Additional tool accelerates personalized medicine research
Johns Hopkins stem cell biologists have found a way to reprogram a patient’s skin cells into cells that mimic and display many biological features of a rare genetic disorder called familial dysautonomia.
courtesy Cell Press
Neural crest cells were made from reprogrammed adult skin cells. A single neural crest cell divided many times and these cells (green) were coaxed to become four different types of adult cells, as shown by the presence of cell-specific proteins (red). Clockwise from upper left corner: nerve cells, smooth muscle cells, pigment-producing skin cells and cells that protect and support nerve cells.
The process requires growing the skin cells in a bath of proteins and chemical additives while turning on a gene to produce neural crest cells, which give rise to several adult cell types.
The researchers say their work substantially expedites the creation of neural crest cells from any patient with a neural crest-related disorder, a tool that lets physicians and scientists study each patient’s disorder at the cellular level.
Previously, the same research team produced customized neural crest cells by first reprogramming patient skin cells into induced pluripotent stem (iPS) cells, which are similar to embryonic stem cells in their ability to become any of a broad array of cell types.
“Now we can circumvent the iPS cells step, saving seven to nine months of time and labor and producing neural crest cells that are more similar to the familial dysautonomia patients’ cells,” says Gabsang Lee, Ph.D., an assistant professor of neurology at the Institute for Cell Engineering and the study’s senior author. A summary of the study will be published online in the journal Cell Stem Cell on Aug. 21.
Neural crest cells appear early in human and other animal prenatal development, and they give rise to many important structures, including most of the nervous system (apart from the brain and spinal cord), the bones of the skull and jaws, and pigment-producing skin cells.
Dysfunctional neural crest cells cause familial dysautonomia, which is incurable and can affect nerves’ ability to regulate emotions, blood pressure and bowel movements. Less than 500 patients worldwide suffer from familial dysautonomia, but dysfunctional neural crest cells can cause other disorders, such as facial malformations and an inability to feel pain.
The challenge for scientists has been the fact that by the time a person is born, very few neural crest cells remain, making it hard to study how they cause the various disorders.
To make patient-specific neural crest cells, the team began with laboratory-grown skin cells that had been genetically modified to respond to the presence of the chemical doxycycline by glowing green and turning on the gene Sox10, which guides cells toward maturation as a neural crest cell.
Testing various combinations of molecular signals and watching for telltale green cells, the team found a regimen that turned 2 percent of the cells green. That combination involved turning on Sox10 while growing the cells on a layer of two different proteins and giving them three chemical additives to “rewind” their genetic memory and stimulate a protein network important for development.
Analyzing the green cells at the single cell level, the researchers found that they showed gene activity similar to that of other neural crest cells. Moreover, they discovered that 40 percent were “quad-potent,” or able to become the four cell types typically derived from neural crest cells, while 35 percent were “tri-potent” and could become three of the four. The cells also migrated to the appropriate locations in chick embryos when implanted early in development.
The team then applied a modified version of the technique to skin cells from healthy adults and found that the skin cells became neural crests at a rate similar to the team’s previous experiments.
Finally, the investigators used their regimen on skin cells from patients with familial dysautonomia, then compared these familial dysautonomia-neural crest cells to the control neural crest cells made from healthy adults. They identified 412 genes with lower activity levels in the familial dysautonomia-neural crest cells, of which 98 are involved in processing RNA products made from active genes.
According to the authors, this new observation offers insight into what goes wrong in familial dysautonomia.
“It seems as though the neural crest cells created directly from patient skin cells show more of the characteristics of familial dysautonomia than the neural crest cells we created previously from induced pluripotent stem cells,” says Lee. “That means they should be better predictors of what happens in a particular familial dysautonomia patient, and whether or not a potential treatment will work for any given individual.”
The method they devised should also be applicable to skin cells taken from people with any of the other diseases that result from dysfunctional neural crest cells, such as congenital pain disorders and Charcot-Marie-Tooth diseases, Lee says.
Other authors of the report include Yong Jun Kim, HoTae Lim, Zhe Li, Yohan Oh, Irina Kovlyagina, InYoung Choi and Xinzhong Dong of the Johns Hopkins University School of Medicine.
This work was supported by grants from the New York Stem Cell Foundation (Robertson Investigator Award) and the Maryland Stem Cell Research Fund (TEDCO).
On the Web:
Link to article (live after embargo lifts): http://dx.doi.org/10.1016/j.stem.2014.07.013
Senior Communications Specialist
Catherine Kolf | newswise
Identifying drug targets for leukaemia
02.05.2016 | The Hong Kong Polytechnic University
A cell senses its own curves: New research from the MBL Whitman Center
29.04.2016 | Marine Biological Laboratory
If a person pushes a broken-down car alone, there is a certain effect. If another person helps, the result is the sum of their efforts. If two micro-particles are pushing another microparticle, however, the resulting effect may not necessarily be the sum their efforts. A recent study published in Nature Communications, measured this odd effect that scientists call “many body.”
In the microscopic world, where the modern miniaturized machines at the new frontiers of technology operate, as long as we are in the presence of two...
Researchers from the Max Planck Institute Stuttgart have developed self-propelled tiny ‘microbots’ that can remove lead or organic pollution from contaminated water.
Working with colleagues in Barcelona and Singapore, Samuel Sánchez’s group used graphene oxide to make their microscale motors, which are able to adsorb lead...
Neutron scattering and computational modeling have revealed unique and unexpected behavior of water molecules under extreme confinement that is unmatched by any known gas, liquid or solid states.
In a paper published in Physical Review Letters, researchers at the Department of Energy's Oak Ridge National Laboratory describe a new tunneling state of...
Honeycomb structures as the basic building block for industrial applications presented using holo pyramid
Researchers of the Alfred Wegener Institute (AWI) will introduce their latest developments in the field of bionic lightweight design at Hannover Messe from 25...
Polymer solar cells can be even cheaper and more reliable thanks to a breakthrough by scientists at Linköping University and the Chinese Academy of Sciences (CAS). This work is about avoiding costly and unstable fullerenes.
Polymer solar cells can be even cheaper and more reliable thanks to a breakthrough by scientists at Linköping University and the Chinese Academy of Sciences...
27.04.2016 | Event News
15.04.2016 | Event News
12.04.2016 | Event News
02.05.2016 | Power and Electrical Engineering
02.05.2016 | Trade Fair News
02.05.2016 | Earth Sciences