionally, the age-related disruption of regenerative processes produced by senescent cells and chronic inflammation tends to empower fibroblasts to produce fibrosis in the heart even in the absence of injury. One potential approach to the challenge of poor heart regeneration and growing fibrosis is to reprogram the fibroblasts of scar tissue into functional heart muscle cells, cardiomyocytes. Given recent demonstrations of in situ cell reprogramming, it is plausible to think that this can be accomplished. The challenge is to do so without disrupting the vital structural and electrical properties of heart tissue.

A heart attack leaves damaged scar tissue on the heart and limits its ability to beat efficiently. But what if scientists could reprogram scar tissue cells called fibroblasts into healthy heart muscle cells called cardiomyocytes? Researchers have made great strides on this front with lab experiments and research in mice, but human cardiac reprogramming has remained a great challenge. Now, for the first time, researchers have developed a stable, reproducible, minimalistic platform to reprogram human fibroblast cells into cardiomyocytes.

The researchers introduced a cocktail of three genes - Mef2c, Gata4, and Tbx5 - to human cardiac fibroblast cells with a specific optimized dose. To increase efficiency, they performed a screen of supplementary factors and identified MIR-133, a small RNA molecule that when added to the three-gene cocktail - and with further in-culture modifications - reprogrammed human cardiac fibroblast cells into cardiomyocytes at an efficiency rate of 40 to 60 percent.

Analysis identified a critical point during the reprogramming process when a cell has to "decide" between progressing into a cardiomyocyte or regressing to their previous fibroblast cell fate. Once that process begins, a suite of signaling molecules and proteins launch the cells onto different molecular routes that dictate their cell type development. The researchers also created a unique cell fate index to quantitatively assess the progress of reprogramming. Using this index, they determined that human cardiac reprogramming progresses at a much slower pace than that of the previously well-described mouse reprogramming, revealing key differences across species and reprogramming conditions.

Link: http://news.unchealthcare.org/news/2019/june/scientists-make-single-cell-map-to-reprogram-scar-tissue-into-healthy-heart-cells