Towards Universal Cell Lines and Tissues Grown from Induced Pluripotent Stem Cells

There is an enormous difference in logistics and cost between cell therapies that must use a patient's own cells and cell therapies that arise from a single universal cell line that can be used in any patient. While in principle it is perfectly possible to reprogram a patient's cells into induced pluripotent stem cells, differentiate those cells into the desired cell type, and then even grow functional organoids, that all takes a lot of time and effort, and is as yet far from reliable. It would be much cheaper and much faster to have a factory producing cell lines and organs that can be universally used. When organs and other large tissue sections can be reliably grown from cells in the laboratory, this point will also apply there.

Given that, it is interesting to see signs of progress towards the production of induced pluripotent stem cells that lack the features that would cause a recipient immune system to attack them, but can nonetheless survive in the body. Achieving this goal is the basis for a much more cost-effective regenerative medicine and tissue engineering industry.

The immune system is unforgiving. It's programmed to eradicate anything it perceives as alien, which protects the body against infectious agents and other invaders that could wreak havoc if given free rein. But this also means that transplanted organs, tissues or cells are seen as a potentially dangerous foreign incursion, which invariably provokes a vigorous immune response leading to transplant rejection. When this occurs, donor and recipient are said to be - in medical parlance - "histocompatibility mismatched."

In the realm of stem cell transplants, scientists once thought the rejection problem was solved by induced pluripotent stem cells (iPSCs), which are created from fully-mature cells - like skin or fat cells - that are reprogrammed in ways that allow them to develop into any of the myriad cells that comprise the body's tissues and organs. If cells derived from iPSCs were transplanted into the same patient who donated the original cells, the thinking went, the body would see the transplanted cells as "self," and would not mount an immune attack. But in practice, clinical use of iPSCs has proven difficult. For reasons not yet understood, many patients' cells prove unreceptive to reprogramming. Plus, it's expensive and time-consuming to produce iPSCs for every patient who would benefit from stem cell therapy.

Scientists wondered whether it might be possible to sidestep these challenges by creating "universal" iPSCs that could be used in any patient who needed them. In their new paper, they describe how after the activity of just three genes was altered, iPSCs were able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems. The researchers first used CRISPR to delete two genes that are essential for the proper functioning of a family of proteins known as major histocompatibility complex (MHC) class I and II. MHC proteins sit on the surface of almost all cells and display molecular signals that help the immune system distinguish an interloper from a native. Cells that are missing MHC genes don't present these signals, so they don't register as foreign. However, cells that are missing MHC proteins become targets of immune cells known as natural killer (NK) cells.

The team found that CD47, a cell surface protein that acts as a "do not eat me" signal against immune cells called macrophages, also has a strong inhibitory effect on NK cells. Believing that CD47 might hold the key to completely shutting down rejection, the researchers loaded the CD47 gene into a virus, which delivered extra copies of the gene into mouse and human stem cells in which the MHC proteins had been knocked out. CD47 indeed proved to be the missing piece of the puzzle. When the researchers transplanted their triple-engineered mouse stem cells into mismatched mice with normal immune systems, they observed no rejection.

Link: https://www.ucsf.edu/news/2019/02/413311/crispr-gene-editing-makes-stem-cells-invisible-immune-system

Comments

Sounds like great news. I'm a total dummy when it comes to biology, but those universal cells won't have the patients' DNA right ?

Posted by: Jonathan Weaver at February 22nd, 2019 6:45 AM

I'm not an immune system expert, but I feel like there might be some unintended consequences from giving cells a blank check like this process seems to be; both the aberrant senescent cells that accumulate with age and cancer cells are characterized by evasion of immune surveillance. I admit not really familiar with the mechanism by which that occurs, but wouldn't this be giving these cells one of the hallmarks of cancer straight out of the gate?

Posted by: Dylan Mah at February 22nd, 2019 8:13 AM

We can remove telomerase gene from those cells to remove any risk of cancer.

Posted by: Ariel at February 23rd, 2019 10:40 AM

@Ariel: Can we say that for sure though? Certain cancers exhibit telomerase independent mechanisms for maintaining telomeres, so called ALT pathways, otherwise telomerase inhibitors would be the cure for cancer; are we really that sure ALT capable cancer won't be able to spontaneously emerge?

Posted by: Dylan James Mah at February 24th, 2019 10:36 AM

We don't remove telomerase from cancer cells now for other reason: we cannot make the removal selective. We will kill not only cancer cells but all adult stem cell.

ALT causes only 10 - 15% of cancer and their genes can be removed as well in principle.

Posted by: Ariel at February 24th, 2019 11:06 AM

As far as books say there are only two known ways cancer can grow: telomerase and ALT

Posted by: Ariel at February 24th, 2019 11:09 AM

Regardless of the mechanism we can in theory create cancer-resistant or at least not very cancer prone cell lines. Might have triple or quadruple dna repair modules, backup mitochondrial proteins in the nucleus, and make the sells easier to kill too in case they go rogue. If we can have multiple lines in the same person and those lines might be easy to kill individually by using some exotic small molecule.

Additionally, those cells might be resistant to other dangers like having macrophages gracefully handling the oxidized lipids without dying. Or HIV resistance. There are lot of possibilities if the technology works in humans...

Posted by: cuberat at February 24th, 2019 6:24 PM

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