title: Directed induction of functional motor neuron-like cells from genetically engineered human mesenchymal stem cells.
abstract: Cell replacement using stem cells is a promising therapeutic approach to treat degenerative motor neuron (MN) disorders, such as amyotrophic lateral sclerosis and spinal cord injury. Human bone marrow-derived mesenchymal stem cells (hMSCs) are a desirable cell source for autologous cell replacement therapy to treat nervous system injury due to their plasticity, low immunogenicity, and a lower risk of tumor formation than embryonic stem cells. However, hMSCs are inefficient with regards to differentiating into MN-like cells. To solve this limitation, we genetically engineered hMSCs to express MN-associated transcription factors, Olig2 and Hb9, and then treat the hMSCs expressing Olig2 and Hb9 with optimal MN induction medium (MNIM). This method of induction led to higher expression (>30% of total cells) of MN markers. Electrophysiological data revealed that the induced hMSCs had the excitable properties of neurons and were able to form functional connections with muscle fibers in vitro. Furthermore, when the induced hMSCs were transplanted into an injured organotypic rat spinal cord slice culture, an ex vivo model of spinal cord injury, they exhibited characteristics of MNs. The data strongly suggest that induced Olig2/Hb9-expressing hMSCs were clearly reprogrammed and directed toward a MN-like lineage. We propose that methods to induce Olig2 and Hb9, followed by further induction with MNIM have therapeutic potential for autologous cell replacement therapy to treat degenerative MN disorders.
authors.affiliation: Department of Oral Anatomy, Dental Research Institute and School of Dentistry, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hwan-Woo
authors.initials: HW
authors.lastname: Park
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Cho
authors.forename: Chul-Kyu
authors.initials: CK
authors.lastname: Park
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Jung
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.forename: Shin-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Seog Bae
authors.initials: SB
authors.lastname: Oh
authors.forename: Young-Seok
authors.initials: YS
authors.lastname: Park
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Chang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000235:genetics / Q000502:physiology; D005818:Genetic Engineering / Q000379:methods*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D018482:Muscle, Skeletal / Q000294:innervation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics* / Q000502:physiology; D000076104:Oligodendrocyte Transcription Factor 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000502:physiology; D013119:Spinal Cord Injuries / Q000628:therapy
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C405708:OLIG2 protein, human; C522729:Olig2 protein, rat