Regulation of boundary cap neural crest stem cell differentiation after transplantation.
Success of cell replacement therapies for neurological disorders will depend largely on the optimization of strategies to enhance viability and control the developmental fate of stem cells after transplantation. Once transplanted, stem/progenitor cells display a tendency to maintain an undifferentiated phenotype or differentiate into inappropriate cell types. Gain and loss of function experiments have revealed key transcription factors which drive differentiation of immature stem/progenitor cells toward more mature stages and eventually to full differentiation. An attractive course of action to promote survival and direct the differentiation of transplanted stem cells to a specific cell type would therefore be to force expression of regulatory differentiation molecules in already transplanted stem cells, using inducible gene expression systems which can be controlled from the outside. Here, we explore this hypothesis by employing a tetracycline gene regulating system (Tet-On) to drive the differentiation of boundary cap neural crest stem cells (bNCSCs) toward a sensory neuron fate after transplantation. We induced the expression of the key transcription factor Runx1 in Sox10-expressing bNCSCs. Forced expression of Runx1 strongly increased transplant survival in the enriched neurotrophic environment of the dorsal root ganglion cavity, and was sufficient to guide differentiation of bNCSCs toward a nonpeptidergic nociceptive sensory neuron phenotype both in vitro and in vivo after transplantation. These findings suggest that exogenous activation of transcription factors expression after transplantation in stem/progenitor cell grafts can be a constructive approach to control their survival as well as their differentiation to the desired type of cell and that the Tet-system is a useful tool to achieve this.
Aldskogius
Hakan
H
Department of Neuroscience, Neuroanatomy, Uppsala University Biomedical Center, Uppsala, Sweden.
Berens
Christian
C
Kanaykina
Nadezda
N
Liakhovitskaia
Anna
A
Medvinsky
Alexander
A
Sandelin
Martin
M
Schreiner
Silke
S
Wegner
Michael
M
Hjerling-Leffler
Jens
J
Kozlova
Elena N
EN
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055757:SOXE Transcription Factors / Q000235:genetics / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse