In addition to preclinical results, a case report of an infant with hypoplastic left heart syndrome indicated that intracoronary infusion of autologous BM-derived progenitor cells was associated with improved RV function and RVEF.15 A study of 9 children with severe terminal heart failure demonstrated improvement in LVEF and New York Heart Association classification after intracoronary infusion of autologous BM-derived MNC.16
In a phase 1 clinical trial, children with hypoplastic left heart syndrome showed improvements in RVEF and clinical status after intracoronary administration of autologous cardiac progenitor cells compared with patients who underwent palliation surgery without stem cell therapy.17
“Given that administration of stem cells targeting the LV has already been shown to yield clinical benefits, there is ample reason to similarly use stem cells to treat the RV,” the authors concluded. “We hypothesize that reinforcing the RV rather than trying to treat the lungs in PAH could be an alternative approach to increasing patient survival.”
To further explore the topic, Pulmonology Advisor spoke with Reza Ardehali, MD, PhD, associate professor of medicine in the University of California, Los Angeles, Division of Cardiology and a member of the university’s Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research.
Pulmonology Advisor: What does the evidence to date suggest about the potential role of stem cell therapy as a treatment for RV failure in PAH?
Dr Ardehali:The role of stem cells in RV failure and PAH is poorly understood. This is largely [because of] our lack of knowledge regarding differences between RV and LV cardiomyocytes. [Although] the majority of the LV cardiomyocytes are derived from the first heart field progenitors during early embryonic development, the RV cardiomyocytes have their origin in the second heart field.
Traditionally, it has been suggested that at the cellular levels, LV and RV cardiomyocytes are similar, but they are exposed to different pressures and stresses during embryonic and postnatal development that shape their functional characteristics. To realize the potential of stem cell therapy to treat RV failure, it is necessary to generate chamber-specific cardiomyocytes. Therefore, more research is needed to determine the subtle but important cellular differences between RV and LV cardiomyocytes.
Pulmonology Advisor: What are the proposed mechanisms by which this may be an effective treatment strategy?
Dr Ardehali: Transplantation of cardiomyocytes derived from pluripotent stem cells could theoretically replace the damaged myocardium. However, current attempts have shown poor engraftment of the transplanted cells. Furthermore, our inability to generate chamber-specific cardiomyocytes is also a problem with transplantation studies, in which any contamination with nonmyocytes or nodal cells may induce arrhythmia after cell transplantation.
Pulmonology Advisor: What should be the focus of future research in this area?
Dr Ardehali:Future research should focus on developing strategies to produce chamber-specific cardiomyocytes from pluripotent stem cells. In addition, improving the survival of the transplanted cells and ensuring their structural and functional integration into the host myocardium is a priority.
- Ghio S, Gavazzi A, Campana C, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol. 2001;37(1):183-188.
- Loisel F, Provost B, Haddad F, et al. Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy? Pulm Circ. 2018; 8(2):2045893218755979
- Cantero Peral S, Burkhart HM, Oommen S, et al. Safety and feasibility for pediatric cardiac regeneration using epicardial delivery of autologous umbilical cord blood-derived mononuclear cells established in a porcine model system. Stem Cells Transl Med. 2015;4(2):195-206.
- Yerebakan C, Sandica E, Prietz S, et al. Autologous umbilical cord blood mononuclear cell transplantation preserves right ventricular function in a novel model of chronic right ventricular volume overload. Cell Transplant. 2009;18(8):855-868.
- Oommen S, Yamada S, Cantero Peral S, et al. Human umbilical cord blood-derived mononuclear cells improve murine ventricular function upon intramyocardial delivery in right ventricular chronic pressure overload. Stem Cell Res Ther. 2015;6:50.
- Umar S, de Visser YP, Steendijk P, et al. Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2009;297(5):H1606-H1616.
- Luan Y, Zhang X, Kong F, et al. Mesenchymal stem cell prevention of vascular remodeling in high flow-induced pulmonary hypertension through a paracrine mechanism. Int Immunopharmacol. 2012;14(4):432-437.
- Yip H-K, Chang L-T, Sun C-K, et al. Autologous transplantation of bone marrow-derived endothelial progenitor cells attenuates monocrotaline-induced pulmonary arterial hypertension in rats. Crit Care Med. 2008;36(3):873-880.
- Ormiston ML, Deng Y, Stewart DJ, et al. Innate immunity in the therapeutic actions of endothelial progenitor cells in pulmonary hypertension. Am J Respir Cell Mol Biol. 2010;43(5):546-554.
- Yen C-H, Tsai T-H, Leu S, et al. Sildenafil improves long-term effect of endothelial progenitor cell-based treatment for monocrotaline-induced rat pulmonary arterial hypertension. Cytotherapy. 2013;15(2):209-223.
- Nagata H, Ii M, Kohbayashi E, et al. Cardiac adipose-derived stem cells exhibit high differentiation potential to cardiovascular cells in C57BL/6 mice. Stem Cells Transl Med. 2016;5(2):141-151.
- Luo L, Lin T, Zheng S, et al. Adipose-derived stem cells attenuate pulmonary arterial hypertension and ameliorate pulmonary arterial remodeling in monocrotaline-induced pulmonary hypertensive rats. Clin Exp Hypertens. 2015;37(3):241-248.
- Somanna NK, Wörner PM, Murthy SN, et al. Intratracheal administration of cyclooxygenase-1-transduced adipose tissue-derived stem cells ameliorates monocrotaline-induced pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol. 2014;307(8):H1187-H1195.
- Huang W-C, Ke M-W, Cheng C-C, et al. Therapeutic benefits of induced pluripotent stem cells in monocrotaline-induced pulmonary arterial hypertension. PLoS One. 2016;11(2):e0142476.
- Rupp S, Zeiher AM, Dimmeler S, et al. A regenerative strategy for heart failure in hypoplastic left heart syndrome: intracoronary administration of autologous bone marrow-derived progenitor cells. J Heart Lung Transplant. 2010;29(5):574-577.
- Rupp S, Jux C, Bönig H, et al. Intracoronary bone marrow cell application for terminal heart failure in children. Cardiol Young. 2012;22(5):558-563.
- Ishigami S, Ohtsuki S, Tarui S, et al. Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial. Circ Res. 2015;116(4):653-664.