Using Patient Stem Cells to Make “Heart-Disease-on-a-Chip”


Personalized medicine is a new but quickly advancing innovation in medicine that tailors the diagnosis and treatment of a particular patient according to their specific genetic and physiological idiosyncrasies. As an example, if a patient has high blood pressure, which treatment would work the best? If the patient is an African-American, it is unlikely that a group of drugs called ACE inhibitor or another group called ARBs would work terribly well because African-American patients tend to lack sufficient quantities of the targets of these two type of drugs for them to work properly. Therefore, diuretics or beta blockers are better drugs to lower the blood pressure of such patients.

Other examples include the enzymes that chemically modify drugs are they circulate throughout our bodies. Some patients have excessive amounts of a liver enzyme called CYP2D6, and this enzyme modifies the painkiller codeine.  Codeine, you see, is not given in an active form.  It only becomes active after the liver enzyme CYP2D6 modifies it.  People with large amounts of CYP2D6, which includes about 10% of Arabs, over-activate codeine, which causes side effects like profound sedation and stomach cramps (codeine or hydrocodone is a form of morphine).  Therefore, before the patient is prescribed codeine, which is present in several different types of prescription painkillers (e.g., Norco, Lortab, Tusnel-HC, Canges-HC, Drocon-CS, Excof-SF, TriVent-HC, etc.), it would be immensely useful to know if your patient had this condition in order to cut their codeine dose or prescribe an altogether different pain-killer.

Now that you have, hopefully been convinced that personalized medicine can potentially save lives, I hope to tell you about a new advance that brings stem cells into the personalized medicine arena.  Kevin Kit Parker and William Pu have used stem cell and “organ-on-a-chip” technologies to grow functioning heart tissue that carries an inherited cardiovascular disease.  This research appears to be a big step forward for personalized medicine.

Parker and Pu modeled a cardiovascular disease called Barth Syndrome, which is caused by mutations on a gene that resides on the X chromosome called TAZ, which encodes the Tafazzin protein.  Barth Syndrome is also affects heart and skeletal muscle function.  Skin biopsies were taken from two male patients who suffer from Barth Syndrome.  These cells were de-differentiated into induced pluripotent stem cells (iPSCs) that were further differentiated into heart muscle cells.  To differentiate the iPSCs into heart muscle cells , the cells were grown on small slides known as chips lined with human extracellular matrix proteins that mimicked the environment of the human heart.  The cells were tricked into thinking that they were in a heart and they differentiated into heart tissue.  Not surprisingly, the heart tissue made on a chip contracted very weakly compared to normal heart tissue.

To confirm that they were not barking up the wrong tree, Parker and Pu used normal cells that had been genetically engineered to possess mutations in the TAZ gene.  When these engineered cells were used to make heart tissue on a chip, they too contracted very weakly.  This told Parker and Pu that they were definitely on the right track.

“You don’t relay understand the meaning of a single cell’s genetic mutation until you build a huge function,” said Parker, who has spent over a decade working on “organs-on-a-chip” technology.  “In the case of the cells grown out of patients with Barth Syndrome, we saw much weaker contractions and irregular tissue assembly.  Being able to model the disease from a single cell all the way up to heart tissue, I think that’s a big advance.”.

The TAZ mutation disrupts the activity of the powerhouse of the cell, a small structure called the mitochondrion.  Even though the TAZ mutation did not affect the over all energy supply of the cells, it seems to affect the way the heart muscle constructs itself so that it can properly contract.

Since mitochondria use a process known as oxidative phosphorylation to make the lion share of their chemical energy in the form of the molecule ATP (adenosine triphosphate), mitochondria also generate toxic byproducts called reactive oxygen species or ROS.  Cells have mechanisms to squelch ROS, but these mechanisms can be overwhelmed if cells make excessive quantities of ROS.  Heart muscle that contains the TAZ mutation seems to make excessive quantities of ROS, and this affects the integrity of the heart muscle.

Can drugs that quench ROS be used to retreat patients with Barth Syndrome?  It is difficult to say, but this chip-on-a-dish is surely an excellent model system to determine if such an approach can work.  Already, Pu and his colleagues are testing drugs to treat this disorder by testing those drugs on heart tissue grown on chips.

“We tried to thread multiple needles at once and it certainly paid off,” said Parker.  “I feel that the technology that we’ve got arms industry and university-based researchers with the tools they need to go after this disease.”.

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Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).