Ren-Ke Li

Research Synopsis

Ren-Ke Li’s research focuses on translational research to apply new insights discovered through basic science research to clinical applications for heart regeneration and repair after myocardial infarction.

Research areas are:

1. Cell transplantation into damaged tissue to regenerate myocardium and restore heart function.
2. Tissue engineering to create a muscle graft using stem cells and biomaterials for repair of cardiac defects.

My research focuses on the development of novel therapies for repairing and regenerating the injured myocardium and improving cardiac function after a myocardial infarction (MI). Cardiomyocyte loss after an MI initiates a cascade of events which frequently results in progressive heart failure despite the best medical, interventional and surgical interventions. Novel therapies are needed to treat these patients and prevent progressive deterioration of cardiac function.

Cell transplantation from bench to bedside

Since 1993 I have focused on cellular therapy to prevent progressive heart failure.

My initial studies described the transplantation of cardiac muscle cells into a myocardial scar which limited ventricular dilatation, stimulated angiogenesis and improved heart function.

In 1996, I demonstrated for the first time that transplanted cardiomyocytes can improve heart function. Since then, I have performed many studies in small and large animal models to evaluate a variety of cardiac cell transplantation approaches.

My preclinical studies demonstrate the safety and efficacy of cell transplantation to restore heart function. In collaboration with cardiac surgeons, we translated this new treatment to the clinic.

Over the past 20 years, I have published more than 200 peer-reviewed papers on cell therapy, which has been translated from bench to bedside.

The following is a summary of my most significant contributions that demonstrate my expertise and highlights the network of experts in my program:

1. Cell transplantation to restore heart function after injury: I transplanted cardiomyocytes, smooth muscle cells, heart cells and bone marrow (BM) cells into myocardial scar tissue and demonstrated that the implanted cells replace the scar with muscle tissue, augment cardiac function and prevent progressive heart failure.
2. Identification of the mechanisms responsible for the beneficial effects of cell therapy: Muscle formation: The implanted muscle cells formed muscle-like tissue in the fibrotic scar tissue which prevented ventricular dilation and restored heart function. Angiogenesis: Implantation of stem cells (SCs) into the damaged tissue produced less muscle, but stimulated a more extensive network of new capillaries and arterioles. I discovered and established that the benefits achieved were the result of the secretion of paracrine factors by the transplanted cells. Matrix modulation: I found that cells implanted into scar tissue decreased matrix metalloproteinase (MMP) activity by increasing tissue levels of tissue inhibitor of MMPs. I discovered and confirmed that the rebalancing of protease and protease inhibitor activities prevent myocardial matrix degradation and heart failure.
3. Evaluation of the safety and efficacy of cell therapy for clinical applications: To establish the potential of cell therapy for clinical application, we performed cell transplantation in a pig model of MI. Cardiac function was evaluated using clinically-relevant technology (echocardiography and SPECT MIBI). We demonstrated that cell therapy was safe and effective to prevent cardiac dysfunction. 
4. Identification of aging as a major limitation for the clinical results of cell therapy: The results of the clinical trials did not produce the significant beneficial effects that we found in our preclinical studies. These incongruent effects could be a result of multiple factors. However, we found that the quantity and quality of SCs in aged individuals with heart disease was much lower than those in younger patients, which could be a major contributor to the reduced efficacy of cell therapy in aged patients.
5. Rejuvenation, a new concept for stem cell therapy for aged patients: We demonstrated that BM SC dysfunction diminished cardiac repair after MI. We created BM chimeras by rejuvenating aged mice with young BM SCs. These rejuvenated mice had a greater cardiac repair capacity compared to non-rejuvenated mice. These data suggest a new direction for cell therapy: rejuvenation of cells and the host to enhance the efficacy of cell therapy in aged patients.

Development of a platform for non-invasive, repetitive, targeted and double-targeted gene delivery for cardiac regeneration and cell therapy. We have created an antibody-conjugated, cationic microbubble to enhance targeted gene delivery.

Creation of cardiac tissue for repair of congenital heart defects

Congenital heart disease affects ~1% of newborns, many of which require surgical intervention with the insertion of a patch.

Most biomaterial patches becomes stiff and scarred and do not grow with the children.

Tissue-engineered grafts have the potential to reduce mortality and improve the quality of life of these patients.

We have created cytokine-enriched biomaterials to enhance cell survival and tissue formation by immobilizing multiple cytokines onto biomaterials.