Transplantation of Human Umbilical Cord Blood-Derived Cellular Fraction Improves Left Ventricular Function and Remodeling After Myocardial Ischemia/Reperfusion

Lin Zhao; Guangming Cheng; Kashyap Choksi; Anweshan Samanta; Magdy Girgis; Rupal Soder; Robert J Vincent; Michael Wulser; Matt De Ruyter; Patrick McEnulty; Jeryl Hauptman; Yanjuan Yang; Carl P Weiner; Buddhadeb Dawn

doi:10.1161/CIRCRESAHA.119.315216

Transplantation of Human Umbilical Cord Blood-Derived Cellular Fraction Improves Left Ventricular Function and Remodeling After Myocardial Ischemia/Reperfusion

Circ Res. 2019 Sep 27;125(8):759-772. doi: 10.1161/CIRCRESAHA.119.315216. Epub 2019 Aug 29.

Authors

Affiliations

¹ From the Department of Internal Medicine, University of Nevada, Las Vegas School of Medicine (L.Z., G.C., M.G., J.H., Y.Y., B.D.).
² Cardiology Consultants of South Georgia, Thomasville (K.C.).
³ Department of Internal Medicine (A.S.), University of Missouri-Kansas City.
⁴ Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City (R.S., R.J.V., M.W., C.P.W.).
⁵ Department of Orthopedic Surgery (M.D.R.), University of Missouri-Kansas City.
⁶ Department of Radiology, University of Kansas School of Medicine-Wichita (P.M.).

PMID: 31462157
DOI: 10.1161/CIRCRESAHA.119.315216

Abstract

Rationale: Human umbilical cord blood (hUCB) contains diverse populations of stem/progenitor cells. Whether hUCB-derived nonhematopoietic cells would induce cardiac repair remains unknown. Objective: To examine whether intramyocardial transplantation of hUCB-derived CD45^-Lin^- nonhematopoietic cellular fraction after a reperfused myocardial infarction in nonimmunosuppressed rats would improve cardiac function and ameliorate ventricular remodeling. Methods and Results: Nonhematopoietic CD45^-Lin^- cells were isolated from hUCB. Flow cytometry and quantitative polymerase chain reaction were used to characterize this subpopulation. Age-matched male Fischer 344 rats underwent a 30-minute coronary occlusion followed by reperfusion and 48 hours later received intramyocardial injection of vehicle or hUCB CD45^-Lin^- cells. After 35 days, compared with vehicle-treated rats, CD45^-Lin^- cell-treated rats exhibited improved left ventricular function, blunted left ventricular hypertrophy, greater preservation of viable myocardium in the infarct zone, and superior left ventricular remodeling. Mechanistically, hUCB CD45^-Lin^- cell injection favorably modulated molecular pathways regulating myocardial fibrosis, cardiomyocyte apoptosis, angiogenesis, and inflammation in postinfarct ventricular myocardium. Rare persistent transplanted human cells could be detected at both 4 and 35 days after myocardial infarction. Conclusions: Transplantation of hUCB-derived CD45^-Lin^- nonhematopoietic cellular subfraction after a reperfused myocardial infarction in nonimmunosuppressed rats ameliorates left ventricular dysfunction and improves remodeling via favorable paracrine modulation of molecular pathways. These findings with human cells in a clinically relevant model of myocardial ischemia/reperfusion in immunocompetent animals may have significant translational implications.Visual Overview: An online visual overview is available for this article.

Keywords: angiogenesis effect; cord blood stem cell transplantation; inflammation; myocardial infarction; ventricular remodeling.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Apoptosis
Cell Line
Humans
Leukocyte Common Antigens / genetics
Leukocyte Common Antigens / metabolism
Male
Mesenchymal Stem Cell Transplantation / methods*
Mesenchymal Stem Cells / cytology
Mesenchymal Stem Cells / metabolism
Myocardial Reperfusion Injury / therapy*
Myocytes, Cardiac / metabolism
Neovascularization, Physiologic
Rats
Rats, Inbred F344
Umbilical Cord / cytology
Ventricular Function, Left*
Ventricular Remodeling*

Substances

Leukocyte Common Antigens

Grants and funding

R01 HL-117730/HL/NHLBI NIH HHS/United States