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Stem Cell Genes Edited to Avoid Immune Rejection

Sonja Schrepfer and Tobias Deuse

Sonja Schrepfer, left, and Tobias Deuse (Univ of California – San Francisco)

19 Feb. 2019. A new study shows editing the genomes of adult stem cells can avoid their rejection by the immune system when implanted in lab mice other than the stem cell donor. A team from institutions in the U.S. and Germany describe their techniques to develop universal stem cells in yesterday’s issue of the journal Nature Biotechnology (paid subscription required).

Researchers led by professor of surgery Sonja Schrepfer, and cardiac surgeon Tobias Deuse, both at University of California in San Francisco, are seeking ways of making stem cells more widely available for regenerative medicine. While induced pluripotent stem cells or iPSCs — also known as adult stem cells, since they’re derived from existing human tissue rather than embryos — can grow and transform into many types of working human cells and tissue, they need to be donated by the person needing the regenerative treatment. Donating stem cells from other individuals, like donated tissue or organs, requires a close genetic match or they run the risk of immune system rejection.

Because stem cells need to be donated and used by the same person, their growth and transformation, which can take extended periods of time, can only be done only after the cells are donated. Thus, stem cells are often of little help to patients today in urgent need of regenerative treatments, such as emergency surgeries. While some drugs can suppress the immune system to lower the risk of rejection, they also increase the risk of infections and even cancer.

Adult stem cell treatments, while promising, are also not yet considered a reliable treatment option for many patients. Deuse notes in a UC-San Franciso statement that with adult stem cells, “the biggest hurdles are quality control and reproducibility. We don’t know what makes some cells amenable to reprogramming, but most scientists agree it can’t yet be reliably done. Most approaches to individualized iPSC therapies have been abandoned because of this.”

The UC-San Francisco team, with colleagues from University of North Carolina in Chapel Hill and the German Center for Cardiovascular Research in Hamburg, developed techniques with the genome editing technique Crispr to create adult stem cells for use in any patient for regenerative medicine. Crispr, short for clustered regularly interspaced short palindromic repeats, is a technique for editing genomes based on bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. The actual editing of genomes with Crispr in most cases today uses an enzyme known as Crispr-associated protein 9 or Cas9.

The researchers used Crispr-Cas9 in this case to edit genes regulating the immune system. The team focused first on the major histocompatibility complex genes with the code for proteins that govern tissue compatibility and rejection. The 2 main types of major histocompatibility complex proteins reside on most cell surfaces and react to foreign cells with signals about the invaders to the immune system. Thus the team set the 2 major histocompatibility complex genes as targets for removal by Crispr.

But cells without major histocompatibility complex proteins are also susceptible to attack by natural killer T-cells in the immune system. As a result, the team needed to provide extra protection for stem cells, and found it in the CD47 gene, which codes for proteins that protect against natural killer T-cells. Here, the researchers edited the stem cell genomes with extra copies of CD47.

In lab culture tests, the researchers found Crispr-edited stem cells from mice and humans grew and transformed into skin, smooth muscle, and heart muscle cells as well as unedited stem cells. In tests with lab mice grafted with human heart tissue, implanted cardiac cells derived from edited stem cells transformed and grew into working heart muscle and blood vessels, and with no immune system rejection. Other tests with mice whose native immune systems were replaced with immune systems from humans, also showed no rejection when implanted with edited stem cells.

The team believes their process offers a more widely accessible and economical stem cell technology. “Our technique,” says Deuse, “can benefit a wider range of people with production costs that are far lower than any individualized approach. We only need to manufacture our cells one time and we’re left with a product that can be applied universally.”

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