Small molecule inhibitors and culture conditions enhance therapeutic cell and EV potency via activation of beta-catenin and suppression of THY1.
Publication Year:
2021
PubMed ID:
33321216
Funding Grants:
Public Summary:
Using living cells as therapy can be tricky because their quality and effectiveness can vary depending on the donor and how they’re made. Cardiosphere-derived cells (CDCs) are special cells that help repair damaged tissue, especially in the heart.
Scientists found that a specific cell process increases a key signaling protein called β-catenin and boosts helpful microRNAs in tiny particles these cells release. They also noticed that when CDCs lose their ability to work well, they don’t form these cell clusters (cardiospheres) properly.
The researchers discovered that by using certain chemicals that boost β-catenin activity, they can improve the CDCs’ quality and make them more consistent for therapy. This work helps find ways to keep these cells strong and reliable for treating patients.
Scientific Abstract:
Primary cell therapy continues to face significant hurdles to therapeutic translation including the inherent variations that exist from donor to donor, batch to batch, and scale-up driven modifications to the manufacturing process. Cardiosphere-derived cells (CDCs) are stromal/progenitor cells with clinically demonstrated tissue reparative capabilities. Mechanistic investigations have identified canonical Wnt/beta-catenin signaling as a therapeutic potency marker, and THY1 (CD90) expression as inversely correlated with potency. Here we demonstrate that the cardiosphere formation process increases beta-catenin levels and enriches for therapeutic miR content in the extracellular vesicles of these cells, namely miR-146a and miR-22. We further find that loss of potency is correlated with impaired cardiosphere formation. Finally, our data show that small GSK3beta inhibitors including CHIR, and BIO and "pro-canonical Wnt" culturing conditions can rescue beta-catenin signaling and reduce CD90 expression. These findings identify strategies that could be used to maintain CDC potency and therapeutic consistency.