Stem Cell Homing Factor Used to Treat Heart Patients


In a clinical trial that is probably one of the first of its kind, researchers from the laboratory of Marc Penn at the Summa Cardiovascular Institute in Akron, Ohio, activated the stem cells of heart failure patients by means of gene therapy.

Penn and his colleagues delivered a gene that encodes stromal-cell derived factor-1 or SDF-1. SDF-1 is a member of the chemokine family of signaling proteins, and chemokines are proteins that direct cells to get up and move somewhere. Thus, for stem cells, SDF-1 acts as a kind of “homing” signal.

Stromal-cell derived factor
Stromal-cell derived factor

In this unique study, Penn and his collaborators introduced SDF-1 into the heart in order to summon stem cells to the site of injury and enhance the body’s stem cell-based repair process. In a typical stem cell-based study, researchers extract and expand the number of cells, then deliver them back to the subject, but in this study, no stem cells were extracted. Instead they were summoned to the site of injury by SDF-1.

Marc Penn, professor of medicine at Northeast Ohio Medical University in Rootstown, Ohio and the director of research at Summa Cardiovascular Institute said of his clinical trial: “We believe stem cells are always trying to repair tissue, but they don’t do it well — not because we lack stem cells but, rather, the signals that regulate our stem cells are impaired.”

Previous research by Penn and colleagues has shown SDF-1 activates and recruits the body’s stem cells to sites of injury and this increases healing. Under normal conditions, SDF-1 is made after an injury but its effects are short-lived. For example, SDF-1 is naturally expressed after a heart attack but this augmented expression of SDF-1 only lasts only a week.

In the study, researchers attempted to re-establish and extend the time that SDF-1 could stimulate patients’ stem cells. The trial enrolled 17 NYHA Class III heart failure patients, with left ventricular ejection fractions less than 40% and an average time from heart attack of 7.3 years. Three escalating JVS-100 doses were evaluated: 5 mg (cohort 1), 15 mg (cohort 2) and 30 mg (cohort 3). The average age of the participants was 66 years old.

Researchers injected one of three doses of the SDF-1 gene (5mg, 15mg or 30mg) into the hearts of these patients, and monitored them for up to a year. Four months after treatment, they found:
1. Patients improved their average distance by 40 meters during a six-minute walking test.
2. Patients reported improved quality of life.
3. The heart’s pumping ability improved, particularly for those receiving the two highest doses of SDF-1 compared to the lowest dose.
4. No apparent side effects occurred with treatment.
According to Penn, “We found 50 percent of patients receiving the two highest doses still had positive effects one year after treatment with their heart failure classification improving by at least one level,” Penn said. “They still had evidence of damage, but they functioned better and were feeling better.”

Penn’s study suggests that our stem cells have the potential to induce healing without having to be taken out of the body. Penn said, “Our study also shows gene therapy has the potential to help people heal their own hearts.”

At the start of the study, participants didn’t have significant reversible heart damage, but lacked blood flow in the areas bordering their damaged heart tissue. The study’s results — consistent with other animal and laboratory studies of SDF-1 — suggest that SDF-1 gene injections can increase blood flow around an area of damaged tissue, which has been deemed irreversible by other testing.

In further research, Penn and his team are comparing results from heart failure patients receiving SDF-1 with patients who are not receiving SDF-1. If the trial goes well, the therapy could be widely available to heart failure patients within four to five years, Penn said.

Bringing the Dysfunctional Bone Marrow of Diabetics Back to Life


One of the most insidious consequences of diabetes mellitus is its nocuous effects on the ability of the circulatory system to repair itself. The small vessels within our organ undergoes constant remodeling and repair in response to the wears and tears of life. Diabetes seriously decreases the ability of the circulatory system to execute this repair.

This day-to-day circulatory repair relies upon a group of bone marrow stem cells known as “bone marrow-derived early outgrowth cells or EOCs, and EOCs from patients with diabetes mellitus are impaired in their ability to repair the circulatory system (See Fadini GP, Miorin M, Facco M et al. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol 2005;45:1449–1457).

Is there are way to reverse this destructive trend? There is a protein known as SIR1, which stands for Silent Information Regulator 1. This gene product regulates aging and the formation of blood vessels, and might very well play a role in the diabetes-induced decrease in blood vessels repair and EOC impairment.

To answer this question, the laboratory of Richard E. Gilbert from the University of Toronto, Toronto, Ontario, Canada, used drugs to increase SIR1 activity in EOCs from diabetic rodents to determine if such treatments abrogated the diabetes-induced decrease in EOC function.

Gilbert’s lab isolated EOCs from normal and diabetic mice and subjected them to a variety of tests. They determined how many blood vessel-inducing molecules were made by these cells, and the EOCs from diabetic mice produced much less of such molecules and had reduced levels of SIR1.  EOCs from diabetic mice also performed poorly in blood vessel-making assays in culture dishes.

Would kicking up the levels of SIR1 in EOCs from diabetic mice improve the function of their EOCs? By using a drug to increase SIR1 activity in EOCs, GIlbert and others were able to show that increased SIR1 activity in EOCs from diabetic mice restored their production of blood-vessel-inducing molecules, and also improved their ability to make blood vessels in culture.

This extraordinary publication shows that the diminished abilities of bone marrow from diabetic or aged individuals is not irreversible. Perhaps research such as this can spur the discovery of drugs that reserve the decline of SIR1 activity in diabetics and aged patients to beef up their circulatory self-repair mechanisms.

See Darren A. Yuen, et al., “Angiogenic Dysfunction in Bone Marrow-Derived Early Outgrowth Cells from Diabetic Animals Is Attenuated by SIRT1 Activation,” Stem Cells Translational Medicine 2012;1:921–926.