Mash1 and neurogenin 2 enhance survival and differentiation of neural precursor cells after transplantation to rat brains via distinct modes of action.
Neural precursor cells (NPCs) are regarded as a promising source of donor cells in transplantation-based therapies for neurodegenerative disorders. However, poor survival and limited neuronal differentiation of the transplanted NPCs remain critical limitations for developing therapeutic strategies. In this study, we investigated the effects of the proneural basic helix-loop-helix (bHLH) transcription factors Mash1 and Neurogenin 2 (Ngn2) in neuronal differentiation and survival of NPCs. Induction of Mash1 or Ngn2 expression strikingly enhanced neuronal differentiation of cultured NPCs in vitro. Ngn2-transduced NPCs underwent a rapid cell cycle arrest, which often accompanies differentiation. In contrast, cells continuously expanded upon Mash1 expression during NPC differentiation. Notably, sonic hedgehog (SHH) was upregulated by Mash1 and mediated the proliferative and survival effects of Mash1 on NPCs. Upon transplantation into adult rat brains, Mash1-expressing NPCs yielded large grafts enriched with neurons compared to control LacZ-transduced NPCs. Interestingly, enhancements in neuronal yield, as well as in donor cell survival, were also achieved by transplanting Ngn2-transduced NPCs. We show that a differentiation stage- and cell density-dependent survival effect of Ngn2 involves neurotrophin3 (NT3)/TrkC-mediated signaling. Together, these findings suggest potential benefits of bHLH gene manipulation to develop successful transplantation strategies for brain disorders.
Yi
Sang-Hoon
SH
Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea.
Jo
A-Young
AY
Park
Chang-Hwan
CH
Koh
Hyun-Chul
HC
Park
Rae-Hee
RH
Suh-Kim
Haeyoung
H
Shin
Incheol
I
Lee
Yong-Sung
YS
Kim
Jaesang
J
Lee
Sang-Hun
SH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000637:transplantation*; D053823:Hedgehog Proteins / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000637:transplantation*; D020933:Neurotrophin 3 / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014161:Transduction, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; C499318:Ascl1 protein, rat; C534807:Neurog2 protein, rat