Stem Cell Treatments Cure Mice With MS-Like Disease


University of California researchers have discovered that human stem cells can reverse a multiple sclerosis-type condition in mice. Soon to be published in the journal Stem Cell Reports, this work could potentially lead to new treatments for multiple sclerosis (MS).

When this team first transplanted the stem cells into severely disabled MS mice, they were quite sure that the immune systems of the mice would attack these transplanted stem cells, which were from humans, would attack and reject them. However, the experiment had surprising results.

“My postdoctoral fellow Dr. Lu Chen came to me and said, ‘The mice are walking.’ I didn’t believe her,” said co-senior author, Tom Lane, PhD., who is presently a professor of pathology at the University of Utah, who began this study at University of California, Irvine.

Within next 10 to 14 days, the mice regained their lost motor skills, and six months later, they still show no signs of slowing down.

“This result opens up a whole new area of research for us,” said co-senior author Jeanne Loring, PhD, a professor at The Scripps Research Institute in La Jolla, Calif.

A chronic disease, MS results from the body’s own immune system attacks the body’s central nervous system. In particular, the insulating layer that surrounds many nerve fibers – a fatty substance called myelin – is slowly destroyed and this exposes nerves and slows or interrupts the transmission of nerve impulses. The symptoms of MS may be mild or severe, and includes numbness in the limbs, difficulty walking, paralysis, loss of vision, fatigue and pain.

Researchers say the MS mice treated with human stem cells experienced a dramatic reversal of symptoms within days. Immune attacks were blunted and damaged myelin was repaired.

Chen, Loring and their colleagues were further surprised that not only did the mice not initially reject these implanted stem cells, but they never showed any signs of rejection, even after one week.

Now Lane and others are eager to test this therapy in human clinical trials.

“Rather than having to engraft stem cells into a patient, which can be challenging, we might be able to put those chemical signals into a drug that can be used to deliver the therapy much more easily,” said Lane. He continued: “I would love to see something that could promote repair and ease the burden that patients with MS have.”

Previous work with stem cells has shown some promise in the treatment of MS. For example, in 2013, the US Food and Drug Administration (FDA) approved a small clinical trial of genetically modified mesenchymal stem cells initially harvested from bone marrow of MS patients. These stem cells were injected into the cerebrospinal fluid that surrounds the spinal cords of MS patients. Previous small studies conducted between 2005 and 2007 of this therapy in humans found that implantation of these modified stem cells reduced brain inflammation and repaired damaged layers of myelin. This small study only treated and tested seven patients.

There is no known cure for MS and drugs to treat it have limited effectiveness. An estimated 400,000 Americans have the disease and more than 2 million worldwide.

Mesenchymal Stem Cells Engineered to Express Tissue Kallikrein Increase Recovery After a Heart Attack


Julie Chao is from the Department of Biochemistry and Molecular Biology, at the Medical University of South Carolina. Dr. Chao and her colleagues have published a paper in Circulation Journal about genetically modified mesenchymal stem cells and their ability to help heal a heart that has just experienced a heart attack.

Several laboratories have used mesenchymal stem cells (MSCs), particularly from bone marrow, to treat the hearts of laboratory animals that have recently experienced a heart attack. However, heart muscle after a heart attack is a very hostile place, and implanted MSCs tend to pack up and die soon after injection. Therefore, such injected cells do little good.

To fix this problem, researchers have tried preconditioning cells by growing them in a harsh environment or by genetically engineering them with genes that can increase their tolerance of harsh environments. Both procedures have worked rather well. In this paper, Chao and her group engineered bone marrow-derived MSCs to express the genes that encode “tissue kallikrein” (TK). TK circulates throughout our bloodstream but several different types of cells also secrete it. It is an enzyme that degrades the protein “kininogen” into small bits that have several benefits. Earlier studies from Chao’s own laboratory showed that genetically engineering TK into the heart improved heart function after a heart attack and increased the ability of MSCs to withstand harsh conditions (see Agata J, Chao L, Chao J. Hypertension 2002; 40: 653 – 659; Yin H, Chao L, Chao J. Journal of  Biol Chem 2005; 280: 8022 – 8030). Therefore, Chao reasoned that using MSCs engineered to express TK might also increase the ability of MSCs to survive in the post-heart attack heart and heal the damaged heart.

In this paper, Chao and others made adenoviruses that expressed the TK gene. Adenoviruses place genes inside cells, but they do not integrate those genes into the genome of the host cell. Therefore, they are safer to use than retroviruses. Chao and others used these TK-expressing adenoviruses to infect tissue and MSCs.

When TK-expressing MSCs were exposed to low-oxygen conditions, like what cells might experience in a post-heart attack heart, the TK-expressing cells were much heartier than their non-TK-expressing counterparts. When injected into rat hearts 20 minutes after a heart attack had been induced, the TK-expressing MSCs showed good survival and robust TK expression. Control hearts that had been injected with non-TK-expression MSCs or had not been given a heart attack showed no such elevation of TK expression.

There were also added bonuses to TK-expressing MSC injections. The amount of inflammation in the hearts was significantly less in the hearts injected with TK-expressing MSC injections compared to the controls. There were fewer immune cells in the heart 1 day after the heart attack and the genes normally expressed in a heart that is experiencing massive inflammation were expressed at lower levels relative to controls, if they were expressed at all.

Reduced inflammation by TK-MSC administration was determined by (C) ED-1 immunohistochemical staining, (D) monocyte/macrophage quantification, (E) neutrophil quantification, and gene expression of (F) TNF-α, (G) ICAM-1, and (H) MCP-1. ED-1-positive cells are indicated by arrows. Original magnification, ×200. Data are mean ± SEM (n=5–8). *P<0.05 vs. other MI groups; **P<0.05 vs. MI/Control group. MSC, mesenchymal stem cell.
Reduced inflammation by TK-MSC administration was determined by (C) ED-1 immunohistochemical staining, (D) monocyte/macrophage quantification, (E)
neutrophil quantification, and gene expression of (F) TNF-α, (G) ICAM-1, and (H) MCP-1. ED-1-positive cells are indicated by arrows.
Original magnification, ×200. Data are mean ± SEM (n=5–8). *P

Another major bonus to the injection of TK-expressing MSCs into the hearts of rats was that these cells protected the heart muscle cells from programmed cell death. To make sure that this was not some kind of weird artifact, Chao and her team placed the TK-expressing MSCs in culture with heart muscle cells and then exposed them to low-oxygen tension conditions. Sure enough, the heart muscle cells co-cultured with the TK-expressing MSCs survived better than those co-cultured with non-TK-expressing MSCs.

TK-MSCs protect against cardiac cell apoptosis at 1 day after myocardial infarction (MI) and in vitro. TK-MSC administration reduced apoptosis in the infarct area at 1 day after MI, as determined by (A) TUNEL staining, (B) quantification of apoptotic cells, and (C) caspase-3 activity. Original magnification, ×200. Data are mean ± SEM (n=5–8). *P<0.05 vs. other MI groups. Cultured cardiomyocytes treated with 0.5 ml of TK-MSC-conditioned medium exhibit higher tolerance to hypoxia-induced apoptosis, as evidenced by (D) Hoechst staining,
TK-MSCs protect against cardiac cell apoptosis at 1 day after myocardial infarction (MI) and in vitro. TK-MSC administration
reduced apoptosis in the infarct area at 1 day after MI, as determined by (A) TUNEL staining, (B) quantification of apoptotic
cells, and (C) caspase-3 activity. Original magnification, ×200. Data are mean ± SEM (n=5–8). *Pcardiomyocytes treated with 0.5 ml of TK-MSC-conditioned medium exhibit higher tolerance to hypoxia-induced apoptosis, as
evidenced by (D) Hoechst staining,

Finally, when the hearts of the rats were examined 2 weeks after the heart attack, it was clear that the enlargement of the heart muscle (so-called “remodeling”) occurred in animals that had received non-TK-expressing MSCs or had received no MSCs at all, but did not occur in the hearts of rats that had received injections of TK-expressing MSCs. The heart scar was also significantly smaller in the hearts of rats that had received injections of TK-expressing MSCs, and had a greater concentration of new blood vessels. Apparently, the TK-expressing MSCs induced the growth of new blood vessels by recruiting EPCs to the heart to form new blood vessels.

In conclusion, the authors write that “MSCs genetically-modified with human TK are a potential therapeutic for ischemic heart diseases.”

Getting FDA approval for genetically engineered stem cells will not be easy, but TK engineering seems much safer than some of the other modifications that have been used. Also the vascular and cardiac benefits of this gene seem clear in this rodent model. Pre-clinical trials with larger animals whose cardiac physiology is more similar to humans is definitely warranted and should be done before any talk of human clinical trials ensues.