Researchers Demonstrate the Use of Thymus Organoids to Generate T Cells from Induced Pluripotent Stem Cells

One of the potential approaches to ameliorate the age-related failure of the immune system is to periodically inject competent T cells in large numbers. This could compensate to some degree for the greatly diminished rate at which new T cells are created in older individuals. For what it is worth, I think there are much better approaches, but this one is arguably closer to feasibility. Nonetheless, the goal isn't as easy to accomplish as it is to describe. The mix of T cell types must be appropriate, roughly the same as is generated naturally in young people. The T cells must go through a complex multi-stage process of maturation, to gain self-tolerance and correct function. This maturation occurs in the thymus, an organ that atrophies in old age, so while it has been possible for years now to generate immature T cells, called thymocytes, from patient-matched induced pluripotent stem cells, injecting them into the body would run right into the problem of a run-down and poorly functional thymus.

In the research results I'll point out today, scientists demonstrate that thymus tissue grown outside the body can be used to mature T cells in volume. That means that patient-matched T cells for therapy in arbitrary numbers are a feasible goal. Generate induced pluripotent stem cells from a patient skin sample, then build thymus organoids from that starting point. Lastly run thymocytes produced from the same induced pluripotent stem cells through the organoids. The output is a supply of functional patient-matched T cells, though as noted, there are still problems to be ironed out.

Patient-matched cells for any use are an expensive prospect, however. Present therapies with this requirement are among the most costly of any modern medicine. Further, they require a great deal of time to deploy. Months can pass between obtaining an initial patient tissue sample and the readiness of cells for therapy. A major focus for the research community is to find ways, wherever possible, to create universal cell lines. A universal cell line centralizes all of the hard work, and the therapies that employ it can thus be much less costly, and more rapidly deployed. This is a plausible goal for immune cells, where the adjustments required to render them non-patient-specific are fairly well understood.

As an additional thought on this topic, it is worth noting that Lygenesis is in the business of developing therapies based on the implantation of thymus organoids into lymph nodes. This has been demonstrated to restore the natural supply of T cells in animal models. Given that project, using thymus organoids to produce patient-matched T cells seems unnecessarily convoluted. Expensive or not, it is an extra step that isn't needed, provided that the Lygenesis approach can be made to work in humans reliably enough to get past the regulatory gauntlet.

Scientists create a renewable source of cancer-fighting T cells

T cell therapies, including CAR T-cell therapy, have shown great promise for treating certain types of cancer. Current approaches involve collecting T cells from a patient, genetically engineering the T cells with a receptor that helps them recognize and destroy cancer cells, and then infusing the cells back into the patient. But engineered T cells do not always function well, treatment is expensive because it is tailored to each patient, and some people with cancer don't have enough T cells to undergo the therapy. Therefore, a technique that produces T cells without relying on collecting them from patients is an important step toward making T cell therapies more accessible, affordable and effective.

Other researchers have been only partially successful in their attempts to generate T cells using methods that involve combining pluripotent stem cells with a layer of supporting cells. But the T cells produced in those previous studies did not mature to become fully functional T cells. However, it was demonstrated that the 3D structure of an artificial thymic organoid allowed mature T cells to develop from adult blood stem cells. A new study now demonstrates the use of such organoids to coax pluripotent stem cells - which can give rise to every cell type in the body and which can be grown indefinitely in the lab - into becoming mature T cells capable of killing tumor cells.

The research demonstrated that artificial thymic organoids can efficiently make mature T cells from both kinds of pluripotent stem cells currently used in research: embryonic stem cells, which originate from donated embryos, and induced pluripotent stem cells, which are created by reprogramming adult skin or blood cells back to an embryonic-like state. The researchers also showed they could genetically engineer pluripotent stem cells to express a cancer-targeting T cell receptor and, using artificial thymic organoids, generate T cells capable of targeting and killing tumor cells in mice.

Organoid-Induced Differentiation of Conventional T Cells from Human Pluripotent Stem Cells

Engineered T cell therapies hold promise for the effective treatment of cancer and chronic viral infections. The ability to generate T cells on demand from self-renewing human pluripotent stem cells (PSC) may substantially advance the cell therapy field by permitting production of universal-donor T cells from stably gene-modified PSC lines. Although protocols to differentiate PSC into essentially any non-hematopoietic or hematopoietic lineage have been extensively reported, generation of fully functional mature T cells that resemble their adult counterparts has been more problematic. Differentiation of T cells from human PSCs has been limited on two fronts: the ability to specify hematopoietic progenitor cells with T-lineage potential, and the capacity of existing methods to support the positive selection and maturation of T-lineage committed precursors to conventional, naive T cells.

We recently reported that a three-dimensional (3D) artificial thymic organoid (ATO) culture system permits in vitro differentiation of human HSPCs to functional, mature T cells using a standardized Notch ligand-expressing stromal cell line in serum-free conditions. Notably, we observed that both the medium and the 3D structure were critical. We report here that a modified ATO system (PSC-ATO) permits the differentiation of human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC)-derived human embryonic mesodermal progenitors (hEMPs) to mature, conventional T cells in vitro.

Comments

@Reason, others: Will the same be possible with heart. Implant heart organdies into lymph nodes so a person can live without the heart?

Posted by: thomas.a at January 23rd, 2019 5:40 PM

@Thomas
Speaking allegorically there after people without heart. However, there heart has a macro function of pumping and moving the blood around. If you replace it with a bunch of smaller pumps it might work. In fact, there are artificial hearts and pumps that don't have to replace the natural hearts but rather supplement and aid the blood flow.

What's interesting if we can grow and implant a pancreatic organoid. Even if it provides less than 100 percent of the needed insulin it would be very helpful for diabetes type one patients.

There might be other hormones that might be produced by imperfect organoids..

Posted by: Cuberat at January 23rd, 2019 8:58 PM

@thomas.a: No. This only works for factory-like organs for which larger-scale structure and location are not important.

Posted by: Reason at January 23rd, 2019 8:59 PM

It seems more research should be done on improving the NK cell population in the elderly, as NK levels decline rapidly after 60 with normal aging. Often it is accompanied by zinc deficiency which is necessary for NK cell response.

Posted by: Biotechy Marcks at January 24th, 2019 12:35 PM

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