Reprogramming cells with a nanochip, electricity and DNA to help the body to heal itself

The axolotl, a member of the salamander family, has amazing regenerative abilities. You can cut off its limbs or crush its spinal cord and it will repair itself with no scarring. A human’s healing powers, of course, are much more limited.

To get around this unfortunate fact, the field of regenerative medicine aims to develop stem cell-based therapies that provide the body with that extra oomph of regenerative ability to rid itself of disease or injury. But most of the current approaches in development rely on complex and expensive manufacturing processes in clinical labs before the cells can be safely transplanted in a patient’s body. Wouldn’t it be nice if we could just give the cells already in our bodies some sort of spark to allow them to repair other diseased or damaged cells?

A research team at Ohio State University have taken a fascinating step toward that seemingly science fiction scenario. Reporting this week in Nature Nanotechnology, the scientists describe a technique that – with some DNA, a nanochip and an electric current placed on the skin – can help mice regrow blood vessels to restore dying tissue.

Researchers demonstrate a process known as tissue nanotransfection (TNT). In laboratory tests, this process was able to heal the badly injured legs of mice in just three weeks with a single touch of this chip. The technology works by converting normal skin cells into vascular cells, which helped heal the wounds. Photo: Wexner Medical Center/The Ohio State University

The foundation of this technique is cellular reprogramming. Induced pluripotent stem cells are the most well-known example of reprogramming in which adult cells, like skin or blood, are converted, in a lab dish, to an embryonic stem cell-like state by introducing a set of reprogramming genes into the cells. From there, the stem cells can be specialized into any cell type.

Now, you wouldn’t want to convert skin or blood cells inside the body into quasi embryonic stem cells because they could generate tumors due to their limitless ability to multiply. In this study, the researchers rely on a related method, direct reprogramming, that skips the stem cell step and uses a different set of genes to directly convert one cell type into another. They focused on the direct reprogramming of skin cells to endothelial cells, a key component of blood vessels, in mice that were given symptoms mimicking those seen in human injury-induced limb ischemia. This condition leads to a risk of gangrene and amputation when severely injured limbs deteriorate due to blocked blood vessels.

It’s one thing to introduce, or transfect, reprogramming genes into cells that are grown in the very controlled environment of a petri dish. But how the heck does one get DNA into skin cells on the leg of a mouse? That’s where the team’s tissue nano-transfection (TNT) approach comes into the picture. After rubbing off a small section of dead skin on the leg, the TNT device, composed of an nanochip electrode and tiny channels of liquid containing reprogramming DNA, is placed on the skin. A short pulse of electricity is applied which opens miniscule holes in the membranes of skin cells that are in contact with the electrode which allows the DNA to enter the cells. Here’s a short video describing the process:

Three weeks after the procedure, blood vessels had formed, blood flow was restored and the legs of the mice were saved. Team leader, Dr. Chandan Sen, described the results in an interview with National Public Radio:

“Not only did we make new cells, but those cells reorganized to make functional blood vessels that plumb with the existing vasculature and carry blood.”

It’s surprising that TNT reprogramming affects more than just the skin cells that were in contact with the device. But it appears the reprogramming instructions from the introduced DNA was somehow spread to other cells through tiny vesicles called exosomes. When Sen’s team extracted those exosomes and introduced them to skin cells in a petri dish, those cells specialized into blood vessel cells.

This result did attract some skepticism from the field. In the NPR story, stem cell expert Dr. Sean Morrison had this to say:

“There are all manners of claims of these vesicles. It’s not clear what these things are, and if it’s a real biological process or if it’s debris.”

Clearly, more work is needed before TNT is ready for clinical trials in humans. But if it holds up, the technique could bring us closer to the incredible self-healing powers of the axolotl.

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