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Heart attack study could change the game in regenerative medicine

Heart attack study could change the game in regenerative medicine
Genome-wide TF screen identifies Atf7ip, JunB, Sp7, and Zfp207 (ZNF207) as barriers to cell fate reprogramming. a Schematic of the cardiac reprogramming assay and experimental rationale. b Volcano plot depicting genome-wide TF screen results. X-axis shows % of Myh6-EGFP + positive normalized to siControl. Y axis represents −log of P value as compared to siControl. The screen was run in experimental quadruplicate. c Validation of top 20 hits identifies eight siRNAs with confirmed activity. Student’s t-test: *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. d Representative images of top hit siAtf7ip- and siControl-transfected iMGT-MEFs on day 3 after MGT induction. Myh6-eGFP is shown in green and nuclei are stained with DAPI (blue, top right insets). e Schematic of the combinatorial screening approach. A total of 255 combinations was tested, each in quadruplicate. f Volcano plot depicting genome-wide combinatorial screen results. Data were normalized and compared to the most potent single hit (siAtf7ip). 1–4 indicates top combinations that were significantly more potent than siAtf7ip alone (p < 0.05). siAtf7ip, siJunb, siSp7, and siZfp207 (siAJSZ) are shown in red. g Visualization of top 4 siRNA combinations in a histogram plot as in (c). h Representative images of iMGT-MEFs transfected with siAJSZ (siAtf7ip, siJunb, siSp7, and siZfp207) 3 days after MGT induction. n = 4 per condition for all data in this figure. Groups were compared using two-tailed unpaired analysis. Data in the figure are presented as mean values ±  standard deviation. Scale bars: 50 µm. a, e Schematics are modified from Cunningham, T. J. et al. Id genes are essential for early heart formation. Genes & development, (2017). - CC-BY 4.0. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-37256-8

Sanford Burnham Prebys researchers have identified a group of proteins that could be the secret to cellular reprogramming, an emerging approach in regenerative medicine in which scientists transform cells to repair damaged or injured body tissues. The researchers were able to reprogram damaged heart cells to repair heart injuries in mice following a heart attack. The findings, which appear in the journal Nature Communications, could one day transform the way we treat a variety of diseases, including cardiovascular disease, Parkinson's and neuromuscular diseases.

"Even if a person survives a , there could still be long-term damage to the heart that increases the risk of heart problems down the line," says lead author Alexandre Colas, Ph.D., an assistant professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys. "Helping the heart heal after injury is an important medical need in its own right, but these findings also pave the way for wider applications of cell reprogramming in medicine."

Even though each of our has the same number of genes—approximately 20,000—cells can select which genes to "turn on" and "turn off" to change what they look like and what they do. This is the foundation of .

"Cellular reprogramming could, in theory, allow us to control the activity and appearance of any cell," says Colas. "This concept has huge implications in terms of helping the body regenerate itself, but barriers to reprogramming mechanisms have prevented the science from moving from the lab to the clinic."

The researchers identified a group of four proteins, named AJSZ, that help solve this problem. "By blocking the activity of these proteins, we were able to reduce scarring on the heart and induce a 50% improvement in overall heart function in mice that have undergone a attack," says Colas.

Although the researchers were primarily focused on , they determined that AJSZ is universal to all cell types. This suggests that targeting AJSZ could be a promising treatment approach for a variety of human diseases.

"This is helping us solve a very big problem that a lot of researchers are interested in," says Colas. "Even more important, this breakthrough is a significant step forward on our way to turning these promising biological concepts into real treatments."

The next steps in translating their discovery into a potential treatment is to explore different ways of blocking the function of the AJSZ proteins. According to Colas, the most promising option would be to use a small molecule drug to block the activity of AJSZ.

"We need to find a way to inhibit these proteins in a way we can control to make sure we are only reprogramming the cells that need it," says Colas. "We will be screening for drugs that can help us inhibit these proteins in a controlled and selective manner in the coming months."

More information: Maria A. Missinato et al, Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells, Nature Communications (2023). DOI: 10.1038/s41467-023-37256-8

Journal information: Nature Communications

Citation: Heart attack study could change the game in regenerative medicine (2023, March 29) retrieved 31 May 2023 from
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