A beating heart muscle cell that was created from a human skin cell using a cocktail of only nine chemicals. This is the first instance of purely chemical cellular reprogramming, without adding external genes to the cell. [Nan Cao, Ph.D., Gladstone Institutes]

 

Neurons created from chemically induced neural stem cells. The cells were created from skin cells that were reprogrammed into neural stem cells using a cocktail of only nine chemicals. This is the first time cellular reprogramming has been accomplished without adding external genes to the cells. [Mingliang Zhang, Ph.D., Gladstone Institutes]
Neurons created from chemically induced neural stem cells. The cells were created from skin cells that were reprogrammed into neural stem cells using a cocktail of only nine chemicals. This is the first time cellular reprogramming has been accomplished without adding external genes to the cells. [Mingliang Zhang, Ph.D., Gladstone Institutes]

Cellular reprogramming of stem cells derived from one tissue type into a different vastly different tissue typically requires the labor-intensive use of external genes to modify and coax the existing genetic machinery down the desired path. Now, scientists at the Gladstone Institutes have established what they believe is a major breakthrough for stem cell research.

The researchers were able to transform skin cells into heart cells and brain cells using only a combination of chemicals. Previous research on cellular reprogramming required a complex amount of genetic engineering, which makes these new results an important discovery and accomplishment. Moreover, this study lays the groundwork for being able to regenerate lost or damaged cells with pharmaceutical drugs.

The results of this research were published recently in two different studies.  One was published in Science in an article entitled “Conversion of Human Fibroblasts into Functional Cardiomyocytes by Small Molecules.” The study’s second set of results were published in Cell Stem Cell in an article entitled “Pharmacological Reprogramming of Fibroblasts into Neural Stem Cells by Signaling-Directed Transcriptional Activation.”

In both studies, the Gladstone researchers used chemical cocktails to gradually coax skin cells to change into organ-specific stem cell-like cells and, ultimately, into heart or brain cells. 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,” explained co-senior author for both studies Sheng Ding, Ph.D., a senior investigator at the Roddenberry Center for Stem Cell Biology and Medicine within the Gladstone Institutes. “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.”

Because adult hearts have a limited ability to generate new cells, researchers have continually searched for ways to replace cells lost after a heart attack, such as transplanting adult heart cells or stem cells into the damaged heart. However, many of these efforts have been largely ineffective, as most transplanted adult cells fail to survive or integrate properly into the heart and few stem cells can be coaxed into becoming heart cells. Alternative approaches have used genes to convert scar-forming cells in the heart of animals into new muscle that improved the function of the heart. Yet, the Gladstone researchers hypothesized that a chemical reprogramming approach might offer an easier way to provide the cues that induce heart muscle to regenerate locally.

In the Science study, the researchers used a mixture of nine chemicals to change human skin cells into beating heart cells. Through trial and error, they found the best combination of chemicals to begin the process—changing the cells into a state resembling multipotent stem cells.

With this method, more than 97% of the cells started 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. Astonishingly, 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,” noted co-senior author on the Science paper Deepak Srivastava, M.D., director of cardiovascular and stem cell research at Gladstone. “Reprogramming a patient's own cells could provide the safest and most efficient way to regenerate dying or diseased heart muscle.”

In the Cell Stem Cell study, the scientists created neural stem cells from mouse skin cells using a similar approach. Once again the chemical cocktail consisted of nine molecules, some of which overlapped with those employed 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 three basic types of brain cells—neurons, oligodendrocytes, and astrocytes. The neural stem cells were also able to self-replicate, making them 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,” remarked co-senior author of the Cell Stem Cell paper Yadong Huang, M.D., Ph.D., a senior investigator at 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.”