Stem cell-based regeneration

Electron microscopy image of wild-type control stem cell Electron microscopy image of stem cell. Wild-type control (WT).
Electron microscopy image of stem cell with gene knockout Electron microscopy image of stem cell. Gene knockout, calreticulin gene (crt).

The next frontier of cardiac tissue repair

Coronary artery disease (CAD) is a major cause of morbidity and mortality. Potent pharmacotherapy, revascularization strategies, cardiac rehabilitation and aggressive management of cardiovascular risk factors have reduced the recurrence of cardiac events.

"A major barrier in the treatment of cardiovascular disease is the inability of the myocardium for self-renewal," explains Carmen M. Terzic, M.D., Ph.D., chair of the Department of Physical Medicine and Rehabilitation at Mayo Clinic in Rochester, Minn. Testing the hypothesis that replacing injured tissue with healthy tissue could rescue a failing phenotype, Dr. Terzic and other Mayo Clinic researchers have focused on developing a stem cell-based strategy to repair diseased cardiac tissue.

Stem cell-based regeneration offers the next frontier of medical therapy through delivery of unlimited pools of progenitor cells to achieve structural and functional restoration. Ultimately, augmentation of natural healing or rejuvenation exemplifies on-demand tissue self-renewal without the need for invasive intervention.

Internationally, the use of stem cell therapy in patients is currently limited, but preliminary data suggest that this approach may yield modest improvements in cardiac function and structure when treating acute myocardial infarction or chronic heart failure.

Dr. Terzic has engaged in a variety of research efforts to direct stem cells toward cardiogenesis, to assess the role of nuclear transport during stem cell differentiation and optimize their properties for cardiac commitment. These efforts include developing techniques by which direct injection of stem cells in a murine model of cardiac infarction engrafts and repopulates the diseased heart with cardiac cells derived from the stem cells. The ultimate goal is to establish cardiovascular regenerative medicine as a new therapeutic modality for heart disease.

Dr. Terzic's team has also gathered preliminary data indicating significant variation in the cardiogenic potential of stem cells among patients. Based on these findings, the Mayo Clinic Cardiovascular Health Clinic, Department of Physical Medicine and Rehabilitation, and Cardiovascular Research Laboratory are joining forces to introduce stem cell science into the innovative practice of prophylactic medicine to advance personalized wellness.

This project involves exploring the individual variation in the number of circulating progenitor cells and their potential to differentiate into cardiac tissue and examining the individual correlation between the cardiogenic potential of circulating progenitor cells and cardiovascular disease risk factors, risk indicators, and clinical outcome. These findings have the potential to help researchers identify:

  • Novel biomarkers of cardiovascular disease risk, severity and prognosis
  • An individual's self-repair capacity
  • The restorative-regenerative effectiveness of secondary prevention therapies

"We are hopeful that a personalized algorithm based on progenitor cell potential would help us identify a high-risk target population with ischemic heart disease that could benefit from cell-based therapy designed to replace progenitor cell deficiencies," says Dr. Terzic.

"Because we've found that stem cell therapy is not beneficial for all patients, we're examining whether risk factors such as smoking and high glucose may mediate the effectiveness of stem cell therapy for a given individual or a group of individuals with similar risk profiles," explains Dr. Terzic. Correlating the response to stem cell treatment with presence of specific risk factors for cardiovascular disease may ultimately allow physicians to better predict who can best benefit from stem cell therapy.

Inducible progenitor stem cells

Inducible progenitor cells are another type of recently described stem cells that have been used by Dr. Terzic. What makes these cells incredible is the fact that inducible progenitor stem cells are obtained by expressing a set of four genes into a mature cell, such as a fibroblast. The fibroblasts expressing these genes regress to a state of undifferentiated stem cells that are similar to the embryonic stem cells.

"This approach is of importance because it could allow us to obtain pluripotent embryonic cells without using embryos, eliminating ethical issues," says Dr. Terzic. "It also prevents the rejection of these cells, as we can obtain the pluripotent cells from fibroblasts derived from the skin of the same individual who is in need of the stem cells."

Translating cardiac cell repair therapy into clinical practice is an intriguing and challenging objective. Dr. Terzic and her colleagues are hopeful that this new knowledge will eventually guide clinicians in choosing the most effective reparative phenotype for each patient and help them optimize the delivery, dosing and timing of these new forms of intervention. This fascinating field is making rapid progress that certainly merits close attention.

Points to remember

  • Mayo Clinic researchers seek to promote myocardial self-renewal with stem cells by gaining a better understanding of the role of nuclear transport during stem cell differentiation and optimizing their properties for cardiac commitment.
  • Preliminary data indicate significant variation in the cardiogenic potential of stem cells among patients.
  • Correlating the response to stem cell treatment with presence of specific risk factors for cardiovascular disease may ultimately allow physicians to better predict who can best benefit from stem cell therapy.