A human heart cell that was chemically reprogrammed from a human skin cell. Credit: Nan Cao, PhD, Gladstone Institutes
Breakthrough 1st purely chemical cellular reprogramming, changing a cell’s identity without adding external genes. The research lays the groundwork for one day being able to regenerate lost or damaged cells with pharmaceutical drugs.
This discovery offers a more efficient and reliable method to reprogram cells and avoids medical concerns surrounding genetic engineering. “This method brings us closer to being able to generate new cells at the site of injury in patients,” said Sheng Ding, PhD. “Our hope is to one day treat diseases like heart failure or Parkinson’s disease with drugs that help the heart and brain regenerate damaged areas from their own existing tissue cells. This process is much closer to the natural regeneration that happens in animals like newts and salamanders, which has long fascinated us.”
An alternative approach to adult stem cell transplant was pioneered by Deepak Srivastava, MD, director of cardiovascular and stem cell research at Gladstone, used genes to convert scar-forming cells in the heart of animals into new muscle that improved the function of the heart. A chemical reprogramming approach to do the same may offer an easier way to provide the cues that induce heart muscle to regenerate locally.
In the Science study, the researchers used a cocktail of 9 chemicals to change human skin cells into beating heart cells. By trial and error, they found the best combination of chemicals to begin the process by changing the cells into a state resembling multi-potent stem cells, which can turn into many different types of cells in a particular organ. A second cocktail of chemicals and growth factors helped transition the cells to become heart muscle cells. More than 97% of the cells began beating, a characteristic of fully developed, healthy heart cells. The cells also responded appropriately to hormones, and molecularly, they resembled heart muscle cells, not skin cells. What’s more, when the cells were transplanted into a mouse heart early in the process, they developed into healthy-looking heart muscle cells within the organ.
“The ultimate goal in treating heart failure is a robust, reliable way for the heart to create new muscle cells,” said Srivastava, co-senior author on the Science paper. “Reprogramming a patient’s own cells could provide the safest and most efficient way to regenerate dying or diseased heart muscle.”
In the second study, the scientists created neural stem cells from mouse skin cells using a similar approach. The chemical cocktail again consisted of 9 molecules, some of which overlapped with those used in the first study. Over 10 days, the cocktail changed the identity of the cells, until all of the skin cell genes were turned off and the neural stem cell genes were gradually turned on. When transplanted into mice, the neural stem cells spontaneously developed into the 3 basic types of brain cells: neurons, oligodendrocytes, and astrocytes. The neural stem cells were also able to self-replicate, ideal for treating neurodegenerative diseases or brain injury.
“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 Yadong Huang, MD, PhD, Gladstone. “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.” https://gladstone.org/about-us/news/scientists-turn-skin-cells-heart-cells-and-brain-cells-using-drugs
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