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TRANSLATIONAL AND CLINICAL RESEARCH

Neural Induction with Neurogenin1 Increases the Therapeutic Effects of Mesenchymal Stem Cells in the Ischemic Brain

^aDepartments of Anatomy,
^dMolecular Science Technology, and
^hNeurosurgery,
^bCenter for Cell Death Regulating Biodrug,
^cBK21, Division of Cell Transformation and Restoration, and
ⁱBrain Disease Research Center, Ajou University School of Medicine, Suwon, Korea;
^eDepartment of Medical Engineering, Graduate School of East-West Medicine, Kyunghee University, Suwon, Korea;
^fDepartment of Physiology, School of Medicine, Dankook University, Cheonan, Korea;
^gDepartment of Physiology, Chonnam National University Medical School, Gwangju, Korea;
^jDepartment of Anatomy, School of Medicine, Kyunghee University, Seoul, Korea;
^kDepartment of Anatomy, Yonsei University College of Medicine, Seoul, Korea

Key Words. Mesenchymal stem cells • Neurogenin1 • Transdifferentiation • Stroke • Transplantation

Correspondence: Correspondence: Haeyoung Suh-Kim, Ph.D., Department of Anatomy, Ajou University School of Medicine, San 5, Woncheon-dong, Yeongtong-gu, Suwon 443-721, South Korea. Telephone: 82-31-219-5033; Fax: 82-31-219-5039; e-mail: hysuh{at}ajou.ac.kr

Received on February 6, 2008; accepted for publication on June 30, 2008.

First published online in STEM CELLS EXPRESS  July 10, 2008.

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.

Disclosure of potential conflicts of interest is found at the end of this article.

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