Direct Conversion Making Nerve From Skin, Without Stem Cells

Bioethics   |   David Prentice, Ph.D.   |   Aug 16, 2011   |   11:08AM   |   Washington, DC

A passel of scientific papers have recently reported the direct conversion of skin cells to nerve cells, without going through an intervening stem cell step.

No fewer than seven studies published in the last three months have shown different methods for directly converting ordinary skin cells into types of nerve cells.

The direct conversion technique, also called direct reprogramming, builds on the reprogramming work of Dr. Shinya Yamanaka. In 2006, Dr. Yamanaka announced his groundbreaking technique of adding four genes to a normal cell, reprogramming it to act like an embryonic stem cell, yet without use of embryos, eggs, or cloning. The newly-reprogrammed stem cell, termed an induced pluripotent stem cell (iPS cell), was first developed in mice, and then the same technique was shown to work with human cells in 2007. Yamanaka’s iPS cell method bypasses the ethical problems of embryonic stem cells. However, the iPS cells still need to be differentiated into specialized cell types for tissues, and still show the same practical problems of a tendency to form tumors, as seen with embryonic stem cells.

The even newer technique of direct conversion skips the stem cell intermediary, directly transforming one specialized cell type into another specialized cell type.

In late July, researchers at the Gladstone Institute led by Dr. Sheng Ding published details of an efficient method to turn human adult skin cells directly into functional brain cells. The technique, published in the journal Cell Stem Cell, uses two specific genes in combination with a small strand of genetic material called a microRNA; adding the three components to normal human skin cells converts the cells into nerve cells. The newly-formed nerve cells are functional, able to fire signals and form connections with other nerve cells.

An earlier publication by this group in May showed that mouse fibroblasts could be directly converted to neural stem cells, using a transient treatment with Yamanaka gene factors. The brief exposure to the gene factors produced neural stem cells that could be grown further in numbers in cell culture and then specialized to various types of nerve cells.

In early August, a collaboration of New York scientists showed that they could directly convert skin cells from Alzheimer’s patients into neurons, bypassing stem cells. The process they developed, published in the journal Cell, uses a set of three-five genes normally expressed in brain; the genes were introduced into fibroblast cells (generic connective tissue and skin cells) and the cells were grown in the presence of nerve-stimulatory factors. Within three weeks, the skin cells looked and acted like neuronal cells. When made from normal healthy adult skin cells, the new nerve cells could send and receive signals, just like normal neurons. Furthermore, when placed into the brains of developing mice, the converted nerve cells were able to connect with the existing nervous system circuitry. The researchers also converted skin cells from Alzheimer’s disease patients into nerve cells, and observed abnormalities in the converted nerve cells similar to those seen in Alzheimer’s brain cells. They hope to use the converted cells to study details of the disease and potentially to test therapeutic drugs.

In mid-August, the journal Nature published three separate papers describing methods for direct conversion of normal skin cells into nerve cells.

In one paper (Pang et al.), a group of Stanford researchers showed that forced expression of three-four genes could directly convert human iPS cells and human skin cells into functioning nerve cells, complete with functional connections to other nerve cells. They note that their method may provide patient-specific human neurons for lab-based modeling of disease and possibly future applications in regenerative medicine.” The paper had been previously published online in May.

A second group of Stanford scientists (Yoo et al.) took a different route, showing that small molecules called microRNA could nudge human skin cells into become neurons. While microRNA usually is involved in turning off expression of specific genes in a cell, in this case two specific microRNA molecules were sufficient to convince human skin cells to turn directly into nerve cells, and the efficiency could be enhanced by adding a few other genes associated with nerve development.

A third paper (Caiazzo et al.) published by an Italian group showed that mouse as well as human skin cells could be directly converted to functional dopaminergic neurons, using expression of three specific nerve-associated genes. Dopaminergic neurons are the type of nerves lost during Parkinson’s disease. The researchers found that they could produce this type of nerve from both healthy donors and Parkinson’s disease patients. The technique could have significance for studying Parkinson’s disease in the laboratory, as well as possible treatments.

Similar results were reported by a Swedish group in June. They found that they could directly convert human fibroblasts into nerve cells by adding three genes normally associated with nerves, and could specifically produce dopaminergic neurons by including two specific additional genes. Research leader Dr. Malin Parmar said he was surprised at how receptive the fibroblasts were to new instructions:

“We didn’t really believe this would work, to begin with it was mostly just an interesting experiment to try. However, we soon saw that the cells were surprisingly receptive to instructions.”

The Swedish team noted that using the direct conversion technique to bypass stem cells avoided the ethical problems inherent with embryonic stem cells, as well as the tendency of embryonic stem cells to form tumors. The paper was published in the journal Proceedings of the National Academy of Sciences.

The direct conversion technique provides a powerful, yet ethical, technique to produce various specialized cells in the lab.

Adult stem cells remain the gold standard for actual patient treatments.