Chemical Hacking Lets Skin Cells Beat as Heart Cells

... and function as neurons.

Apr 27 2016, 6:00pm

Image: Oleksandr Lysenko/Shutterstock

Researchers from the Gladstone Institute have reprogrammed non-cardiac cells to serve as healthy replacement cells in damaged heart tissue. The work, which is described in this week's issue of Science, offers rare hope for a mostly hopeless health condition.

Heart disease is a bleak death—a mostly irreversible downward spiral in which the heart itself becomes progressively less viable. It is also how most Americans will die, according to CDC statistics. The numbers say that you, in particular, will probably die of heart failure, as will I.

Heart failure goes a little something like this. Thanks to the usual combo of poor diet and sedentary lifestyle—meat, fat, desks—a person will have a heart attack. A blood vessel will become blocked. This blockage will deprive some part of their heart of the blood it needs to do its job and to just survive. This tissue dies.

It's replaced by scar tissue, but scar tissue doesn't do the same work as regular cardiac tissue. It's just sort of filler. The heart will try to compensate by getting bigger and seemingly more capable, as it tries to ensure that as much oxygenated blood is being pumped away from the heart as is received by it from the lungs. It works harder, strains harder. Meanwhile, the damaged heart's already narrowed, and crusty blood vessels struggle to keep up with the increased demand from the straining, wheezing heart.

It's time for heart-attack number two.

Image: Mingliang Zhang/Gladstone Institutes

Eventually, the heart just can't keep up—not enough blood is being pumped out, and so it backs up in different parts of the body, where fluid leaks into surrounding tissues, causing the characteristic swelling of congestive heart failure. So, whoever comes up with a viable way to repair heart tissue stands to save and improve a great many lives. Maybe yours.

Last ditch interventions current include heart transplants and temporary artificial hearts. Neither are something you really want to bank on.

These researchers found a method of first inducing skin cells to behave as polymorphic cells known as fibroblasts, which are responsible for synthesizing various types of connective tissues. In a second stage, they took the fibroblasts, and, through another process of chemical hacking, turned them into functioning heart cells. (This is all in mice, so far.)

Crucially, the manipulation involved is not genetic, thus avoiding certain pitfalls of DNA tweaking, such as rejection by the body's immune system. By using combinations of chemicals, the researchers were able to not so much make one sort of cell into another, but change the functioning of one sort of cell into that of another. It winds up being an important distinction.

"Small molecules have certain advantages," the paper explains. "They are convenient to use, can be efficiently delivered into cells, provide greater temporal control, are nonimmunogenic and more cost-effective. Moreover, their effects can be fine-tuned by varying their concentrations and combinations."

These researchers began with a pool of 89 different molecules known to induce cell reprogramming. Different combinations were tested in conditions chemically mimicking those of an actual heart. Eventually, they were able to narrow things down to two different chemical cocktails. The first set did the work of tricking skin cells into acting like fibroblasts, while the second turned the fibroblasts into functioning heart cells.

Eventually, 97 percent of the original skin cells began beating as heart cells. That's pretty neat.

The researchers are nonetheless cautious. "This finding may lay a foundation for ultimate in situ repair of the heart by targeting endogenous cardiac fibroblasts with small molecules," the paper concludes. "However, many critical challenges (e.g., reprogramming efficiency and tissues-specific delivery of multiple drugs in an efficient and controllable manner) need to be resolved before this strategy can be considered for in vivo therapeutic applications."

In the meantime, maybe we can just go running.

In a separate study out this week in the journal Cell Stem Cell, the same group describe pulling off basically the same trick, with neurons. The chemical cocktail required to get from skin cell to functioning brain cell was different, but the basic idea was the same. What's more, neural stem cells were able to self-replicate, a required property for repairing damaged tissue.

"With their improved safety, these neural stem cells could one day be used for cell replacement therapy in neurodegenerative diseases like Parkinson's disease and Alzheimer's disease," said co-senior author (of the second study) Yadong Huang in a statement.

"In the future, we could even imagine treating patients with a drug cocktail that acts on the brain or spinal cord, rejuvenating cells in the brain in real time."