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.

Differentiation Potential of Human Chorion-Derived Mesenchymal Stem Cells into Motor Neuron-Like Cells in Two- and Three-Dimensional Culture Systems

“…It also induces the expression of a motor neuron marker, called Islet-1 in postmitotic precursors [35]. Treatment of MSCs with RA and Shh induces the upregulation of Islet-1 and ChAT in genetically engineered human mesenchymal stem cells which induced to express Hb-9 transcription factor [36].…”

Cell Transplantation for Spinal Cord Injury: A Systematic Review

“…According to his method, human MSCs were exposed to histone deacetylases inhibitor (Trichostatin), DNA methyltransferase inhibitor (RG-108), biologically active form of cAMP, and phosphodiesterases inhibitor (Rolipram) in a medium consisting of NeuroCult/N2 supplemented with bFGF for two weeks before transplantation. Park et al, reported a new method to generate functional motor neuron (MN)-like cells from genetically engineered human MSCs [141]. They transduced motor neuron-associated transcription factor gene expression into the human MSC, then they treated the genetically engineered MSCs expressing Olig2 and Hb9 with optimal MN induction medium.…”

Stem Cells for Neuro-regeneration: State of the Art

“…(36) Altered iron homeostasis also has been described in Huntington disease (HD), invitro studies results supported this data. (37) Amylotropic lateral sclerosis (ALS) ALS IS a devastating neurological disorder which has a vascular component. Invitro studies proved that molecules like vascular endothelial growth factor (VEGF) have a therapeutic, diagnostic and prognostic potential in ALS.…”