Stem and Progenitor Cell Therapy for Pulmonary Arterial Hypertension: Effects on the Right Ventricle (2013 Grover Conference Series)

Abstract

In experimental animals and in patients with pulmonary arterial hypertension (PAH), a wide spectrum of structural and functional conditions is known that may be responsible for the switch of a state of "compensated" right ventricular (RV) hypertrophy to a state of RV failure. In recent years, therapy with differentiated cells, endothelial progenitor cells, and mesenchymal stem cells has been shown to cause partial or complete reversal of pathological characteristics of PAH. The therapeutic effects of stem or progenitor cell therapy are considered to be (1) paracrine effects from stem or progenitor cells that had engrafted in the myocardium (or elsewhere), by compounds that have anti-inflammatory, antiapoptotic, and proangiogenic actions and (2) unloading effects on the right ventricle due to stem or progenitor cellinduced decrease in pulmonary vascular resistance and decrease in pulmonary artery pressure. Pulmonary arterial hypertension (PAH) is associated with right ventricular (RV) hypertrophy (RVH) or RV failure (RVF), considered to be the result of RV pressure overload. Pharmacotherapy, gene therapy, stem and progenitor cell therapy, and combinations of these treatment modalities have been shown to treat PAH, by lowering pulmonary artery pressure, lowering RV weight, and relieving RVF, thereby improving exercise capacity and life span. 1 Here we review the evidence that, in animals with PAH, stem and progenitor cell therapy leads to lower RV weight and relief of RVF by mechanisms that can be ascribed to (1) lowering of RV afterload and (2) direct effects of the stem and progenitor cells on RV myocardial structure and function. RVH DUE TO PAH-INDUCED RV OVERLOAD: PATHOLOGICAL OR PHYSIOLOGICAL HYPERTROPHY?Originally, left ventricular (LV) hypertrophy (LVH) secondary to pressure overload was considered to be "compensatory," 2 but several studies have clearly demonstrated that LVH is a risk factor and has unfavorable prognostic implications. [3][4][5] On the other hand, the athlete's heart often implies the presence of LVH, but this LVH is considered an adaptation to volume overload that occurs during longlasting rowing, running, and cycling. 6 To date, the healthy aspects of exercise training have been documented firmly and are not restricted to healthy individuals, such as athletes, but even to patients with heart failure. 7,8 The two main forms of myocardial hypertrophy are often termed "pathological" hypertrophy, as occurs secondary to pressure overload, and "physiological" hypertrophy, as occurs in the athlete's heart. Pathological and physiological hypertrophy have been characterized in detail, 9-13 and the most significant differences are found in the membrane receptor and signaling pathways that convey the message to the nucleus, where hypertrophy is effectuated with or without changes in gene expression. In pathological hypertrophy, Ca 2+ -dependent calcineurin activation and calcineurin-induced dephosphorylation of

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition

“…Precedent literature has described cytotherapy with mesenchymal stem cells to partially reverse the phenotype of pulmonary arterial hypertension produced by monocrotaline. 39 This would be especially important in the socalled type 4 CTEPH, caused by widespread distal emboli, rendering it less amenable to surgical treatment or pulmonary balloon angioplasty of proximal obstruction. 40,41 The lack of a markedly widened A-a O 2 tension difference gradient in animals with PE alone argues against a large physiological shunt from bronchiolar dilation or collateral vessel formation, which has been suggested to occur in CTEPH.…”

Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy?

“… 27 MSC have the ability to migrate to injured lung tissue where they secrete angiogenic (VEGF), anti-apoptotic (Bcl-2), and anti-inflammatory factors (IFN, IL-10, VEGF, and HGF). 28 In normal or hypoxic conditions, they secrete factors that stimulate endothelial cell chemotaxis and adhesion. 29 The immune tolerance of MSC is an important feature that makes them very suitable for clinical use.…”

Drug abuse and HIV-related pulmonary hypertension

“…These therapies if successful may also be helpful in managing HIV-PAH as mechanisms such as high PDGF expression [34], BMPR2/SMAD/TGF-β modulation [28, 31, 132], ECM remodeling and inflammation [32] have been reported in HIV-PAH including in response to drugs of abuse. Furthermore, recent studies have elucidated the protective role of endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) [169–172] as well as extracellular vesicles /exosomes [173, 174] derived from MSCs in lung inflammation, vascular remodeling and PAH [170, 172, 175, 176]. Modulation of small non-coding miRNAs during the development of PAH including HIV-PAH further creates an opportunity to implement miR-based therapies [151, 167, 168, 174, 177].…”