Thymus Mesenchymal Stem Cells for Right Ventricle Failure in HLHS

Doctor's Name: 
Ming-Sing Si, MD
Hospital/Institution: 
Mott Children’s Hospital, Ann Arbor, MI

Funded through the Graeme McDaniel Memorial Fund

Hypoplastic left heart syndrome (HLHS) is the most common functional single ventricle congenital heart defect. HLHS is characterized by an undersized left ventricle which is usually the main workhorse of the heart that is responsible for pumping blood to the entire body. Current standard treatment requires a series of three heart surgeries over the first 2 years of life to achieve palliation. HLHS patients depend on the right ventricle (RV) to function as the main pump of the heart, and therefore must perform a greater workload due to the increased pressures it must generate. The RV in this setting is prone to early failure, which decreases the life expectancy of patients with HLHS. The failure prone nature of the RV in HLHS is also seen in other congenital heart defects where the RV is required to perform increased pressure related work.

The RV muscle in HLHS patients loses their microscopic blood vessels as a result of the increased pressure load and over time this contributes to heart failure. Our laboratory has recently discovered that pressure overload in the RV of rats is associated with the decrease in the potent blood vessel promoting factor, SLIT3.

The long term objective of our research is to develop a stem cell therapy to prevent and treat RV failure in HLHS patients. Our laboratory was the first to discover the therapeutic properties of especially potent stem cells isolated from discarded thymus tissue obtained from HLHS patients undergoing the first stage palliation surgery, or Norwood procedure. These stem cells are readily isolated using existing technology used in current stem cell trials for adult heart disease today. We have since established the excellent ability of these thymus stem cells to promote blood vessel formation which is superior to those of other types of stem cells. This exceptional therapeutic characteristic is mediated by an increased production of SLIT3. We believe that these thymus derived stem cells are the ideal candidate to target RV failure in HLHS.

The first goal of this research is to evaluate these neonatal human thymus stem cells in a RV pressure overload animal model. We will determine the ability of these stem cells to promote survival in this animal model as well as determine the effects of these stem cells on RV function and density of microscopic blood vessels. The second goal of this research is to identify an fraction of especially potent thymus stem cells. We will accomplish this by studying gene networks to obtain clues as to which may be suitable markers to identify these especially potent stem cells.

Successfully accomplishing this research will be an important and major step towards obtaining a regenerative medicine based therapy for patients with HLHS. The results of this research will provide the necessary rationale for continued large animal testing followed by clinical evaluation in HLHS patients

Award Date 1: 
2015
Award Amount 1: 
$100,000
Award Date 2: 
2016
Award Amount 2: 
$100,000