Stem Cell Therapy for RV Failure in PAH: Overview and Clinician Interview

Right ventricular (RV) function is well-established as 1 of the main prognostic risk factors in patients with pulmonary arterial hypertension (PAH). Pathological changes in the pulmonary vascular bed in PAH lead to increased pulmonary arterial pressure, which subjects the right ventricle to an increased afterload and can ultimately result in RV failure and death.¹

As the disease progresses, the “RV remodeling shifts from an adaptive to a maladaptive state that includes RV dilatation, decreased contractility, and VA uncoupling,” according to a recent review published in Pulmonary Circulation.² The authors proposed that “targeting angiogenesis in the RV myocardium appears to be a promising approach to improve its function…[and the] use of stem cells as therapeutic agents could, hence, represent a new treatment option for PAH.”

Although there is a dearth of studies focusing on stem cell therapies directed at the RV in PAH, various cell types have been explored as potential treatment to improve pulmonary circulation in PAH, and may ultimately prove relevant to therapies targeting the RV. “Given the nature of the pathophysiology of PAH induced by RV failure, the stem cells should ideally be readily available, immuno-compatible, proangiogenic, and anti-inflammatory,” wrote the authors.

Several of these cell types, and examples of related findings from PAH research using animal models, are highlighted here.

Mononuclear Stem Cells

• Studies using mononuclear stem cells (MNCs) isolated from umbilical cord blood (UCB-MNC) have demonstrated
• The feasibility and safety of RV epicardial injection of autologous UCB-MNC³;
• Improved diastolic and systolic RV function and increased capillary density after epicardial UCB-MNC injection⁴; and
• Improved RV structure and function, increased angiogenesis biomarkers, and reduced RV fibrosis.⁵

Mesenchymal Stromal Cells

Mesenchymal stromal cells, derived from various tissues and administered via injection or intratracheally, have been shown to

• Improve right ventricular hypertrophy (RVH), right ventricular ejection fraction (RVEF), and right ventricular systolic pressure (RVSP)⁶; and
• Reduce ratio of RV to LV + septal weight.⁷

Endothelial Progenitor Cells

Endothelial progenitor cells, which can be isolated from peripheral blood, UCB, or bone marrow (BM), have been reported to

• Reduce RVSP and RVH⁸;
• Prevent increases in RVSP and RVH⁹; and
• More effectively limit PAH progression when combined with PAH drug therapies.¹⁰

Adipose-Derived Stem Cells

Adipose-derived stem cells have been found to

• Promote angiogenesis in models of ischemic wounds “by undergoing differentiation into endothelial cells which are incorporated into the walls of newly formed vessels and by secretion of paracrine factors,” as described in the new review²;
• Have potential to differentiate into cardiovascular lineage cells¹¹;
• Reduce RVH and improve pulmonary vascular remodeling¹²; and
• Attenuate monocrotaline-induced PAH and RVH.¹³

Induced Pluripotent Stem Cells

Induced pluripotent stem (IPS) cells can generate cardiomyocytes, endothelial cells, or smooth muscle cells. In studies of IPS cells,

• Transplantation of iPS-derived cardiomyocytes was found to “integrate into host myocardium and generate organized sarcomeric structures, while endothelial and smooth muscle cells contribute to the host vasculature,” as reported in the review. “This trilineage cell transplantation can significantly improve left ventricular function and angiogenesis, while reducing infarct size and cell apoptosis.”
• IPS cell transplantation in MCT-induced PAH rats led to significant reductions in RVSP, RVH, and lung tissue inflammation.¹⁴