The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors.
OBJECTIVE
Risk of tumorigenesis is a major obstacle to human embryonic and induced pluripotent stem cell therapy. Likely linked to the stage of differentiation of the cells at the time of implantation, formation of teratoma/tumors can also be influenced by factors released by the host tissue. We have analyzed the relative effects of the stage of differentiation and the postischemic environment on the formation of adverse structures by transplanted human embryonic stem cell-derived neural progenitors.


METHODS
Four differentiation stages were identified on the basis of quantitative polymerase chain reaction expression of pluripotency, proliferation, and differentiation markers. Neural progenitors were transplanted at these 4 stages into rats with no, small, or large middle cerebral artery occlusion lesions. The fate of each transplant was compared with their pretransplantation status 1 to 4 months posttransplantation.


RESULTS
The influence of the postischemic environment was limited to graft survival and occurrence of nonneuroectodermal structures after transplantation of very immature neural progenitors. Both effects were lost with differentiation. We identified a particular stage of differentiation characterized in vitro by a rebound of proliferative activity that produced highly proliferative grafts susceptible to threaten surrounding host tissues.


CONCLUSIONS
The effects of the ischemic environment on the formation of teratoma by transplanted human embryonic stem cell-derived neural progenitors are limited to early differentiation stages that will likely not be used for stem cell therapy. In contrast, hyperproliferation observed at later stages of differentiation corresponds to an intrinsic activity that should be monitored to avoid tumorigenesis.
Seminatore
Christine
C
INSERM UMR861, Université Evry-Val d'Essonne, Evry, France.
Polentes
Jerome
J
Ellman
Ditte
D
Kozubenko
Nataliya
N
Itier
Valerie
V
Tine
Samir
S
Tritschler
Laurent
L
Brenot
Marion
M
Guidou
Emmanuelle
E
Blondeau
Johanna
J
Lhuillier
Mickael
M
Bugi
Aurore
A
Aubry
Laetitia
L
Jendelova
Pavla
P
Sykova
Eva
E
Perrier
Anselme L
AL
Finsen
Bente
B
Onteniente
Brigitte
B
D000367:Age Factors; D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology / Q000601:surgery*; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000637:transplantation*; D004777:Environment; D006801:Humans; D008297:Male; D009474:Neurons / Q000166:cytology / Q000637:transplantation*; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation / Q000009:adverse effects; D013724:Teratoma / Q000209:etiology / Q000473:pathology*