October 27, 2020

The Niche

Knoepfler lab stem cell blog

Stem cells gone wild? What really happens after a transplant

What really happens to cells after they a stem cell transplant into a patient?

Geron, stem cell transplant
Geron.

Once these cells, which have spent weeks in a lab environment, are injected into a person, what happens next?

This is arguably the most important question in the regenerative medicine field, but there are few answers. We are literally mostly in the dark about what cells do after transplant, but there are some things that can be predicted pretty confidently.

Barring the introduction of some kind of suicide gene, once cells are transplanted into a patient, nobody has any control over them at all. They are free to do whatever their programming tells them and whatever the host body will allow them. One good analogy is that they are like pets (domesticated cells used to living in a lab) released or who wander into the wild (the universe of trillions of cells of a human body).  How does Rover behave?  He might not make it. He might survive but still act like a dog or his wild instinct might start taking over.

After cells are transplanted, what happens first?

Let’s take a hypothetical look at the case of Geron’s GRNOPC1 treatment, which now has been given to two spinal cord injury patients.

What happens when doctors inject 2 million OPCs (oligodendrocyte progenitor cells)  into a patient?

The first thing is that the shock of being transplanted kills a significant fraction of the cells. Going from a relatively cozy home growing in media designed to make them happy to the injured spinal cord (or any other tissue in vivo) is an enormous shock. It may be sort of like what happens when you go from a sauna and jump into an icy lake, except multiply the shock by 10-fold. The pH is likely different, the temperature may be a degree or two different, the salt concentration outside the cell is different, there’s a difference in pressure, and then there are certainly going to be some immune cells realizing that the transplanted cells are foreign even if a full immune response is not initiated because of transient immune suppression.

Let’s say despite all of this, that half of the transplanted OPCs survive so there are 1 million, reasonably happy cells left soon following the transplant. The number could be lower, but let’s work with this figure.

What do they do next? A key question is “Do the remaining OPCs proliferate?”  Do the cells undergo cell division?

An interesting publication by Dr. Hans Keirstead in 2005 indicates that in a pre-clinical rodent model, transplanted OPCs do proliferate to some extent. You can read this paper here.  What happens in a human recipient? Who knows, but let’s say the cells on average divide once after transplant. That means our 1 million survivors will turn into 2 million cells before cell division is generally over. This is a fine line to walk because limited proliferation is a good thing, but too much or sustained proliferation is undesirable.  It could lead to tumor formation.

What next?

Another important question follows: do the cells stay put? Do they migrate? Keirstead’s paper says they do migrate in pre-clinical studies.

Like proliferation, this is kind of a double-edged sword. In some sense you do not want the cells to stay exactly where you put them. You want them to migrate through part of the region of injury and do their work as little micro-doctors to heal. On the other hand you do not want the cells to go too far to exit the spinal cord because they could end up doing the wrong thing if they are in the wrong place. We recently did a blog post from the ASGCT meeting in Seattle where Geron VP Lebkowski gave a talk. In it she said they monitored for undesired presence of OPC1 cells outside the spinal cord, and did not detect any. So that’s good news.

What does this all mean? The bottom line is that once cells are transplanted, they will do whatever their molecular instructions and the surrounding environment tells them to do. And at this point, the field is so new we do not know much about how this will all play out.  However, based on pre-clinical data there is reason for hope that the cells will behave well and act to heal.

In the case of Viacyte, since their product is encapsulated, there is control over the transplanted cells since they, in theory at least, cannot escape the capsule (and even if they did the immune system of the host would likely kill them)  and the capsule could even be removed easily by doctors if need be. But that is not an approach that is likely to help the injured spinal cord.

While it is true that there is data from bone marrow transplants, which are a form of regenerative medicine, that is very different from the kind of therapies people are imagining now because with bone marrow transplant you destroy the normal marrow first, and the transplanted cells have to home through the blood to the mostly empty marrow space, a process that alone can take months.

As the field of regenerative medicine advances, we will learn a lot more about how transplanted cells behave in a patient. In the mean time we wait to see what the earliest studies tell us about how transplanted cells behave.

I am cautiously optimistic.

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