Neural induction with neurogenin1 increases the therapeutic effects of mesenchymal stem cells in the ischemic brain.
Mesenchymal stem cells (MSCs) have been shown to ameliorate a variety of neurological dysfunctions. This effect is believed to be mediated by their paracrine functions, since these cells rarely differentiate into neuronal cells. It is of clinical interest whether neural induction of MSCs is beneficial for the replacement therapy of neurological diseases. Here we report that expression of Neurogenin1 (Ngn1), a proneural gene that directs neuronal differentiation of progenitor cells during development, is sufficient to convert the mesodermal cell fate of MSCs into a neuronal one. Ngn1-expressing MSCs expressed neuron-specific proteins, including NeuroD and voltage-gated Ca2+ and Na+ channels that were absent in parental MSCs. Most importantly, transplantation of Ngn1-expressing MSCs in the animal stroke model dramatically improved motor functions compared with the parental MSCs. MSCs with Ngn1 populated the ischemic brain, where they expressed mature neuronal markers, including microtubule associated protein 2, neurofilament 200, and vesicular glutamate transporter 2, and functionally connected to host neurons. MSCs with and without Ngn1 were indistinguishable in reducing the numbers of Iba1+, ED1+ inflammatory cells, and terminal deoxynucleotidyl transferase dUTP nick-end labeling(+) apoptotic cells and in increasing the numbers of proliferating Ki67+ cells. The data indicate that in addition to the intrinsic paracrine functions of MSCs, motor dysfunctions were remarkably improved by MSCs able to transdifferentiate into neuronal cells. Thus, neural induction of MSCs is advantageous for the treatment of neurological dysfunctions.
Kim
Sung-Soo
SS
Department of Anatomy, Ajou University School of Medicine, San 5, Woncheon-dong, Yeongtong-gu, Suwon 443-721, South Korea.
Yoo
Seung-Wan
SW
Park
Tae-Seok
TS
Ahn
Seung-Cheol
SC
Jeong
Han-Seong
HS
Kim
Ji-Won
JW
Chang
Da-Young
DY
Cho
Kyung-Gi
KG
Kim
Seung U
SU
Huh
Youngbuhm
Y
Lee
Jong-Eun
JE
Lee
Soo-Yeol
SY
Lee
Young-Don
YD
Suh-Kim
Haeyoung
H
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C486336:Neurog1 protein, mouse