Open AccessBone Marrow Endothelial Progenitor Cells Are the Cellular Mediators of Pulmonary Hypertension in the Murine Monocrotaline Injury Model
Author(s) -
Aliotta Jason M.,
Pereira Mandy,
Wen Sicheng,
Dooner Mark S.,
Del Tatto Michael,
Papa Elaine,
Cheng Yan,
Goldberg Laura,
Ventetuolo Corey E.,
Liang Olin,
Klinger James R.,
Quesenberry Peter J.
Publication year - 2017
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.1002/sctm.16-0386
Subject(s) - progenitor cell , bone marrow , pulmonary hypertension , in vivo , mesenchymal stem cell , medicine , ventricle , transplantation , lung , pulmonary artery , stem cell , chemistry , andrology , pathology , biology , microbiology and biotechnology
The role of bone marrow (BM) cells in modulating pulmonary hypertensive responses is not well understood. Determine if BM‐derived endothelial progenitor cells (EPCs) induce pulmonary hypertension (PH) and if this is attenuated by mesenchymal stem cell (MSC)‐derived extracellular vesicles (EVs). Three BM populations were studied: (a) BM from vehicle and monocrotaline (MCT)‐treated mice (PH induction), (b) BM from vehicle‐, MCT‐treated mice that received MSC‐EV infusion after vehicle, MCT treatment (PH reversal, in vivo), (c) BM from vehicle‐, MCT‐treated mice cultured with MSC‐EVs (PH reversal, in vitro). BM was separated into EPCs (sca‐1+/c‐kit+/VEGFR2+) and non‐EPCs (sca‐1‐/c‐kit‐/VEGFR2‐) and transplanted into healthy mice. Right ventricular (RV) hypertrophy was assessed by RV‐to‐left ventricle+septum (RV/LV+S) ratio and pulmonary vascular remodeling by blood vessel wall thickness‐to‐diameter (WT/D) ratio. EPCs but not non‐EPCs from mice with MCT‐induced PH (MCT‐PH) increased RV/LV+S, WT/D ratios in healthy mice (PH induction). EPCs from MCT‐PH mice treated with MSC‐EVs did not increase RV/LV+S, WT/D ratios in healthy mice (PH reversal, in vivo). Similarly, EPCs from MCT‐PH mice treated with MSC‐EVs pre‐transplantation did not increase RV/LV+S, WT/D ratios in healthy mice (PH reversal, in vitro). MSC‐EV infusion reversed increases in BM‐EPCs and increased lung tissue expression of EPC genes and their receptors/ligands in MCT‐PH mice. These findings suggest that the pulmonary hypertensive effects of BM are mediated by EPCs and those MSC‐EVs attenuate these effects. These findings provide new insights into the pathogenesis of PH and offer a potential target for development of novel PH therapies. S tem C ells T ranslational M edicine 2017;6:1595–1606