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MINI-FOCUS: CELL-BASED THERAPY

Myogenic Endothelial Cells Purified From Human Skeletal Muscle Improve Cardiac Function After Transplantation Into Infarcted Myocardium

Masaho Okada, MD^_*,, Thomas R. Payne, PhD^_*,,||, Bo Zheng, MD^_*,, Hideki Oshima, MD, PhD^_*,, Nobuo Momoi, MD, Kimimasa Tobita, MD^,||, Bradley B. Keller, MD, Julie A. Phillippi, PhD^_*,¶, Bruno Péault, PhD^_*, and Johnny Huard, PhD^_*,,,||,_*

^_* Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
^|| Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
^¶ Carnegie Mellon University, Pittsburgh, Pennsylvania

Manuscript received April 21, 2008; revised manuscript received July 16, 2008, accepted July 21, 2008.

^_* Reprint requests and correspondence: Dr. Johnny Huard, Stem Cell Research Center, 4100 Rangos Research Center, 3460 Fifth Avenue, Pittsburgh, Pennsylvania 15213 (Email: jhuard{at}pitt.edu).

Objectives: The aim of this study was to evaluate the therapeutic potential of human skeletal muscle-derived myoendothelial cells for myocardial infarct repair.

Background: We have recently identified and purified a novel population of myoendothelial cells from human skeletal muscle. These cells coexpress myogenic and endothelial cell markers and produce robust muscle regeneration when injected into cardiotoxin-injured skeletal muscle.

Methods: Myoendothelial cells were isolated from biopsies of human skeletal muscle using a fluorescence-activated cell sorter along with populations of regular myoblasts and endothelial cells. Acute myocardial infarction was induced in male immune-deficient mice, and cells were directly injected into the ischemic area. Cardiac function was assessed by echocardiography, and donor cell engraftment, angiogenesis, scar tissue, endogenous cardiomyocyte proliferation, and apoptosis were all evaluated by immunohistochemistry.

Results: A greater improvement in left ventricular function was observed after intramyocardial injection of myoendothelial cells when compared with that seen in hearts injected with myoblast or endothelial cells. Transplanted myoendothelial cells generated robust engraftments within the infarcted myocardium, and also stimulated angiogenesis, attenuation of scar tissue, and proliferation and survival of endogenous cardiomyocytes more effectively than transplanted myoblasts or endothelial cells.

Conclusions: Our findings suggest that myoendothelial cells represent a novel cell population from human skeletal muscle that may hold promise for cardiac repair.

Key Words: human stem cells • myocardial infarction • paracrine factors • skeletal muscle • VEGF

Abbreviations and Acronyms   cTnI = cardiac-specific isoforms of troponin I   cTnT = cardiac-specific isoforms of troponin T   DMEM = Dulbecco's modified Eagle's medium   EDA = end-diastolic area   ELISA = enzyme-linked immunoadsorbent assay   FAC = fractional area change   FACS = fluorescence-activated cell sorting   FBS = fetal bovine serum   fskMyHC = fast skeletal myosin heavy chain   LV = left ventricle/ventricular   MDSC = muscle-derived stem cell   MI = myocardial infarction   nLacZ = nuclear LacZ   PBS = phosphate-buffered saline   PCNA = proliferating cell nuclear antigen   qPCR = quantitative real-time polymerase chain reaction   SkM = skeletal myoblast   TUNEL = terminal dUPT nick end-labeling   VEGF = vascular endothelial growth factor

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