Sox2 transduction enhances cardiovascular repair capacity of blood-derived mesoangioblasts.
BACKGROUND
Complementation of pluripotency genes may improve adult stem cell functions.


OBJECTIVE
Here we show that clonally expandable, telomerase expressing progenitor cells can be isolated from peripheral blood of children. The surface marker profile of the clonally expanded cells is distinct from hematopoietic or mesenchymal stromal cells, and resembles that of embryonic multipotent mesoangioblasts. Cell numbers and proliferative capacity correlated with donor age. Isolated circulating mesoangioblasts (cMABs) express the pluripotency markers Klf4, c-Myc, as well as low levels of Oct3/4, but lack Sox2. Therefore, we tested whether overexpression of Sox2 enhances pluripotency and facilitates differentiation of cMABs in cardiovascular lineages.


RESULTS
Lentiviral transduction of Sox2 (Sox-MABs) enhanced the capacity of cMABs to differentiate into endothelial cells and cardiomyocytes in vitro. Furthermore, the number of smooth muscle actin positive cells was higher in Sox-MABs. In addition, pluripotency of Sox-MABs was shown by demonstrating the generation of endodermal and ectodermal progenies. To test whether Sox-MABs may exhibit improved therapeutic potential, we injected Sox-MABs into nude mice after acute myocardial infarction. Four weeks after cell therapy with Sox-MABs, cardiac function was significantly improved compared to mice treated with control cMABs. Furthermore, cell therapy with Sox-MABs resulted in increased number of differentiated cardiomyocytes, endothelial cells, and smooth muscle cells in vivo.


CONCLUSIONS
The complementation of Sox2 in Oct3/4-, Klf4-, and c-Myc-expressing cMABs enhanced the differentiation into all 3 cardiovascular lineages and improved the functional recovery after acute myocardial infarction.
Koyanagi
Masamichi
M
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Iwasaki
Masayoshi
M
Rupp
Stefan
S
Tedesco
Francesco Saverio
FS
Yoon
Chang-Hwan
CH
Boeckel
Jes-Niels
JN
Trauth
Janina
J
Schütz
Corina
C
Ohtani
Kisho
K
Goetz
Rebekka
R
Iekushi
Kazuma
K
Bushoven
Philipp
P
Momma
Stefan
S
Mummery
Christine
C
Passier
Robert
R
Henschler
Reinhard
R
Akintuerk
Hakan
H
Schranz
Dietmar
D
Urbich
Carmen
C
Galvez
Beatriz G
BG
Cossu
Giulio
G
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000637:transplantation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors / Q000235:genetics; D006614:Hindlimb; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000637:transplantation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000637:transplantation; D018919:Neovascularization, Physiologic; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D036102:Peripheral Blood Stem Cell Transplantation; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000637:transplantation*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012038:Regeneration; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014161:Transduction, Genetic; D055815:Young Adult
D015415:Biomarkers; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors