Researchers publishing in Nature Biotechnology have demonstrated a method of protecting mass-produced stem cells from the immune system, with strongly positive results in two different animal models.
Fake ID for the immune system
While it would be ideal to create stem cells from each person’s existing cells to replace that particular person’s needs and losses, this is still expensive, difficult, and time-consuming. Therefore, there is a great unmet medical need for readily available, off-the-shelf stem cell therapies, both within and outside the context of aging. For example, mass-produced, insulin-producing beta cells could potentially be an effective treatment for diabetes [1].
However, one core problem with this approach is the reaction of the host’s immune system to the grafted cells, and this challenge has to be addressed for these cells to survive. Previous approaches have involved isolating the grafted cells [2] and administering immunosuppressants [3], as is done with organ transplants. Those approaches, however, have their own problems, limiting functionality and causing side effects.
This team of researchers has taken the immune system head-on, focusing on the particular factors that cause it to react. Healthy natural killer (NK) cells are zealous defenders, and if other cells present a chemical identifier that NK cells don’t like, the NK cells will attack to kill. Some previous work in this area has focused on suppressing this identifier, human leukocyte antigen (HLA), in its entirety [4], but this is of limited effectiveness; the NK cells will still attack if the other cells don’t present any ID at all [5].
The goal of this paper was to discover a form of universal fake ID: something that could be introduced into off-the-shelf stem cells to discourage NK cells from attacking, regardless of the recipient.
A single compound seems to be sufficient
The researchers chose four potential targets: HLA-E, HLA-G, PD-L1, and CD47, injecting stem cells that overexpressed these proteins into humanized mice. The first three targets only protected them against NK cells that had the respective receptors, which not all NK cells did. For example, an NK cell that did not recognize HLA-E would still kill a cell that expressed HLA-E. On the other hand, CD47 seemed to be universal in stopping NKs from attacking, and it stopped T cell activation as well.
The researchers then turned to a primate model, rhesus macaques, to confirm these findings. As expected, injecting normal human stem cells into these monkeys caused the monkeys’ T cells, NK cells, and macrophages to react. However, when the researchers took human stem cells, removed their natural identifiers, and caused them to express rhesus macaque CD47, these stem cells were free to proliferate unchecked.
Encouraged, the researchers developed stem cells from this species of monkey, performed the same experiment, and got similar results. The monkeys’ immune systems did not attack, and the engrafted cells divided unrestrained without any unusual inflammatory response, achieving long-term survival.
Finally, the researchers returned to humanized mice, finding that CD47-expressing, insulin-producing cells functioned as intended, reducing the severity of diabetes in a mouse model weeks after injection. The cells had been transplanted successfully without harming the immune systems of the mice.
A true magic bullet?
While it’s obviously a bad idea to inject immune-uncontrolled, freely proliferating cells into human beings, these results are extremely promising on every level. Efforts should be made to determine whether or not this approach actually works, particularly in people. If CD47 expression works as well in human trials as it did in the mice and rhesus macaques in this study, immune rejection of mass-produced stem cells may be relegated to history.
Literature
[1] Kieffer, T. J. (2016). Closing in on mass production of mature human beta cells. Cell stem cell, 18(6), 699-702.
[2] Vegas, A. J., Veiseh, O., Gürtler, M., Millman, J. R., Pagliuca, F. W., Bader, A. R., … & Anderson, D. G. (2016). Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice. Nature medicine, 22(3), 306-311.
[3] Du, Y., Liang, Z., Wang, S., Sun, D., Wang, X., Liew, S. Y., … & Deng, H. (2022). Human pluripotent stem-cell-derived islets ameliorate diabetes in non-human primates. Nature Medicine, 28(2), 272-282.
[4] Mattapally, S., Pawlik, K. M., Fast, V. G., Zumaquero, E., Lund, F. E., Randall, T. D., … & Zhang, J. (2018). Human leukocyte antigen class I and II knockout human induced pluripotent stem cell–derived cells: universal donor for cell therapy. Journal of the American Heart Association, 7(23), e010239.
[5] Deuse, T., Hu, X., Agbor-Enoh, S., Jang, M. K., Alawi, M., Saygi, C., … & Schrepfer, S. (2021). The SIRPα–CD47 immune checkpoint in NK cells. Journal of Experimental Medicine, 218(3).
