Cell therapy using stem cells holds great promise. However, this potential is curbed by the risk of these cells giving rise to malignant tumours. This is in part due to stem cells’ unlimited potential for cell proliferation. A team from Duke-NUS Medical School (Duke-NUS) has devised a new method that limits stem cell proliferation capacity, while simultaneously retaining their pluripotency until differentiation. This invention can potentially reduce the risk of stem cell transplantation-derived tumours when used in therapy.
The need for pluripotent stem cells with limited proliferation capacity
Stem cells are unique in that they can proliferate (divide and renew themselves) indefinitely, and have the pluripotent capacity to differentiate into any type of cell in the body. However, a concern in using stem cells for clinical applications is their tumorigenic potential. They share a number of similarities with tumour cells – rapid proliferation rate, unlimited potential for proliferation and the propensity to accumulate chromosome aberrations, when cultured in vitro.
Current approaches to address the tumorigenic potential of stem cells focus on separating the differentiated cells from undifferentiated ones, which remains a technically challenging task. A team at Duke-NUS has found a way to limit the proliferative capacity of stem cells. These “telomerase-null” stem cells have fixed lifespans, exhibit lower risk of tumorigenicity and yet retain their useful pluripotent capacity. They can therefore potentially be used more safely in clinical applications.
The science behind engineering telomerase-null stem cells
Both stem cells and tumour cells have to maintain their telomeres in order to proliferate continuously. Telomeres are protective caps found at the end of each chromosome, consisting of a repeated DNA sequence. Every time a cell divides, the telomeres get shorter. When the telomeres become too short, the cell can no longer divide and dies. Telomeres are synthesized by an enzyme called telomerase, and pluripotent stem cells express high telomerase activity.
Telomerase is a reverse transcriptase that contains two core components: a catalytic protein called hTERT and an RNA component called hTER. The Duke-NUS team developed a way to modify stem cells so that they can control the expression of hTERT and hTER in the cells. This in turn allows researchers to modulate the telomerase activity of the stem cells. For example, the loss of hTERT or hTER activity leads to the loss of telomerase activity. This halts the synthesis of telomeres, and therefore limits the stem cells’ capacity to proliferate.
This new approach allows the researchers to functionally separate the two unique properties of stem cells – the ability to proliferate indefinitely and the ability to differentiate into various cell types. Doing so provides a way to overcome the current technical hurdles to making stem cell therapy safer.
Duke-NUS applied for patents for this technology in 2016. For more information on Duke-NUS IP related to Telomerase-Driven Cell Therapy, click here.