Like the cells they work with, embryonic stem cell researchers must be flexible.
When they think they have devised the perfect cocktail of factors to turn embryonic stem (ES) cells into immune system cells, for example, they may have created a plate full of nerve cells instead.
That happened to Tiziano Barberi, Ph.D., assistant professor in the Division of Neurosciences, when he was a postdoctoral fellow at Memorial Sloan-Kettering Cancer Center in New York. “I wanted to use ES cells to make blood — and I ended up making neurons,” Barberi said. “I didn’t know whether what I was doing was interesting.”
It was so interesting, though, that Barberi and his former advisor — neuroscientist Lorenz Studer, M.D., Ph.D. — published several papers describing creation of nerve cells and other tissues from ES cells, the most recent of which was published this month in Nature Medicine.
The study reports generation of skeletal muscle cells from human ES cells. Previously, the group had cultured human ES cells together with mouse cells to induce ES cells to turn into bone, cartilage or skeletal muscle precursors. In a big breakthrough, their new method gets rid of the mouse cells.
As the name suggests, ES cells come from embryos — either mouse or human — and, unlike most adult stem cells, can form virtually any cell type of the body. Investigators often grow ES cells together with mouse cells, either to keep the ES cells from maturing or to induce them to turn into a specific cell type.
“If we want to move into a clinical setting, we have to get rid of mouse lines,” explains Barberi. “No one would accept growing human cells together with mouse cells that could be contaminated by viruses or things that you cannot control. You can’t put cells that have been in contact with a mouse cell into a patient.”
For the study, Barberi forced the precursors to mature into skeletal muscle — first in a tissue culture dish and then after transplantation into a living mouse. Not only did the human cells engraft in mice, but they also survived for a long period and continued to provide precursors to repair muscle.
At City of Hope, Barberi will research whether these cells could potentially repair muscle in muscular dystrophy patients. As a first step, he plans to inject human ES cell-derived muscle precursors into the bloodstream of a mouse that serves as an animal model of muscular dystrophy. “We hope that the cells will migrate through the vasculature and then grow and repair the muscle,” he said.
In collaboration with Joe Kornegay, D.V.M, Ph.D., at University of North Carolina at Chapel Hill, he will undertake similar experiments in a breed of golden retrievers naturally susceptible to muscular dystrophy. “These dogs have Duchenne muscular dystrophy exactly like unfortunate children,” he explained. If successful, these experiments could lead in the future to ES cell treatment that could alleviate or slow the progression of the disease in humans, for which there is no cure.
Among other projects, Barberi is trying to identify tumor-initiating cells — single cells that can give rise to a particular cancer — from the pediatric muscle tumor called rhabdomyosarcoma. The STOPCANCER Foundation funds the research.
He also is devising methods to make neural crest cells from ES cells. Neural crest cells form structures such as adrenal glands, facial bone and cartilage, as well as nearly the entire peripheral nervous system. Barberi collaborates with Caltech neural crest expert Marianne Bronner-Fraser, Ph.D., on this project.
At City of Hope he will also direct the Institutional Stem Cell Core Facility. Growing human ES cells requires both money and highly specialized training, and a facility will make the technology more readily available to investigators who do not specialize in stem cells. Added Barberi: “The core will also encourage people from neighboring institutes who don’t have a facility to come and do experiments here.”