Blood outgrowth endothelial cells overexpressing eNOS mitigate pulmonary hypertension in rats

a unique carrier cell enabling autologous cell-based gene therapy

Arif Somani, Sethu L. Nair, Liming Milbauer, Guangshuo Zhu, Suchitra Sajja, Anna Solovey, Yingjie Chen, Robert P Hebbel

Research output: Contribution to journalArticle

Abstract

We have investigated a unique cell type, blood outgrowth endothelial cells (BOEC), as a cell-based gene therapy approach to pulmonary hypertension. BOEC are bona fide endothelial cells, obtained from peripheral blood, that can be expanded to vast numbers, and are amenable to both cryopreservation and genetic modification. We established primary cultures of rat BOEC and genetically altered them to over-express human eNOS plus green fluorescent protein (rBOEC/eNOS) or to express GFP only (rBOEC/GFP). We gave monocrotaline to rats on day 0, and they developed severe pulmonary hypertension. As a Prevention model, we infused saline or rBOEC/GFP or rBOEC/eNOS on day 3, and then examined endpoints on day 24. The rBOEC/eNOS recipients developed elevated NOx (serum and lung) and less severe: elevation of right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary arteriolar muscularization and loss of alveolar density. As an Intervention model, we waited until day 21 to give the test infusions, and we examined endpoints on day 35. The rBOEC/eNOS recipients again developed elevated NOx and manifested the same improvements. Indeed, rBOEC/eNOS infusion not only prevented worsening of RVSP but also partially reversed established arteriolar muscularization. These data suggest that BOEC may be useful as a carrier cell for genetic strategies targeting pulmonary hypertension. Their properties render BOEC amenable to preclinical and scale-up studies, available for autologous therapies, and tolerant of modification and storage for potential future use in patients at risk for PAH, eg, as defined by genetics or medical condition.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalTranslational Research
Volume210
DOIs
StatePublished - Aug 1 2019

Fingerprint

Gene therapy
Endothelial cells
Pulmonary Hypertension
Genetic Therapy
Rats
Blood
Endothelial Cells
Ventricular Pressure
Monocrotaline
Blood Pressure
Right Ventricular Hypertrophy
Lung
Cryopreservation
Medical Genetics
Heterozygote
Polycyclic aromatic hydrocarbons
Green Fluorescent Proteins
Cell culture
Blood Cells
Serum

PubMed: MeSH publication types

  • Journal Article

Cite this

@article{8d91c65075d94fb6b14e2fb0bb0e25fa,
title = "Blood outgrowth endothelial cells overexpressing eNOS mitigate pulmonary hypertension in rats: a unique carrier cell enabling autologous cell-based gene therapy",
abstract = "We have investigated a unique cell type, blood outgrowth endothelial cells (BOEC), as a cell-based gene therapy approach to pulmonary hypertension. BOEC are bona fide endothelial cells, obtained from peripheral blood, that can be expanded to vast numbers, and are amenable to both cryopreservation and genetic modification. We established primary cultures of rat BOEC and genetically altered them to over-express human eNOS plus green fluorescent protein (rBOEC/eNOS) or to express GFP only (rBOEC/GFP). We gave monocrotaline to rats on day 0, and they developed severe pulmonary hypertension. As a Prevention model, we infused saline or rBOEC/GFP or rBOEC/eNOS on day 3, and then examined endpoints on day 24. The rBOEC/eNOS recipients developed elevated NOx (serum and lung) and less severe: elevation of right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary arteriolar muscularization and loss of alveolar density. As an Intervention model, we waited until day 21 to give the test infusions, and we examined endpoints on day 35. The rBOEC/eNOS recipients again developed elevated NOx and manifested the same improvements. Indeed, rBOEC/eNOS infusion not only prevented worsening of RVSP but also partially reversed established arteriolar muscularization. These data suggest that BOEC may be useful as a carrier cell for genetic strategies targeting pulmonary hypertension. Their properties render BOEC amenable to preclinical and scale-up studies, available for autologous therapies, and tolerant of modification and storage for potential future use in patients at risk for PAH, eg, as defined by genetics or medical condition.",
author = "Arif Somani and Nair, {Sethu L.} and Liming Milbauer and Guangshuo Zhu and Suchitra Sajja and Anna Solovey and Yingjie Chen and Hebbel, {Robert P}",
year = "2019",
month = "8",
day = "1",
doi = "10.1016/j.trsl.2019.04.005",
language = "English (US)",
volume = "210",
pages = "1--7",
journal = "Translational research : the journal of laboratory and clinical medicine",
issn = "1931-5244",
publisher = "Mosby Inc.",

}

TY - JOUR

T1 - Blood outgrowth endothelial cells overexpressing eNOS mitigate pulmonary hypertension in rats

T2 - a unique carrier cell enabling autologous cell-based gene therapy

AU - Somani, Arif

AU - Nair, Sethu L.

AU - Milbauer, Liming

AU - Zhu, Guangshuo

AU - Sajja, Suchitra

AU - Solovey, Anna

AU - Chen, Yingjie

AU - Hebbel, Robert P

PY - 2019/8/1

Y1 - 2019/8/1

N2 - We have investigated a unique cell type, blood outgrowth endothelial cells (BOEC), as a cell-based gene therapy approach to pulmonary hypertension. BOEC are bona fide endothelial cells, obtained from peripheral blood, that can be expanded to vast numbers, and are amenable to both cryopreservation and genetic modification. We established primary cultures of rat BOEC and genetically altered them to over-express human eNOS plus green fluorescent protein (rBOEC/eNOS) or to express GFP only (rBOEC/GFP). We gave monocrotaline to rats on day 0, and they developed severe pulmonary hypertension. As a Prevention model, we infused saline or rBOEC/GFP or rBOEC/eNOS on day 3, and then examined endpoints on day 24. The rBOEC/eNOS recipients developed elevated NOx (serum and lung) and less severe: elevation of right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary arteriolar muscularization and loss of alveolar density. As an Intervention model, we waited until day 21 to give the test infusions, and we examined endpoints on day 35. The rBOEC/eNOS recipients again developed elevated NOx and manifested the same improvements. Indeed, rBOEC/eNOS infusion not only prevented worsening of RVSP but also partially reversed established arteriolar muscularization. These data suggest that BOEC may be useful as a carrier cell for genetic strategies targeting pulmonary hypertension. Their properties render BOEC amenable to preclinical and scale-up studies, available for autologous therapies, and tolerant of modification and storage for potential future use in patients at risk for PAH, eg, as defined by genetics or medical condition.

AB - We have investigated a unique cell type, blood outgrowth endothelial cells (BOEC), as a cell-based gene therapy approach to pulmonary hypertension. BOEC are bona fide endothelial cells, obtained from peripheral blood, that can be expanded to vast numbers, and are amenable to both cryopreservation and genetic modification. We established primary cultures of rat BOEC and genetically altered them to over-express human eNOS plus green fluorescent protein (rBOEC/eNOS) or to express GFP only (rBOEC/GFP). We gave monocrotaline to rats on day 0, and they developed severe pulmonary hypertension. As a Prevention model, we infused saline or rBOEC/GFP or rBOEC/eNOS on day 3, and then examined endpoints on day 24. The rBOEC/eNOS recipients developed elevated NOx (serum and lung) and less severe: elevation of right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary arteriolar muscularization and loss of alveolar density. As an Intervention model, we waited until day 21 to give the test infusions, and we examined endpoints on day 35. The rBOEC/eNOS recipients again developed elevated NOx and manifested the same improvements. Indeed, rBOEC/eNOS infusion not only prevented worsening of RVSP but also partially reversed established arteriolar muscularization. These data suggest that BOEC may be useful as a carrier cell for genetic strategies targeting pulmonary hypertension. Their properties render BOEC amenable to preclinical and scale-up studies, available for autologous therapies, and tolerant of modification and storage for potential future use in patients at risk for PAH, eg, as defined by genetics or medical condition.

UR - http://www.scopus.com/inward/record.url?scp=85065804832&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065804832&partnerID=8YFLogxK

U2 - 10.1016/j.trsl.2019.04.005

DO - 10.1016/j.trsl.2019.04.005

M3 - Article

VL - 210

SP - 1

EP - 7

JO - Translational research : the journal of laboratory and clinical medicine

JF - Translational research : the journal of laboratory and clinical medicine

SN - 1931-5244

ER -